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Journal articles on the topic 'Mtb Infection'
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1
Dempsey, Laurie A. "CD153 combats Mtb infection." Nature Immunology 19, no. 11 (October 17, 2018): 1148. http://dx.doi.org/10.1038/s41590-018-0246-4.
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Rosas Mejia, Oscar, Erin S. Gloag, Jianying Li, Marisa Ruane-Foster, Tiffany A. Claeys, Daniela Farkas, Shu-Hua Wang, Laszlo Farkas, Gang Xin, and Richard T. Robinson. "Mice infected with Mycobacterium tuberculosis are resistant to acute disease caused by secondary infection with SARS-CoV-2." PLOS Pathogens 18, no. 3 (March 24, 2022): e1010093. http://dx.doi.org/10.1371/journal.ppat.1010093.
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Mycobacterium tuberculosis (Mtb) and SARS-CoV-2 (CoV2) are the leading causes of death due to infectious disease. Although Mtb and CoV2 both cause serious and sometimes fatal respiratory infections, the effect of Mtb infection and its associated immune response on secondary infection with CoV2 is unknown. To address this question we applied two mouse models of COVID19, using mice which were chronically infected with Mtb. In both model systems, Mtb-infected mice were resistant to the pathological consequences of secondary CoV2 infection, and CoV2 infection did not affect Mtb burdens. Single cell RNA sequencing of coinfected and monoinfected lungs demonstrated the resistance of Mtb-infected mice is associated with expansion of T and B cell subsets upon viral challenge. Collectively, these data demonstrate that Mtb infection conditions the lung environment in a manner that is not conducive to CoV2 survival.
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Olive, Andrew J., Clare M. Smith, Christina E. Baer, Jörn Coers, and Christopher M. Sassetti. "Mycobacterium tuberculosis Evasion of Guanylate Binding Protein-Mediated Host Defense in Mice Requires the ESX1 Secretion System." International Journal of Molecular Sciences 24, no. 3 (February 2, 2023): 2861. http://dx.doi.org/10.3390/ijms24032861.
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Cell-intrinsic immune mechanisms control intracellular pathogens that infect eukaryotes. The intracellular pathogen Mycobacterium tuberculosis (Mtb) evolved to withstand cell-autonomous immunity to cause persistent infections and disease. A potent inducer of cell-autonomous immunity is the lymphocyte-derived cytokine IFNγ. While the production of IFNγ by T cells is essential to protect against Mtb, it is not capable of fully eradicating Mtb infection. This suggests that Mtb evades a subset of IFNγ-mediated antimicrobial responses, yet what mechanisms Mtb resists remains unclear. The IFNγ-inducible Guanylate binding proteins (GBPs) are key host defense proteins able to control infections with intracellular pathogens. GBPs were previously shown to directly restrict Mycobacterium bovis BCG yet their role during Mtb infection has remained unknown. Here, we examine the importance of a cluster of five GBPs on mouse chromosome 3 in controlling Mycobacterial infection. While M. bovis BCG is directly restricted by GBPs, we find that the GBPs on chromosome 3 do not contribute to the control of Mtb replication or the associated host response to infection. The differential effects of GBPs during Mtb versus M. bovis BCG infection is at least partially explained by the absence of the ESX1 secretion system from M. bovis BCG, since Mtb mutants lacking the ESX1 secretion system become similarly susceptible to GBP-mediated immune defense. Therefore, this specific genetic interaction between the murine host and Mycobacteria reveals a novel function for the ESX1 virulence system in the evasion of GBP-mediated immunity.
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Wong, Eileen A., Carolyn Kraus, Keith A. Reimann, and JoAnne L. Flynn. "The role of IL-10 during early M. tuberculosis infection in a non-human primate model." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 123.5. http://dx.doi.org/10.4049/jimmunol.198.supp.123.5.
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Abstract Tuberculosis (TB), caused by M. tuberculosis (Mtb), continues to be a global health problem. Lung granulomas, organized structures of host immune cells to contain Mtb, are the pathologic hallmark of TB. T cell cytokines play a major role in containment of Mtb infection within these granulomas. While the importance of pro-inflammatory cytokines IFN-γ and TNF in controlling Mtb infections has been established, the effects of immunomodulatory cytokines, such as IL-10, in Mtb infections are less well understood. We used cynomolgus macaques, a non-human primate (NHP) model that recapitulates human TB to investigate the role of IL-10 early in Mtb infection. Preliminary ex vivo studies of excised lung granulomas from Mtb-infected NHPs suggested IL-10 may be downregulating IL-2 cytokine production in TB lung granulomas. To further examine the role of IL-10, a cross-reactive, rhesus recombinant anti-IL-10 antibody was used to neutralize IL-10 in vivo in NHPs prior to and during the course of Mtb infection. Peripheral cytokine responses in the presence of IL-10 neutralization were analyzed serially by flow cytometry of peripheral blood mononuclear cells. Disease progression was monitored by PET-CT scans, and local immune responses in the granulomas assessed at necropsy. Our data indicate transient differences in inflammation early in infection between anti-IL-10-treated and control monkeys. Surprisingly, there was less inflammation in granulomas from IL-10 neutralized animals at 3–4 weeks post-infection, compared to control animals. Overall, this unique dataset provides important insight into the contribution of IL-10 to the necessary immunological balance for controlled bacterial burden and disease pathology in Mtb infections.
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Kieswetter, Nathan S., Mumin Ozturk, Lerato Hlaka, Julius Ebua Chia, Ryan J. O. Nichol, Jasmine M. Cross, Leah M. C. McGee, et al. "Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to Mycobacterium tuberculosis infection." Journal of Antimicrobial Chemotherapy 77, no. 4 (January 25, 2022): 1061–71. http://dx.doi.org/10.1093/jac/dkac001.
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Abstract Background Previously, we evaluated the intracellular mycobactericidal activity of the minor groove binder, S-MGB-364 against the clinical Mycobacterium tuberculosis (Mtb) strain HN878 in macrophages. Objectives To assess the mycobactericidal activity of S-MGB-364 in Mtb-infected mice. Further, we investigated a plausible DNA binding mechanism of action of S-MGB-364. Methods The anti-TB and host immune effects of intranasal S-MGB-364 or S-MGB-364 encapsulated in non-ionic surfactant vesicles (NIV) were assessed in Mtb-infected mice by cfu enumeration, ELISA, histology, and flow cytometry. DNA binding was examined using native mass spectrometry and UV-vis thermal melt determination. S-MGB interference with DNA-centric biological events was assessed using a representative panel of Mtb and human topoisomerase I, and gyrase assays. Results S-MGB-364 bound strongly to DNA as a dimer, significantly increasing the stability of the DNA:S-MGB complex compared with DNA alone. Moreover, S-MGB-364 inhibited the relaxation of Mtb topoisomerase I but not the human form. In macrophages, S-MGB-364 or S-MGB-364-NIV did not cause DNA damage as shown by the low γ-H2AX expression. Importantly, in the lungs, the intranasal administration of S-MGB-364 or S-MGB-364-NIV formulation in Mtb-infected mice was non-toxic and resulted in a ∼1 log cfu reduction in mycobacterial burden, reduced the expression of proinflammatory cytokines/chemokines, altered immune cell recruitment, and importantly reduced recruitment of neutrophils. Conclusions Together, these data provide proof of concept for S-MGBs as novel anti-TB therapeutics in vivo.
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Wong, Kevin, James Nguyen, Lillie Blair, Marina Banjanin, Bunraj Grewal, Shane Bowman, Hailey Boyd, et al. "Pathogenesis of Human Immunodeficiency Virus-Mycobacterium tuberculosis Co-Infection." Journal of Clinical Medicine 9, no. 11 (November 6, 2020): 3575. http://dx.doi.org/10.3390/jcm9113575.
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Given that infection with Mycobacterium tuberculosis (Mtb) is the leading cause of death amongst individuals living with HIV, understanding the complex mechanisms by which Mtb exacerbates HIV infection may lead to improved treatment options or adjuvant therapies. While it is well-understood how HIV compromises the immune system and leaves the host vulnerable to opportunistic infections such as Mtb, less is known about the interplay of disease once active Mtb is established. This review explores how glutathione (GSH) depletion, T cell exhaustion, granuloma formation, and TNF-α upregulation, as a result of Mtb infection, leads to an increase in HIV disease severity. This review also examines the difficulties of treating coinfected patients and suggests further research on the clinical use of GSH supplementation.
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Bian, Yao, Shaobin Shang, Sharmila Shanmuganad, Sarah Siddiqui, and Chyung-Ru Wang. "Qa-1b has antigen presentation and immunoregulatory roles during aerogenic Mycobacterium tuberculosis infection (P3296)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 134.1. http://dx.doi.org/10.4049/jimmunol.190.supp.134.1.
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Abstract The mouse MHC Ib molecule Qa-1b plays roles in both antigen presentation and immune regulation in different disease models. Further, the human homologue of Qa-1b, HLA-E, can present Mycobacterium tuberculosis (Mtb) peptides to CD8+ T cells. In viral infections, Qa-1b suppresses NK and CD8+ T cell function by interacting with inhibitory CD94/NKG2A molecules. In addition, Qa-1b can activate CD8+ T regulatory cells, which suppress CD4+ T cell responses in EAE. However, the role of Qa-1b in Mycobacterium tuberculosis (Mtb) infection is unknown. In this study, we find Qa-1b expression is upregulated in a mouse model of low-dose, aerogenic infection with Mtb. We find that Qa-1b, like HLA-E, can bind a number of Mtb peptides; a subset of these peptides are recognized by CD8+ T cells and induce IFN-γ production during aerogenic Mtb infection. To determine the overall contribution of Qa-1b to Mtb infection, we infected Qa-1b-deficient and wild-type mice. Qa-1b-deficient mice had increased production of pro-inflammatory cytokines compared to wild-type, indicating Qa-1b plays a regulatory role in Mtb infection. Infected Qa-1b-deficient mice also show increased expression of CD94/NKG2A on CD8+ T cells, indicating a potential mechanism by which Qa-1b controls immune responses in Mtb infection. Our data suggest that during Mtb infection, Qa-1b is uniquely able to both activate immune responses through antigen presentation as well as suppress immune responses via regulatory mechanisms.
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He, Xianbao, Jared J. Eddy, Karen R. Jacobson, Andrew J. Henderson, and Luis M. Agosto. "Enhanced Human Immunodeficiency Virus-1 Replication in CD4+ T Cells Derived From Individuals With Latent Mycobacterium tuberculosis Infection." Journal of Infectious Diseases 222, no. 9 (May 16, 2020): 1550–60. http://dx.doi.org/10.1093/infdis/jiaa257.
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Abstract Background Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) coinfection increases mortality, accelerates progression to acquired immune deficiency syndrome, and exacerbates tuberculosis disease. However, the impact of pre-existing Mtb infection on subsequent HIV infection has not been fully explored. We hypothesized that Mtb infection creates an immunological environment that influences the course of HIV infection, and we investigated whether pre-existing Mtb infection impacts the susceptibility of CD4+ T cells to HIV-1 infection. Methods Plasma and blood CD4+ T cells isolated from HIV-negative individuals across the Mtb infection spectrum and non-Mtb-infected control individuals were analyzed for inflammation markers and T-cell phenotypes. CD4+ T cells were infected with HIV-1 in vitro and were monitored for viral replication. Results We observed differences in proinflammatory cytokines and the relative proportion of memory T-cell subsets depending on Mtb infection status. CD4+ T cells derived from individuals with latent Mtb infection supported more efficient HIV-1 transcription, release, and replication. Enhanced HIV-1 replication correlated with higher percentages of CD4+ TEM and TTD cells. Conclusions Pre-existing Mtb infection creates an immunological environment that reflects Mtb infection status and influences the susceptibility of CD4+ T cells to HIV-1 replication. These findings provide cellular and molecular insights into how pre-existing Mtb infection influences HIV-1 pathogenesis.
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Moriarty, Ryan V., Amy L. Ellis, and Shelby L. O’Connor. "Monkeying around with MAIT Cells: Studying the Role of MAIT Cells in SIV and Mtb Co-Infection." Viruses 13, no. 5 (May 8, 2021): 863. http://dx.doi.org/10.3390/v13050863.
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There were an estimated 10 million new cases of tuberculosis (TB) disease in 2019. While over 90% of individuals successfully control Mycobacterium tuberculosis (Mtb) infection, which causes TB disease, HIV co-infection often leads to active TB disease. Despite the co-endemic nature of HIV and TB, knowledge of the immune mechanisms contributing to the loss of control of Mtb replication during HIV infection is lacking. Mucosal-associated invariant T (MAIT) cells are innate-like T cells that target and destroy bacterially-infected cells and may contribute to the control of Mtb infection. Studies examining MAIT cells in human Mtb infection are commonly performed using peripheral blood samples. However, because Mtb infection occurs primarily in lung tissue and lung-associated lymph nodes, these studies may not be fully translatable to the tissues. Additionally, studies longitudinally examining MAIT cell dynamics during HIV/Mtb co-infection are rare, and lung and lymph node tissue samples from HIV+ patients are typically unavailable. Nonhuman primates (NHP) provide a model system to characterize MAIT cell activity during Mtb infection, both in Simian Immunodeficiency Virus (SIV)-infected and SIV-naïve animals. Using NHPs allows for a more comprehensive understanding of tissue-based MAIT cell dynamics during infection with both pathogens. NHP SIV and Mtb infection is similar to human HIV and Mtb infection, and MAIT cells are phenotypically similar in humans and NHPs. Here, we discuss current knowledge surrounding MAIT cells in SIV and Mtb infection, how SIV infection impairs MAIT cell function during Mtb co-infection, and knowledge gaps to address.
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Nusbaum, Rebecca, Matthew Huante, Putri Sutjita, Veronica Calderon, Sudhamathi Vijayakumar, Judith Aronson, Robert Hunter, et al. "HIV-1 promotes neutrophil infiltration and lung damage in humanized mice co-infected with Mycobacterium tuberculosis (HUM1P.266)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 52.15. http://dx.doi.org/10.4049/jimmunol.194.supp.52.15.
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Abstract Co-infection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (Mtb) promotes aggressive disease through mechanisms that are poorly understood. A recent study suggests an association between peripheral blood neutrophil count and Mtb load in the sputum of human subjects with HIV co-infection. We used our humanized BLT mouse (HuMouse) model of HIV/Mtb co-infection as an investigative tool to study the role of neutrophils in co-infection pathobiology. Humanized mice were infected intravenously with HIV-1 for 3 weeks and then co-infected intranasally with Mtb. Compared to HuMice with Mtb or HIV mono-infections, increased neutrophil numbers were observed in the lungs of co-infected animals, as determined by detection of myeloperoxidase using immunohistochemistry. Consistent with the role of neutrophils to promote immune-mediated pathology in TB disease, greater tissue necrosis and increased mycobacterial burden was observed in the lungs of co-infected animals. In support of these findings, an increased pulmonary production of cytokines and chemokines associated with neutrophil recruitment including IL-8, CXCL5, fractalkine, and IL-17 were also observed in co-infected animals. These studies identify mechanisms for immune-mediated pathology due to HIV/Mtb co-infection that can be targeted to restore immune balance in the lung and complement antimycobacterials.
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Harari, Alexandre, Virginie Rozot, Felicitas Bellutti Enders, Matthieu Perreau, Jesica Mazza Stalder, Laurent P. Nicod, Matthias Cavassini, et al. "Dominant TNF-α Mycobacterium Tuberculosis-specific CD4 T-cell responses discriminate between latent infection and active disease (99.10)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 99.10. http://dx.doi.org/10.4049/jimmunol.186.supp.99.10.
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Abstract Background: Diagnosis of Mtb infection requires several parameters. IFNg-release assays do not discriminate between active TB disease and latent Mtb infection. Methods: Mtb-specific T-cell responses were investigated in a test cohort of 283 subjects with known diagnosis of latent Mtb infection or active TB disease and subsequently in a validation cohort of 114 subjects with blinded clinical status. Mtb-specific T-cell responses were analyzed by polychromatic flow cytometry using ESAT-6 and CFP-10 peptide pools. Results: Mtb-specific IFNg ELISpot responses were not different between patients with active TB disease or latent Mtb infection. In contrast, the functional profile of Mtb-specific CD4 T-cell responses was significantly different between active TB disease and latent Mtb infection (ESAT-6 or CFP-10, all P<0.0001) in the test cohort. Overall, Mtb-specific CD4 T-cell responses from patients with latent Mtb infection were TNFa+IFNg+IL-2+, while single TNFa-producing Mtb-specific CD4 T-cell responses were dominant in patients with active TB disease. Using this parameter (i.e. % of single TNFa-producing cells) as a diagnostic tool in an independent cohort of 101 patients with blinded TB diagnosis, we obtained >90% concordance between the clinical and the cytokines profile in predicting active TB disease and latent Mtb infection Conclusions: Polychromatic flow cytometry is a novel and reliable laboratory tool for the timely diagnosis of acute TB disease.
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Dunlap, Micah, Nicole Howard, Shibali Das, Mushtaq Ahmed, Oliver Prince, Javier Rangel-Moreno, Bruce Rosa, Makedonka Mitreva, Gwendalyn J. Randolph, and Shabaana Khader. "C-C motif chemokine receptor 2 drives protective immunity by mediating alveolar macrophage localization in tuberculosis granulomas." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 43.21. http://dx.doi.org/10.4049/jimmunol.200.supp.43.21.
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Abstract C-C motif chemokine receptor 2 (CCR2) axis is a major chemokine axis that recruits myeloid cells including monocytes and macrophages. Thus far, CCR2−/− mice have not been found to be more susceptible to infection with Euro-American lineage 4 strains of Mycobacterium tuberculosis (Mtb). Here, using a prototype W-Beijing family lineage 2 clinical Mtb strain, HN878, we show that CCR2−/− mice exhibit increased susceptibility to tuberculosis (TB). Following exposure to Mtb HN878, alveolar macrophages (AMs) are amongst the earliest cells infected. Using a novel labeling technique, we show that AMs accumulate early in the airways following Mtb HN878 infection and express CCR2. During disease progression, CCR2-expressing AMs exit the airways and localize within the TB granulomas to mediate protective immunity. RNA-sequencing of sorted airway and non-airway AMs show distinct gene expression profiles, suggesting that upon exit from airways, AMs become classically activated. Furthermore, absence of CCR2+ cells specifically at the time of AM egress from the airways resulted in enhanced susceptibility to Mtb infection, increased accumulation of neutrophils, and loss of Mtb control. Interestingly, we provide new evidence that infection with an Mtb strain HN878 mutant lacking phenolic glycolipid (PGL) expression still resulted in increased susceptibility in CCR2−/− mice. Together, our data provide novel evidence for a critical protective role for CCR2 in AM localization within the TB granulomas to mediate protective immunity against clinically relevant and emerging Mtb infections.
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Tocheny, Claire, Prakash Senbagavalli, Zhidong Hu, Keith Kauffman, Shunsuke Sakai, Bo Yan, Yanzhen Song, et al. "Eosinophils actively participate in the host response to Mtb infection." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 131.9. http://dx.doi.org/10.4049/jimmunol.198.supp.131.9.
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Abstract Mycobacterium tuberculosis (Mtb) is the leading cause of mortality worldwide due to a single infectious agent. Mtb resides in pulmonary macrophages, neutrophils and phagocytes, which are also key effector cells that limit bacterial growth. The role of other granulocytic phagocytes during Mtb infection is largely unknown. Eosinophils have comparable phagocytic function to neutrophils and an overlapping repertoire of granular contents capable of limiting bacterial growth. Here we characterized eosinophil responses to Mtb in vitro and in vivo. Eosinophils from healthy human donors responded to Mtb in vitro by CD69 up-regulation and CD62L down-regulation. Mtb induced the release of the eosinophil-specific granule proteins EDN and ECP. Mtb exposure resulted in secretion of IL-1a, TNFa, MIP-1a, MIP-1b, and IL-8. These results suggest that Mtb directly affects eosinophil degranulation, and that eosinophils are able to contribute to Mtb-driven inflammation. To investigate whether eosinophils actively participate in the cellular immune response to Mtb in vivo we followed the eosinophilic response after pulmonary Mtb infection in non-human primates. Eosinophils were significantly increased in the BAL fluid of Mtb infected rhesus macaques, providing evidence that eosinophils are being actively recruited to the lung in response to Mtb in vivo. Indeed, when we analyzed Mtb infected lung tissue from patients who had undergone lung resection, eosinophils were enriched in fibrotic TB consolidations, cavity wall and necrotic caseum. We are currently investigating the biological relevance of the eosinophilic response during Mtb infection in the mouse model. This work was supported by the intramural research programs of NIAID, NIH.
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Potian, Julius A., Wasiulla Rafi, Kamlesh Bhatt, Amanda McBride, William C. Gause, and Padmini Salgame. "Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway." Journal of Experimental Medicine 208, no. 9 (August 8, 2011): 1863–74. http://dx.doi.org/10.1084/jem.20091473.
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Tuberculosis and helminthic infections coexist in many parts of the world, yet the impact of helminth-elicited Th2 responses on the ability of the host to control Mycobacterium tuberculosis (Mtb) infection has not been fully explored. We show that mice infected with the intestinal helminth Nippostrongylus brasiliensis (Nb) exhibit a transitory impairment of resistance to airborne Mtb infection. Furthermore, a second dose of Nb infection substantially increases the bacterial burden in the lungs of co-infected mice. Interestingly, the Th2 response in the co-infected animals did not impair the onset and development of the protective Mtb-specific Th1 cellular immune responses. However, the helminth-induced Th2 environment resulted in the accumulation of alternatively activated macrophages (AAMs) in the lung. Co-infected mice lacking interleukin (IL) 4Rα exhibited improved ability to control Mtb infection, which was accompanied by significantly reduced accumulation of AAMs. Moreover, IL-4Rα−/− mice adoptively transferred with wild-type macrophages had a significantly higher Mtb load in their lungs compared with those that received IL-4Rα−/− macrophages, suggesting a direct contribution for the IL-4R pathway to the heightened susceptibility of co-infected animals. The Th2 response can thus enhance the intracellular persistence of Mtb, in part by mediating the alternative activation of macrophages via the IL-4Rα signaling pathway.
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Larson, Erica C., Mark A. Rodgers, Amy L. Ellis, Cassaundra L. Ameel, Tonilynn M. Baranowski, Alexis J. Balgeman, Pauline A. Maiello, Shelby L. O’Connor, and Charles A. Scanga. "Pre-existing SIV infection decreases cytokine responses by T cells in lung during the early stages of M. tuberculosis co-infection." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.36. http://dx.doi.org/10.4049/jimmunol.202.supp.190.36.
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Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death among HIV+ individuals. The precise mechanisms by which HIV impairs the immune response to subsequent Mtb infection are unknown. We previously established a model of co-infection in Mauritian cynomolgus macaques (MCM). We found SIV/Mtb co-infected MCM had rapidly progressive TB and reached humane endpoint by 12 weeks post-Mtb infection. We hypothesized that pre-existing SIV impacts T cell responses at the early stages of Mtb infection. We infected MCM with SIVmac239 intrarectally and 6 months later co-infected with a low dose of Mtb. SIV-naïve MCM were infected with Mtb alone as controls. Animals were monitored by clinical parameters, culturing bacilli in gastric and bronchoalveolar lavages, and serial 18F-FDG PET/CT imaging. Six weeks after Mtb infection, animals were necropsied and immune responses in the lung were measured by flow cytometry. The two groups exhibited similar TB disease at time of necropsy. Total bacterial burden was remarkably high in both SIV-naïve and SIV/Mtb groups, although co-infected animals tended to have more bacteria in lung tissue. At sites of Mtb infection, SIV/Mtb co-infected animals had fewer CD4+ T cells and significantly more CD8+ T cells. TNFα production by these CD4+ and CD8+ T cells was decreased. Taken together, pre-existing SIV decreases the quality of cytokine responses by T cell at sites of Mtb infection during the early stages of TB disease. This appears to be a critical time point at which the immunologic defect from pre-existing SIV infection begins to impact the arc of TB disease.
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Lysenko, A. P., M. V. Kuchvalskiy, E. I. Yakobson, E. L. Krasnikova, and A. N. Pritychenko. "DETECTION OF MARKERS OF LATENT TUBERCULOSIS INFECTION IN ULTRAPASTEURIZED MILK PRODUCED IN DIFFERENT COUNTRIES." Ecology and Animal World, no. 2 (December 11, 2021): 13–25. http://dx.doi.org/10.47612/2224-1647-2021-2-13-25.
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The genome of tuberculosis mycobacterium (MTB) was detected in ultrapasteurized milk from countries that have and do not have free status from bovine tuberculosis. Also cell wall deficient (CWD) MTB were isolated from all milk samples, that indicates latent tuberculosis infection in herds supplying milk to dairy enterprises.
It was found that ultrasmall (less than 0.22 μm) thermally stable protective forms of MTB were present in milk. They can restore viability as CWD MBT and possibly play a role in the induction of oncogenesis and other pathological conditions.
The existing criteria determining the status of herds do not allow the detection of latent tuberculosis infection, since persistent CWD (L-) forms of MBT do not cause the development of macroscopic changes and hypersensitivity to tuberculin. To identify the real situation in the herds, it is necessary to use PCR and to inoculate special nutrient media with blood and milk mixed with mycobacterial growth stimulants.
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Ramon-Luing, Lucero A., Claudia Carranza, Norma A. Téllez-Navarrete, Karen Medina-Quero, Yolanda Gonzalez, Martha Torres, and Leslie Chavez-Galan. "Mycobacterium tuberculosis H37Rv Strain Increases the Frequency of CD3+TCR+ Macrophages and Affects Their Phenotype, but Not Their Migration Ability." International Journal of Molecular Sciences 23, no. 1 (December 28, 2021): 329. http://dx.doi.org/10.3390/ijms23010329.
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In mycobacterial infections, the number of cells from two newly discovered subpopulations of CD3+ myeloid cells are increased at the infection site; one type expresses the T cell receptor (CD3+TCRαβ+) and the other does not (CD3+TCRαβ−). The role of Mycobacterium tuberculosis (Mtb) virulence in generating these subpopulations and the ability of these cells to migrate remains unclear. In this study, monocyte-derived macrophages (MDMs) infected in vitro with either a virulent (H37Rv) or an avirulent (H37Ra) Mtb strain were phenotypically characterized based on three MDM phenotypes (CD3−, CD3+TCRαβ+, and CD3+TCRαβ−); then, their migration ability upon Mtb infection was evaluated. We found no differences in the frequency of CD3+ MDMs at 24 h of infection with either Mtb strain. However, H37Rv infection increased the frequency of CD3+TCRαβ+ MDMs at a multiplicity of infection of 1 and altered the expression of CD1b, CD1c, and TNF on the surface of cells from both the CD3+ MDM subpopulations; it also modified the expression of CCR2, CXCR1, and CCR7, thus affecting CCL2 and IL-8 levels. Moreover, H37Rv infection decreased the migration ability of the CD3− MDMs, but not CD3+ MDMs. These results confirm that the CD3+ macrophage subpopulations express chemokine receptors that respond to chemoattractants, facilitating cell migration. Together, these data suggest that CD3+ MDMs are a functional subpopulation involved in the immune response against Mtb.
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Foreman, Taylor W., Michelle Sallin, Keith D. Kauffman, Catherine Riou, Elsa Du Bruyn, Shunsuke Sakai, Stella Hoft, et al. "Host Resistance to pulmonary Mycobacterium tuberculosis infection requires CD153 expression." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.78. http://dx.doi.org/10.4049/jimmunol.202.supp.190.78.
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Abstract Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and is among the top ten causes of all human deaths worldwide. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFNγ production is the primary mechanism of CD4 T-cell-mediated protection. However, IFNγ responses do not correlate with host protection, and several reports demonstrate that additional anti-tuberculosis CD4 T-cell effector functions remain unaccounted for. Here we show that the tumour-necrosis factor (TNF) superfamily molecule CD153 (encoded by the gene Tnfsf8) is required for control of pulmonary Mtb infection by CD4 T cells. CD153-deficient mice develop high pulmonary bacterial loads and succumb early to Mtb infection. Reconstitution of T-cell-deficient hosts with Tnfsf8−/− CD4 T cells, similar to Ifng−/− CD4 T cells, fails to rescue mice from early mortality. In Mtb-infected non-human primates, Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In Mtb-infected humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with latent Mtb infection compared to those with active tuberculosis. Thus, CD153 is a major immune mediator of host protection against pulmonary Mtb infection and CD4 T cells are one important source of this molecule.
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Campo, Monica, Chetan Seshadri, Catherine M. Stein, Glenna Peterson, Richard D. Wells, Harriet Mayanja-Kizza, W. Henry Boom, and Thomas Hawn. "The role of histone deacetylases in the innate immune response to Mycobacterium tuberculosis infection." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 126.15. http://dx.doi.org/10.4049/jimmunol.196.supp.126.15.
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Abstract Most of household contacts of pulmonary TB cases, develop latent Mtb infection (LTBI). In a large TB household contact study in Uganda, we found that 9.1% of contacts remained persistently TST negative in 2 years of follow up. We hypothesized that resistance to Mtb infection is mediated by monocytes. We compared genome-wide mRNA profiles of Mtb-infected monocytes from those who are resistant or susceptible to Mtb infection. Using Gene Set Enrichment Analysis, we recently identified a butyrate stimulated gene set that distinguished these two groups. Butyrate inhibits histone deacetylases (HDAC), a gene family that regulates transcription as well as innate immune responses to microbes. We found that treatment of peripheral blood monocytes with class I HDAC inhibitors, depsipeptide and sodium butyrate, led to reduced IL6 and TNF secretion after Mtb infection compared to untreated cells. In contrast, IL1beta levels were increased. Together, these data indicate that class I HDAC inhibitors modulate proinflammatory cytokines after Mtb infection. Future studies will examine how HDAC inhibitors regulate inflammasome-dependent IL-1beta and IL6 secretion differently. HDACs likely regulate multiple pathways that modulate Mtb pathogenesis and mediate clinical to Mtb infection. HDACs are plausible candidate human Mtb resistance genes and promising targets for host-directed therapeutics.
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Scott-Browne, James P., Shahin Shafiani, Glady's Tucker-Heard, Kumiko Ishida-Tsubota, Jason D. Fontenot, Alexander Y. Rudensky, Michael J. Bevan, and Kevin B. Urdahl. "Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis." Journal of Experimental Medicine 204, no. 9 (August 20, 2007): 2159–69. http://dx.doi.org/10.1084/jem.20062105.
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Mycobacterium tuberculosis (Mtb) frequently establishes persistent infections that may be facilitated by mechanisms that dampen immunity. T regulatory (T reg) cells, a subset of CD4+ T cells that are essential for preventing autoimmunity, can also suppress antimicrobial immune responses. We use Foxp3-GFP mice to track the activity of T reg cells after aerosol infection with Mtb. We report that during tuberculosis, T reg cells proliferate in the pulmonary lymph nodes (pLNs), change their cell surface phenotype, and accumulate in the pLNs and lung at a rate parallel to the accumulation of effector T cells. In the Mtb-infected lung, T reg cells accumulate in high numbers in all sites where CD4+ T cells are found, including perivascular/peribronchiolar regions and within lymphoid aggregates of granulomas. To determine the role of T reg cells in the immune response to tuberculosis, we generated mixed bone marrow chimeric mice in which all cells capable of expressing Foxp3 expressed Thy1.1. When T reg cells were depleted by administration of anti-Thy1.1 before aerosol infection with Mtb, we observed ∼1 log less of colony-forming units of Mtb in the lungs. Thus, after aerosol infection, T reg cells proliferate and accumulate at sites of infection, and have the capacity to suppress immune responses that contribute to the control of Mtb.
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Jiang, Yao, Jia-Xuan Zhang, and Rong Liu. "Systematic comparison of differential expression networks in MTB mono-, HIV mono- and MTB/HIV co-infections for drug repurposing." PLOS Computational Biology 18, no. 12 (December 19, 2022): e1010744. http://dx.doi.org/10.1371/journal.pcbi.1010744.
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The synergy between human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (MTB) could accelerate the deterioration of immunological functions. Previous studies have explored the pathogenic mechanisms of HIV mono-infection (HMI), MTB mono-infection (MMI) and MTB/HIV co-infection (MHCI), but their similarities and specificities remain to be profoundly investigated. We thus designed a computational framework named IDEN to identify gene pairs related to these states, which were then compared from different perspectives. MMI-related genes showed the highest enrichment level on a greater number of chromosomes. Genes shared by more states tended to be more evolutionarily conserved, posttranslationally modified and topologically important. At the expression level, HMI-specific gene pairs yielded higher correlations, while the overlapping pairs involved in MHCI had significantly lower correlations. The correlation changes of common gene pairs showed that MHCI shared more similarities with MMI. Moreover, MMI- and MHCI-related genes were enriched in more identical pathways and biological processes, further illustrating that MTB may play a dominant role in co-infection. Hub genes specific to each state could promote pathogen infections, while those shared by two states could enhance immune responses. Finally, we improved the network proximity measure for drug repurposing by considering the importance of gene pairs, and approximately ten drug candidates were identified for each disease state.
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Kothari, Hema, Ramakrishna Vankayalapati, Padmaja Paidipally, L. Vijaya Mohan Rao, and Usha R. Pendurthi. "Mycobacterium Tuberculosis infection and Tissue Factor Expression in Macrophages." Blood 118, no. 21 (November 18, 2011): 1198. http://dx.doi.org/10.1182/blood.v118.21.1198.1198.
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Abstract Abstract 1198 Tissue factor (TF), the primary initiator of the coagulation cascade, is normally absent from cells that regularly come in contact with blood such as endothelial cells and monocytes yet could be induced in these cells in a variety of pathological conditions. The aberrant expression of TF by cells of the monocyte/macrophage lineage is thought to be a major contributor to thrombotic disorders and inflammation. Macrophages play a central role in the innate immune response essential for host defense against pathogenic infections. Tuberculosis (TB), a fatal disease caused by Mycobacterium tuberculosis (Mtb), affects nearly one third of the world's population. A number of studies have reported the presence of thrombotic complications, particularly disseminated intravascular coagulation (DIC) in TB patients. However, it is unclear how Mtb infection causes DIC or other thrombotic disorders as mycobacteria are not known to produce endotoxins or exotoxins that otherwise initiate the clotting cascade. In the present study, we have investigated whether Mtb infection induces TF expression in macrophages and various host and pathogenic factors responsible for TF expression. We have tested the effect of live virulent Mtb H37Rv, gamma-irradiated Mtb H37Rv (γ-Mtb) and various components derived from Mtb H37Rv on TF expression in macrophages. Exposure of human monocyte-derived macrophages (MDM) to live virulent Mtb H37Rv (at 1 to 5 bacteria/macrophage) or γ-Mtb H37Rv (10 μg/ml) markedly increased TF expression in MDM (5 to 20-fold increase compared to untreated MDM). TF expression in macrophages in response to Mtb is predominantly higher in CD14hi (CD14+) macrophages. Although CD14loCD16hi (CD16+) macrophages also expressed TF in response to Mtb, the level of TF induction in these cells was much lower. γ-Mtb induced TF expression in macrophages much more robustly than E.coli-derived LPS. The γ-Mtb-mediated induction of TF expression in macrophages peaked around 9 h and was sustained throughout 48 h, which markedly varies from the kinetics of LPS-induced TF expression, which peaks between 3–6 h and then reduced down to basal level by 18–24 h. To identify the potential macrophage receptor(s) responsible for the induction of TF by Mtb, MDM were pre-treated with antibodies against CD14 and Toll-like receptors (TLR) before they were exposed to γ-Mtb. Although CD14 antibodies markedly inhibited LPS-induced TF activity, they only suppressed Mtb-induced TF activity minimally. Pretreatment of MDMs with TLR2 or TLR4 antibodies had no significant effect on γ-Mtb-induced TF expression. However, combining the CD14 antibodies together with TLR2 and TLR4 antibodies showed nearly a 50% reduction in γ-Mtb-induced TF activity. These data indicate that a cooperative action of multiple receptors and signaling pathways may be responsible for the robust and sustained induction of TF expression. In order to identify the specific component(s) of γ-Mtb that are responsible for TF induction, we have treated MDMs with various subcellular fractions or purified components derived from Mtb H37Rv. The whole cell lysate of Mtb, cell wall, cell membrane and culture filterate proteins induced TF activity to varying degrees. Of all the purified components tested, the mycobacterial cell wall core component mycolyl arabinogalactan peptidoglycan (mAGP), phosphatidylinositol mannoside-6 (PIM6) and lipomannan (LM) elicited induction of TF protein and activity in the order of mAGP > PIM6 > LM. It is interesting to note that the treatment of MDMs with individual components, mycolic acid, arabinogalactan and peptidoglycan of mAGP complex did not induce TF expression, indicating that the structure of mAGP may be required for recognition by pattern recognition receptors on macrophages. In summary, our data show that Mtb induces TF expression in macrophages, probably through a novel mechanism. Although Mtb-induced TF expression in monocytes/macrohages may lead to systemic thrombotic disorders through the release of TF containing microparticles, it may be the localized and sustained expression of TF on macrophages that internalize the infectious bacteria at the site of infection in lung is responsible for granuloma formation in tuberculosis patients that prevents the spread of the bacteria. Disclosures: No relevant conflicts of interest to declare.
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Gideon, Hannah, Philana Lin, and JoAnne Flynn. "T cell cytokine profile of early tuberculosis infection and disease in Cynomolgus macaque model (P3335)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 134.21. http://dx.doi.org/10.4049/jimmunol.190.supp.134.21.
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Abstract Mycobacterium tuberculosis (Mtb) remains one of the world’s most successful human pathogen. Addressing questions on immunological events soon after Mtb infection in human is challenging. Non-human primate model (Cynomolgus macaques) provide the necessary platform to understand the early immunological events in Mtb infection. We infected 28 Cynomolgus macaques with a low dose of Mtb (Erdman strain, ~25-50 CFU) and monitored clinically for signs and symptoms of tuberculosis up to six months post infection and classified to have either latent TB infection or active disease based on chest X-ray and Mtb culture. Peripheral blood was collected at time-points: pre Mtb infection; and at days: 10, 20, 30, 42, 56, 90, 120, 150 and 180 post infection. PBMC were isolated and multi-parametric intracellular flow cytometry was performed in fresh PBMC to track the early CD4 and CD8 T cell cytokine profiles (CD107a, GMCSF, IFN-g, IL-2, IL-4, IL-6, IL-10 and IL-17) during the course of Mtb infection. Preliminary analysis shows difference in the cytokine response in the early phase of infection between those who developed active disease or latent infection. In addition, we find a spectrum of cytokine response, which overlap between active and latent tuberculosis.
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Naik, Sumanta Kumar, Michael Nehls, Yassin Mreyoud, Rachel L. Kinsella, Asya Smirnov, Chanchal S. Chowdhury, Sam Mckee, Neha Dubey, Darren Kreamalmeyer, and Christina L. Stallings. "Determining the mechanistic basis for Irgm1 mediated control of Mycobacterium tuberculosisinfection." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 81.01. http://dx.doi.org/10.4049/jimmunol.210.supp.81.01.
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Abstract Irgm1 is a 47kDa IFN-γ inducible GTPase that has been shown to be essential for controlling Mycobacterium tuberculosis (Mtb) infection in mice. It was originally shown that Irgm1 is recruited to Mtb containing phagosomes in infected macrophages where it was proposed to be involved in autophagy-mediated clearance of Mtb. However, we have previously discovered that autophagy is not required in macrophages to control Mtb replication. In addition, it has since been reported that Irgm1 does not colocalize with phagosomes containing Mycobacterium bovis BCG in IFN-γ treated cells, suggesting that Irgm1 must have non-autophagic roles in TB infection that require detailed investigation. Irgm1 −/−mice were shown to have higher levels of type I interferon signaling, as well as CD4 +T cell survival defect, which could explain the susceptibility to Mtb infection, but this has yet to be determined. We infected Irgm1−/−mice with Mtb and found that they succumbed early to infection with higher bacterial burden, higher numbers of neutrophils, higher numbers of CD19 +B cells, and lower numbers of CD4 +T-lymphocytes in the lungs compared to wild-type (WT) mice. In addition, we found significantly increased expression of interferon-stimulated genes (ISGs) during Mtb infection of Irgm1−/−mice compared to WT. We also observed that T cell proliferation and lymph node responses were severely defective following Mtb infection in Irgm1−/−mice. Bone marrow chimera and transfer of Mtb-specific activated T lymphocytes into Irgm1−/−mice reverses the susceptibility to Mtb infection, indicating that a defect in T cell responses contributes to the susceptibility of Irgm1−/−mice to Mtb infection. This work was supported by Stephen I. Morse fellowship to Sumanta Kumar Naik and the Project supported by NIH AI142784 and AI132697 and BWF PATH Award to Dr. Christina Stallings.
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Pouget, Marion, Anna K. Coussens, Alessandra Ruggiero, Anastasia Koch, Jordan Thomas, Gurdyal S. Besra, Robert J. Wilkinson, Apoorva Bhatt, Georgios Pollakis, and William A. Paxton. "Generation of Liposomes to Study the Effect of Mycobacterium Tuberculosis Lipids on HIV-1 cis- and trans-Infections." International Journal of Molecular Sciences 22, no. 4 (February 16, 2021): 1945. http://dx.doi.org/10.3390/ijms22041945.
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Tuberculosis (TB) is the leading cause of death among HIV-1-infected individuals and Mycobacterium tuberculosis (Mtb) co-infection is an early precipitate to AIDS. We aimed to determine whether Mtb strains differentially modulate cellular susceptibility to HIV-1 infection (cis- and trans-infection), via surface receptor interaction by their cell envelope lipids. Total lipids from pathogenic (lineage 4 Mtb H37Rv, CDC1551 and lineage 2 Mtb HN878, EU127) and non-pathogenic (Mycobacterium bovis BCG and Mycobacterium smegmatis) Mycobacterium strains were integrated into liposomes mimicking the lipid distribution and antigen accessibility of the mycobacterial cell wall. The resulting liposomes were tested for modulating in vitro HIV-1 cis- and trans-infection of TZM-bl cells using single-cycle infectious virus particles. Mtb glycolipids did not affect HIV-1 direct infection however, trans-infection of both R5 and X4 tropic HIV-1 strains were impaired in the presence of glycolipids from M. bovis, Mtb H37Rv and Mtb EU127 strains when using Raji-DC-SIGN cells or immature and mature dendritic cells (DCs) to capture virus. SL1, PDIM and TDM lipids were identified to be involved in DC-SIGN recognition and impairment of HIV-1 trans-infection. These findings indicate that variant strains of Mtb have differential effect on HIV-1 trans-infection with the potential to influence HIV-1 disease course in co-infected individuals.
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Gindeh, Awa, Simon Donkor, and Olumuyiwa Owolabi. "PO 8383 THE ROLE OF PLASMA B CELLS IN MYCOBACTERIUM TUBERCULOSIS INFECTION AND DISEASE." BMJ Global Health 4, Suppl 3 (April 2019): A31.2—A31. http://dx.doi.org/10.1136/bmjgh-2019-edc.80.
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BackgroundTuberculosis (TB) is still a major global health problem with about one-quarter of the global population infected with the causative pathogen, Mycobacterium tuberculosis (Mtb). The role of T-cells in the adaptive immune response against Mtb has been extensively studied with little information on the role of B-cells. B-cells produce antibodies and differentiate into plasma and memory B-cells. Plasmablasts are a subset of plasma cells only present in the peripheral circulation following an ongoing infection or vaccination. Immunoglobulin G(IgG) especially IgG2 mounts more efficient immune response against bacterial infections, mainly attributed to the high affinity of IgG2 binding to the Fcγ receptor. Therefore, we hypothesised that Mtb-specific IgG +plasmablasts may be a useful biomarker of TB infection status.MethodsEx-vivo B-cell enzyme-linked immunospot (ELISPOT) was used to identify plasmablasts responses to Mtb-specific antigens ESAT-6/CFP-10 (EC), together with non-specific Mtb purified protein derivative (PPD) and a positive (total IgG) and negative (media only) control from adults with active TB pre- and post-treatment (n=20) or with latent TB infection (LTBI; n=20) in The Gambia.ResultsFrequencies of Mtb-specific plasmablasts were significantly higher in active TB cases pre-treatment compared to post-treatment (p<0.0001) and LTBI with no difference seen following PPD stimulation. Interestingly, total IgG +cells were lower in the cases at recruitment but increased following treatment indicating the relative proportion of Mtb-specific responses were also significantly different (p=0.034) prior to therapy.ConclusionThese data show that B-cell responses are differentially modulated during active and latent TB infection, suggesting that plasmablasts may be a useful biomarker for TB infection in TB-endemic settings.
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MAGOMBEDZE, GESHAM, WINSTON GARIRA, and EDDIE MWENJE. "IN-VIVOMATHEMATICAL STUDY OF CO-INFECTION DYNAMICS OF HIV-1 ANDMYCOBACTERIUM TUBERCULOSIS." Journal of Biological Systems 16, no. 03 (September 2008): 357–94. http://dx.doi.org/10.1142/s0218339008002551.
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Human Immunodeficiency Virus type-1 (HIV-1) fuels the pathogenesis of Mycobacterium tuberculosis (Mtb) in humans. We develop a mathematical model in an attempt to understand the immune mechanisms that are involved during the co-infection of Mtb and HIV-1. Our study reveals that infection of an Mtb infected individual with HIV-1 results in fast development of active TB. The mathematical model analysis and simulations show that Mtb infection is linked to HIV infection through macrophages and CD4+ T cells. The study shows that depletion of macrophages and CD4+ T cells by HIV-1 worsens the picture of Mtb infection and in-turn Mtb infection affects the progression of HIV-1 infection since it is also capable of inducing rapid replication of HIV. Our analytical and numerical simulations show that macrophages are a potential reservoir of HIV particles during HIV-1 infection. Co-infection simulations reveal that co-infection exacerbates more the pathogen that caused the first infection. Simulations also show that co-infection disease progression patterns converge to a similar trend after a considerable time interval irrespective of which pathogen first caused infection and the second pathogen that caused co-infection. This work suggests directions for further studies and potential treatment strategies.
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Martinez-Martinez, Yazmin Berenice, Matthew B. Huante, Megan Files, Benjamin B. Gelman, Mark Endsley, and Janice J. Endsley. "HIV compromises Th17 and Th22 immunity in a humanized mouse model of Tuberculosis and HIV co-infection." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 58.16. http://dx.doi.org/10.4049/jimmunol.208.supp.58.16.
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Abstract Tuberculosis (TB) kills an estimated 1–2 million people per year and is the leading cause of death in people with HIV (PWH). The CD4+ T helper (Th) populations play significant roles in protective immunity to Mycobacterium tuberculosis (Mtb), and are also important host cells for HIV proliferation and persistence. Emerging evidence in PWH suggests that Th17 and Th22 cells may be preferentially depleted during HIV infection, an outcome that could pose a risk for Mtb containment during co-infection. We employed our humanized mouse model of co-infection to assess pulmonary and peripheral changes in Th17 and Th22 frequency and function due to infection with HIV, Mtb, or both. As determined with multi-plex ELISA, co-infection with HIV suppressed the cytokine response to Mtb including IL-17A, IL-22, IL-6, and IL-1β. Multi-parameter flow cytometric analysis revealed that Mtb and HIV/Mtb infection led to increased Th17+ cells in lung and decreased Th17+ cells in spleen. Following HIV or HIV/Mtb infection, Th22+ cells were significantly decreased in both lung and spleen. Importantly, HIV preferentially infected Th17 cells compared to Th22 and other Th subpopulations. Greater HIV viral load was also observed in the lung, but not spleen, of animals with Mtb/HIV co-infection compared to those with HIV mono-infection. Overall, these results suggest that HIV may compromise Th22 immunity, and exploit Th17+ cells to promote viral pathogenesis, in the setting of Mtb and HIV co-infection. Y.B. Martinez-Martinez is supported by Conacyt-I2T2 in Mexico, Contex, and the James W. McLaughlin Fellowship Fund. Grant support was provided by NIH R01AI147948 award to J. Endsley
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Lee, Junghwan, Ji-Ae Choi, Soo-Na Cho, Sang-Hun Son, and Chang-Hwa Song. "Mitofusin 2-Deficiency Suppresses Mycobacterium tuberculosis Survival in Macrophages." Cells 8, no. 11 (October 30, 2019): 1355. http://dx.doi.org/10.3390/cells8111355.
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Apoptosis is an important host defense mechanism against mycobacterial infection. However, the molecular mechanisms regulating apoptosis during mycobacterial infection are not well known. Recent reports suggest that bacterial infection regulates mitochondrial fusion and fission in various ways. Here, we investigated the role of mitochondria in Mycobacterium tuberculosis (Mtb)-infected macrophages. Mtb H37Rv (Rv) infection induced mitofusin 2 (MFN2) degradation, leading to mitochondrial fission. Interestingly, Mtb H37Ra (Ra) infection induced significantly greater mitochondrial fragmentation than Rv infection. Mtb-mediated Parkin, an E3 ubiquitin ligase, contributed to the degradation of MFN2. To evaluate the role of endoplasmic reticulum stress in the production of Parkin during Mtb infection, we analyzed Parkin production in 4-phenylbutyric acid (4-PBA)-pretreated macrophages. Pretreatment with 4-PBA reduced Parkin production in Mtb-infected macrophages. In contrast, the level of MFN2 production recovered to a level similar to that of the unstimulated control. In addition, Ra-infected macrophages had reduced mitochondrial membrane potential (MMP) compared to those infected with Rv. Interestingly, intracellular survival of mycobacteria was decreased in siMFN2-transfected macrophages; in contrast, overexpression of MFN2 in macrophages increased Mtb growth compared with the control.
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Ganchua, Sharie Keanne C., Anthony M. Cadena, Forrest F. Hopkins, Sarah Fortune, and JoAnne L. Flynn. "Drug treatment of tuberculosis diminishes but does not abolish the protection against secondary M. tuberculosis challenge." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.33. http://dx.doi.org/10.4049/jimmunol.202.supp.190.33.
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Abstract Early human studies found that individuals with latent M. tuberculosis (Mtb) infection are less likely to develop active tuberculosis (TB) compared to naïve individuals with similar levels of exposure. Using Mtb-barcoded libraries (Lib A - first infection; Lib B - second infection), we showed that an existing Mtb infection in cynomolgus macaques protects against the establishment and progression of a second Mtb challenge. Studies suggest that humans treated for active TB are at higher risk for developing disease following reinfection. Therefore we hypothesized that drug treatment would compromise the protection against a second Mtb infection. To test this hypothesis, we treated macaques infected with Lib A with anti-TB drugs for three months before infecting with Lib B. As a control, a group of macaques were infected with both Lib A and B following the same timeline but without drug treatment. In both groups, the number of granulomas arising from the second infection (Lib B) was significantly fewer than the number of granulomas from the first infection (Lib A). Comparing with the naïve group from our previous study, both drug and non-drug treated groups had significantly fewer live bacteria in the Lib B granulomas albeit the drug treated group had >10x higher bacterial burden than the untreated group. The Lib B granulomas in both groups were smaller and less inflammed (determined by PET CT) compared to granulomas from the naïve animals. No difference in the T cell response in Lib B granulomas was found in both drug and non-drug treated groups. These data suggest that the protection conferred by the first infection to the secondary Mtb challenge remains intact and that bacteria from the second infection were rapidly controlled regardless of treatment.
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Gorna, Alina E., Richard P. Bowater, and Jaroslaw Dziadek. "DNA repair systems and the pathogenesis of Mycobacterium tuberculosis: varying activities at different stages of infection." Clinical Science 119, no. 5 (May 25, 2010): 187–202. http://dx.doi.org/10.1042/cs20100041.
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Mycobacteria, including most of all MTB (Mycobacterium tuberculosis), cause pathogenic infections in humans and, during the infectious process, are exposed to a range of environmental insults, including the host's immune response. From the moment MTB is exhaled by infected individuals, through an active and latent phase in the body of the new host, until the time they reach the reactivation stage, MTB is exposed to many types of DNA-damaging agents. Like all cellular organisms, MTB has efficient DNA repair systems, and these are believed to play essential roles in mycobacterial pathogenesis. As different stages of infection have great variation in the conditions in which mycobacteria reside, it is possible that different repair systems are essential for progression to specific phases of infection. MTB possesses homologues of DNA repair systems that are found widely in other species of bacteria, such as nucleotide excision repair, base excision repair and repair by homologous recombination. MTB also possesses a system for non-homologous end-joining of DNA breaks, which appears to be widespread in prokaryotes, although its presence is sporadic within different species within a genus. However, MTB does not possess homologues of the typical mismatch repair system that is found in most bacteria. Recent studies have demonstrated that DNA repair genes are expressed differentially at each stage of infection. In the present review, we focus on different DNA repair systems from mycobacteria and identify questions that remain in our understanding of how these systems have an impact upon the infection processes of these important pathogens.
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Simpson, Allison, Taylor W. Foreman, Namita Rout, and Deepak Kaushal. "The Characterization of Nonclassical T cells and their Responses during Mtb Infection." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 200.13. http://dx.doi.org/10.4049/jimmunol.196.supp.200.13.
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Abstract Tuberculosis (TB) is a catastrophic infectious disease, affecting roughly one third of the world’s population. Typically 5–10% of infections will develop into active TB, however co-morbidities such as HIV present an increased risk of TB reactivation, leading to life-threatening active infection. While it is well-known that T cells, and in particular, Class II restricted, IFN-γ expressing classical CD4+ T cells are essential for immunity to TB, these are by themselves not sufficient correlates of protection, especially during reactivation of LTBI by HIV co-infection. Recently lymphocytic subsets that recognize nonpeptidic antigens have been classified as nonclassically activated T cells. These cells are, however, poorly characterized as regulators of the immune system, particularly in patients infected with M. tuberculosis (Mtb). We hypothesize that non-classically activated T cells recognize bacterial antigens during Mtb infection, as well as Mtb/HIV co-infection, and may play a role in protective immunity. As part of this project, we will enumerate and phenotype the populations of nonclassical T cells based on expression of their surface antigens at different time points of Mtb and Mtb/SIV infection in rhesus macaques. Furthermore, we will characterize the function of the non-classical T cells by analyzing their secreted factors. Better understanding the role of nonclassical T cells in TB pathogenesis may enable us to develop better vaccines and treatments against TB.
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Hlaka, Lerato, Mumin Ozturk, Julius E. Chia, Shelby-Sara Jones, Shandre Pillay, Sibongiseni K. L. Poswayo, Thabo Mpotje, et al. "IL-4i1 Regulation of Immune Protection During Mycobacterium tuberculosis Infection." Journal of Infectious Diseases 224, no. 12 (November 5, 2021): 2170–80. http://dx.doi.org/10.1093/infdis/jiab558.
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Abstract Background Interleukin 4 (IL-4i1)–induced gene 1 encodes L-phenylalanine oxidase that catabolizes phenylalanine into phenylpyruvate. IL-4i1 is mainly expressed by antigen-presenting cells (APCs), inhibits T-cell proliferation, regulates B-cell activation, modulates T cell responses, and drives macrophage polarization, but its role in bacterial infections is understudied. Methods We evaluated IL-4i1 deletion in macrophages and mice on infection with virulent H37Rv and W-Beijing lineage hypervirulent HN878 Mycobacterium tuberculosis (Mtb) strains. The bacterial growth and proinflammatory responses were measured in vitro and in vivo. Histopathological analysis, lung immune cell recruitment, and macrophage activation were assessed at the early and chronic stages of Mtb infection. Results IL-4i1–deficient (IL-4i1−/−) mice displayed increased protection against acute H37Rv, HN878 and chronic HN878 Mt infections, with reduced lung bacterial burdens and altered APC responses compared with wild-type mice. Moreover, “M1-like” interstitial macrophage numbers, and nitrite and Interferon-γ production were significantly increased in IL-4i1−/− mice compared with wild-type mice during acute Mtb HN878 infection. Conclusions Together, these data suggest that IL-4i1 regulates APC-mediated inflammatory responses during acute and chronic Mtb infection. Hence, IL-4i1 targeting has potential as an immunomodulatory target for host-directed therapy.
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Tisthammer, Kaho H., Christopher Kline, Tara Rutledge, Collin R. Diedrich, Sergio Ita, Philana Ling Lin, Zandrea Ambrose, and Pleuni S. Pennings. "SIV Evolutionary Dynamics in Cynomolgus Macaques during SIV-Mycobacterium tuberculosis Co-Infection." Viruses 14, no. 1 (December 29, 2021): 48. http://dx.doi.org/10.3390/v14010048.
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Co-infection with Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) is a worldwide public health concern, leading to worse clinical outcomes caused by both pathogens. We used a non-human primate model of simian immunodeficiency virus (SIV)-Mtb co-infection, in which latent Mtb infection was established prior to SIVmac251 infection. The evolutionary dynamics of SIV env was evaluated from samples in plasma, lymph nodes, and lungs (including granulomas) of SIV-Mtb co-infected and SIV only control animals. While the diversity of the challenge virus was low and overall viral diversity remained relatively low over 6–9 weeks, changes in viral diversity and divergence were observed, including evidence for tissue compartmentalization. Overall, viral diversity was highest in SIV-Mtb animals that did not develop clinical Mtb reactivation compared to animals with Mtb reactivation. Among lung granulomas, viral diversity was positively correlated with the frequency of CD4+ T cells and negatively correlated with the frequency of CD8+ T cells. SIV diversity was highest in the thoracic lymph nodes compared to other sites, suggesting that lymphatic drainage from the lungs in co-infected animals provides an advantageous environment for SIV replication. This is the first assessment of SIV diversity across tissue compartments during SIV-Mtb co-infection after established Mtb latency.
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Waters, Robyn, Mthawelanga Ndengane, Melissa-Rose Abrahams, Collin R. Diedrich, Robert J. Wilkinson, and Anna K. Coussens. "The Mtb-HIV syndemic interaction: why treating M. tuberculosis infection may be crucial for HIV-1 eradication." Future Virology 15, no. 2 (February 2020): 101–26. http://dx.doi.org/10.2217/fvl-2019-0069.
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Accelerated tuberculosis and AIDS progression seen in HIV-1 and Mycobacterium tuberculosis ( Mtb)-coinfected individuals indicates the important interaction between these syndemic pathogens. The immunological interaction between HIV-1 and Mtb has been largely defined by how the virus exacerbates tuberculosis disease pathogenesis. Understanding of the mechanisms by which pre-existing or subsequent Mtb infection may favor the replication, persistence and progression of HIV, is less characterized. We present a rationale for the critical consideration of ‘latent’ Mtb infection in HIV-1 prevention and cure strategies. In support of this position, we review evidence of the effect of Mtb infection on HIV-1 acquisition, replication and persistence. We propose that ‘latent’ Mtb infection may have considerable impact on HIV-1 pathogenesis and the continuing HIV-1 epidemic in sub-Saharan Africa.
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Sia, Jonathan Kevin, Maria Georgieva, and Jyothi Rengarajan. "Innate Immune Defenses in Human Tuberculosis: An Overview of the Interactions betweenMycobacterium tuberculosisand Innate Immune Cells." Journal of Immunology Research 2015 (2015): 1–12. http://dx.doi.org/10.1155/2015/747543.
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Tuberculosis (TB) remains a serious global public health problem that results in up to 2 million deaths each year. TB is caused by the human pathogen,Mycobacterium tuberculosis(Mtb), which infects primarily innate immune cells patrolling the lung. Innate immune cells serve as barometers of the immune response against Mtb infection by determining the inflammatory milieu in the lungs and promoting the generation of adaptive immune responses. However, innate immune cells are also potential niches for bacterial replication and are readily manipulated by Mtb. Our understanding of the early interactions between Mtb and innate immune cells is limited, especially in the context of human infection. This review will focus on Mtb interactions with human macrophages, dendritic cells, neutrophils, and NK cells and detail evidence that Mtb modulation of these cells negatively impacts Mtb-specific immune responses. Furthermore, this review will emphasize important innate immune pathways uncovered through human immunogenetic studies. Insights into the human innate immune response to Mtb infection are necessary for providing a rational basis for the augmentation of immune responses against Mtb infection, especially with respect to the generation of effective anti-TB immunotherapeutics and vaccines.
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Gopalakrishnan, Archana, Jillian Dietzold, and Padmini Salgame. "Induction of memory immunity to Mycobacterium tuberculosis is independent of Toll-like receptor 9 signaling (IRC9P.706)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 191.7. http://dx.doi.org/10.4049/jimmunol.192.supp.191.7.
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Abstract Mycobacterium tuberculosis (Mtb) is known to engage Toll-like receptors (TLR) 2 and 9 on macrophages and dendritic cells to initiate an inflammatory response. Nonetheless, studies in the murine model of tuberculosis revealed minimal involvement of TLR2 and TLR9 in host resistance during acute infection. We have published that the induction of memory immunity to Mtb is not compromised in the absence of TLR2. Given that the inclusion of TLR9 ligands in vaccine preparations enhances their efficacy, we hypothesized that TLR9 adjuvanticity is necessary for the induction of memory immunity to Mtb. Mice were immunized with an Mtb auxotroph. Upon challenge with Mtb, WT and TLR9-/- immunized mice demonstrated similarly enhanced control of bacterial burden in the lungs compared to their unimmunized counterparts. The granulomatous response, IFN-gamma production and the frequency of immune cells recruited to the lungs was similar in the two genotypes. These findings indicate that the absence of TLR9 signaling during priming does not affect T cell memory response to Mtb infection. Together, our studies point that induction of effector and memory T cell responses and resistance to acute Mtb infection are independent of TLR2 and TLR9. In a recent study we showed that TLR2 signaling, although nonessential in acute infection, was critical to host resistance during chronic Mtb infection. In ongoing studies we are investigating whether TLR9, like TLR2, has a role in chronic Mtb infection.
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Filinyuk, O. V., A. S. Alliluev, D. E. Аmichba, P. N. Golubchikov, Yu S. Popelo, and M. N. Dobkina. "HIV infection and multiple drug resistant tuberculosis: the frequency of co-infection and treatment efficacy." Tuberculosis and Lung Diseases 99, no. 2 (March 10, 2021): 45–51. http://dx.doi.org/10.21292/2075-1230-2021-99-2-45-51.
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The objective of the study: in Tomsk Region, to establish the frequency of multiple drug resistance (MDR) of mycobacterium tuberculosis (MBT) in new tuberculosis patients with the reference to their HIV status and to assess their treatment outcomes.Subjects and methods. The presented results were obtained from a retrospective cohort study of 788 new tuberculosis patients who were registered for MDR TB treatment at Tomsk Phthisiopulmonology Medical Center from January 2017 to April 2019.Results. In Tomsk Region, the level of primary MDR reaches 31.3% in patients with TB/HIV co-infection, while in HIV negative tuberculosis patients, this rate is 24.2%. The incidence of primary MDR/XDR MTB reaches 40% among deceased patients with TB/HIV co-infection. Treatment efficacy in MDR/XDR TB patients with associated HIV infection is low – the effective treatment was achieved only in 7.3% of them. In general (excluding the data on MTB drug resistance and antiretroviral therapy), treatment efficacy of tuberculosis patients with HIV infection is significantly lower versus HIV negative tuberculosis patients: 37.7% and 61.9%, respectively, OR 0.38 [0.28; 0.50], p = 0.001.
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Huynh, Jeremy P., Chih-Chung Lin, Jacqueline M. Kimmey, Nicholas N. Jarjour, Elizabeth A. Schwarzkopf, Tara R. Bradstreet, Irina Shchukina, et al. "Bhlhe40 is an essential repressor of IL-10 during Mycobacterium tuberculosis infection." Journal of Experimental Medicine 215, no. 7 (May 17, 2018): 1823–38. http://dx.doi.org/10.1084/jem.20171704.
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The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of Il10 in Bhlhe40−/− mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c+ cells is sufficient to cause susceptibility to Mtb. Bhlhe40 represents the first transcription factor found to be essential during Mtb infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in Mtb pathogenesis.
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LIN, S. H., C. C. LAI, S. H. HUANG, C. C. HUNG, and P. R. HSUEH. "Mycobacterial bone marrow infections at a medical centre in Taiwan, 2001–2009." Epidemiology and Infection 142, no. 7 (October 29, 2013): 1524–32. http://dx.doi.org/10.1017/s0950268813002707.
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SUMMARYMycobacterial bone marrow (BM) infection is the most common diagnosis established by BM examinations for fever of unknown origin. In this study, clinical features and outcomes of patients who fulfilled the criteria for BM infection due to Mycobacterium tuberculosis (MTB) and non-tuberculous mycobacteria (NTM) at a medical centre in Taiwan from 2001 to 2009 were investigated. The BM histopathological findings were also analysed. A total of 24 patients (16 men, eight women) with mycobacterial BM infections were found. Of these, nine (38%) were positive for human immunodeficiency virus (HIV) and six (25%) had no pre-existing immunocompromised conditions. MTB isolates were obtained from 11 (46%) patients and NTM species were isolated from 10 (42%) patients, including M. avium complex (MAC, n = 7) and M. kansasii (n = 3). Patients with MTB infections were significantly older than those with NTM infections (60·5 vs. 47·7 years, P = 0·043) and were less likely to have a positive BM culture (45% vs. 100%, P = 0·012). The 90-day survival rates for MTB and NTM BM infections were 68% and 60%, respectively (P = 0·61). In addition, the presence of BM granulomas was significantly more common in patients with MTB BM infections than in those with NTM infections (82% vs. 30%, P = 0·030). In Taiwan, the importance of NTM was not inferior to MTB and besides MAC, M. kansasii might be an important pathogen in non-HIV-infected patients. The presence of BM granulomas and caseation provides valuable information regarding early treatment pending culture results.
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Thandi, Ramya Sivangala, Rajesh kumar Radhakrishnan, Deepak Tripathi, Padmaja Paidipally, and Ramakrishna Vankayalapati. "Ornithine-A urea cycle metabolite enhances autophagy and controls Mycobacterium tuberculosis infection." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 85.16. http://dx.doi.org/10.4049/jimmunol.204.supp.85.16.
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Abstract Alveolar macrophages (AMs) are the first cells encountered by TB pathogen and serve as the primary defense against Mycobacterium tuberculosis (Mtb) in the lungs. Studies have shown that liver macrophages (Kupffer cells; KCs) can control Mtb growth but, it is not clear how KCs completely eliminate mycobacterial infections. Thus, identification of these mechanisms will facilitate the development of immunomodulatory strategies to boost AM-mediated immunity to Mtb. In the current study, we compared Mtb growth in murine AMs, peritoneal (PMs), liver macrophages (Kupffer cells; KCs) and bone marrow-derived monocytes (BDMs). KCs restricted Mtb growth more efficiently than all other macrophages and monocytes despite equivalent infections. Differences in Mtb growth restriction were not due to differences in cytokine production, expression of Toll-like receptors 2 and 4, M1/M2 paradigm or apoptosis. We provide evidence that the enhanced autophagy efficiently restricts Mtb growth in KCs using flow cytometry, western blot, RT-PCR and confocal microscopy. A metabolomic comparison of Mtb-infected macrophages by liquid chromatography mass spectrometry indicated that ornithine (VIP=1.8) and imidazole (VIP=1.6) were two top-scoring metabolites found in Mtb-infected KCs and that acetylcholine was top-scoring in Mtb-infected AMs. Ornithine and imidazole inhibited Mtb growth in AMs by enhancing AMPK mediated autophagy whereas imidazole directly killed Mtb by reducing cytochrome P450 activity. Intranasal delivery of ornithine or imidazole or together restricted Mtb growth in Mtb-infected mouse lungs. Our study demonstrates that the metabolic differences in Mtb-infected AMs and KCs leads to differences in the restriction of Mtb growth.
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Mazahery, Claire, Steven Chirieleison, Supriya Shukla, Sophia Onwuzulike, Mukesh Jain, W. Henry Boom, Derek W. Abbott, and Clifford V. Harding. "Macrophage Krüppel-like factor 4 regulates response to Mycobacterium tuberculosis infection." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 148.22. http://dx.doi.org/10.4049/jimmunol.198.supp.148.22.
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Abstract Krüppel-like factor 4 (KLF4) is a transcription factor that polarizes macrophages towards an anti-inflammatory (M2) phenotype, which suggests that it may regulate immune responses to Mycobacterium tuberculosis (Mtb), as immune evasion by Mtb may be due to an overabundance of anti-inflammatory mediators in response to infection. We hypothesize that myeloid KLF4 is permissive of immune evasion by Mtb, causing decreased control of Mtb infection. There are no prior in vivo data on the role of KLF4 in infection. Using mice with myeloid-specific knockout of KLF4 (LysMCre/CreKLF4fl/fl, abbreviated Mye-KO) we observed decreased Mtb CFU in macrophage cultures in vitro and in lungs of Mye-KO mice early in infection (day 14) relative to wild-type controls. However, these experiments also revealed complexities to the KLF4-Mtb relationship. Despite their improved control of early infection, at later time points Mye-KO mice developed worsened clinical disease features, such as wasting, which suggests that the loss of KLF4 results in pathologic immune state. In addition, we found discrepancy between KLF4 RNA and protein expression during Mtb infection, suggesting that KLF4 is regulated at a posttranslational level during infection. We are designing an in vitro system in which to study the molecular mechanisms of KLF4 regulation and activity in macrophages. Our data indicate that KLF4 plays an important role is regulating immune responses to Mtb with the potential to both diminish host defense mechanisms and repress host-damaging immune mechanisms.
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Mejia, Oscar Rosas, Erin S. Gloag, Jianying Li, Marisa Ruane-Foster, Tiffany A. Claeys, Daniela Farkas, Laszlo Farkas, Gang Xin, and Richard T. Robinson. "Mice infected with Mycobacterium tuberculosis are resistant to secondary infection with SARS-CoV-2." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 58.15. http://dx.doi.org/10.4049/jimmunol.208.supp.58.15.
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Abstract Mycobacterium tuberculosis (Mtb)and SARS-CoV-2 (CoV2) are the leading causes of death due to infectious disease; however, little is known regarding the immunological environment in the Mtb/CoV2 coinfected lung. The goal of this study was to use a mouse model of Mtb/CoV2 coinfection to determine if CoV2 affects Mtb bacterial burden and/or alters the lung immune profile. Using lung collected from human ACE2 transgenic (K18-hACE2) mice infected with both pathogens (Mtb only, SARS-CoV-2 only, and Mtb/SARS-CoV-2 co-infected), we evaluated immune gene expression, cytokine production, and bacterial burden. Surprisingly, these data show that Mtb suppresses CoV2 -related weight loss and lung viral burden in the human ACE2 transgenic mouse model. We also report a reduction in lung interferon gamma production and expression in coinfected mice compared to the Mtb only infected group, suggesting a possible altered T cell profile in the coinfected group. To determine whether Mtb-induced resistance to CoV2 was specific to the ACE2 transgenic model of COVID19, we performed the same set of experiments using a second mouse model of COVID19: Mouse Adapted SARS-CoV-2 (MACoV2) infection of C57BL/6 (B6) mice. In both model systems, Mtb-infected mice were resistant to secondary CoV2 infection and its pathological consequences, and CoV2 infection did not affect Mtb burdens. Single cell RNA sequencing of coinfected and monoinfected lungs demonstrated the resistance of Mtb-infected mice is associated with expansion of T and B cell subsets upon viral challenge. Collectively, these data demonstrate that Mtb infection conditions the lung environment in a manner that is not conducive to CoV2 survival. Supported by OSU Advancing Research in Infection and Immunity Fellowship Award
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Diedrich, Collin R., Tara Rutledge, Pauline Maiello, Tonilynn Baranowski, Alex White, H. Jacob Borish, Paul Karell, et al. "SIV and CD4 depletion distinctly reactivate latent Mycobacterium. tuberculosis infection." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 225.35. http://dx.doi.org/10.4049/jimmunol.204.supp.225.35.
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Abstract Human immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB) regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model, we compared reactivation of latent M. tuberculosis (Mtb) infection induced by simian immunodeficiency virus (SIV) or anti-CD4 antibody (αCD4). Reactivation, as defined by the appearance of a new lung lesion by PET CT, occurred in 5 of 7 αCD4 treated animals compared to 4 of 8 SIV infected animals within 2 months of treatment. αCD4 animals had significantly fewer CD4 T cells within granulomas compared to SIV/Mtb infected animals. However, compared to αCD4 groups, SIV infection caused more dissemination of lung granulomas and higher granuloma bacterial burdens. Within the granulomas, SIV replication was associated with greater Mtb growth and reduced Mtb killing. Granulomas from SIV/Mtb animals displayed a distinctly different profile of T cell cytokine and granzyme B expression compared to αCD4 animals and controls. PET CT imaging prior to treatment could predict reactivation in αCD4-treated animals, but not in SIV/Mtb animals. These data suggest that SIV infection disrupts protective immune responses against Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas.
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Takhelmayum, Umesh, Namjubou Daimai, Kanchana Laishram, Nikhil Juneja, M. L. Yogananda, and Deepa Longjam. "A case of postoperative tubercular spondylitis following microdiscectomy for lumbar disc herniation." Surgical Neurology International 12 (June 7, 2021): 265. http://dx.doi.org/10.25259/sni_469_2021.
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Background: Postoperative infections are one of the most common complications of spine surgery. However, following a lumbar microdiscectomy, a postoperative infection involving Mycobacterium tuberculosis (MTB) is extremely rare. Case Description: One and half months after a L4-5 microdiscectomy, a 47-year-old immunocompromised male with hepatitis B infection presented with low back and bilateral gluteal pain. The MRI revealed a large intraspinal/paraspinal fluid collection spanning from L4 to S1 along with an anterior epidural collection at L5. The patient underwent a L4 lumbar laminectomy for abscess drainage and wound debridement. After obtaining a positive culture for MTB, four antitubercular drug therapies (ATTs) were started, that is, isoniazid (H), rifampicin (R), ethambutol (E), a. One month later, the patient had minimal pain and no residual neurological deficit. Conclusion: MTB infection, although rare, should be considered among the differential diagnoses of postoperative infections following lumbar spine surgery in immunocompromised patients living in areas where tuberculosis is endemic.
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Jung, Yu-Jin, Lynn Ryan, Ronald LaCourse, and Robert J. North. "Properties and protective value of the secondary versus primary T helper type 1 response to airborne Mycobacterium tuberculosis infection in mice." Journal of Experimental Medicine 201, no. 12 (June 13, 2005): 1915–24. http://dx.doi.org/10.1084/jem.20050265.
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Mice immunized against Mycobacterium tuberculosis (Mtb) infection by curing them of a primary lung infection were compared with naive mice in terms of the ability to generate a Th1 cell immune response and to control growth of an airborne Mtb challenge infection. Immunized mice generated and expressed Th1 cell immunity several days sooner than naive mice, as demonstrated by an earlier increase in the synthesis in the lungs of mRNA for Th1 cytokines and for inducible nitric oxide synthase, an indicator of macrophage activation. This Th1 cytokine/mRNA synthesis was accompanied by an earlier accumulation of Mtb-specific Th1 cells in the lungs and the presence of CD4 T cells in lesions. An earlier generation of immunity was associated with an earlier inhibition of Mtb growth when infection was at a 1-log lower level. However, inhibition of Mtb growth in immunized, as well as in naive, mice was not followed by resolution of the infection, but by stabilization of the infection at a stationary level. The results indicate that there is no reason to believe that the secondary response to an Mtb infection is quantitatively or qualitatively superior to the primary response.
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Lysenko, A. P., M. V. Kuchvalski, E. I. Yakobson, E. L. Krasnikova, A. I. Poloz, and N. Y. Anikevich. "NEOPLASTIC DISEASE OF SMALL ANIMALS AND LATENT TUBERCULOSIS INFECTION." Ecology and Animal World, no. 1 (May 30, 2022): 20–32. http://dx.doi.org/10.47612/2224-1647-2022-1-20-32.
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An antigens of tuberculosis mycobacteria (MTB), microgranulomas with acid-fast grains, cell wall deficient (CWD) MTB were found in tumors of small domestic animals. CWD MTB were isolated from tumor in all cases. The isolates did not differ in morphology and antigenic composition, either from each other or from isolates from human tumor cell cultures (Kasumi, Jurkat, Hela), had up to 26 common antigens with typical MTB, were resistant to antibiotics affecting cell wall synthesis. MTB as universal intracellular pathogen with unique filterability and «immortality» can be considered as the most likely etiological agent of oncogenesis based on the hypothesis following: DNA absorption of aging and necrotic normal cells by persistent microorganisms, hybridization of their DNA with host DNA with subsequent expression of the hybrid genome turns normal cells into cancer ones.
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Shafiani, Shahin, Sukhraj Kaur, Imran Siddiqui, Crystal Dinh, and Kevin Urdahl. "Parallel expansion of natural Foxp3+ regulatory T cells and effector CD4+ T cells recognizing the same Mycobacterium tuberculosis epitope (99.4)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 99.4. http://dx.doi.org/10.4049/jimmunol.186.supp.99.4.
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Abstract We have previously shown that regulatory T (T reg) cells restrict immunity during early Mycobacterium tuberculosis (Mtb) infection. Our experiments using T cell receptor (TCR) transgenic T reg cells suggest that T reg cells responding during Mtb infection are pathogen-specific. Nevertheless, the epitopes recognized by T reg cells have not been defined in tuberculosis or other infections. Using MHC class II tetramers containing an immunodominant Mtb epitope (specific for ESAT-64-17:I-Ab), we found that a fraction of Foxp3+ T reg cells in the pulmonary lymph node (pLN) of B6 mice during early Mtb infection were specific for ESAT-64-17, the same epitope recognized by effector CD4+ T cells. These T reg cells peaked in number at day 21 when their abundance ranged between 7-20% of all tetramer-binding cells, and disappeared by day 30-40. Interestingly, they were never observed in the lungs. ESAT-64-17-specific T reg cells expressed the transcription factor Helios, whose expression has been linked to thymically-derived natural T reg cells, suggesting that they expand from the population of pre-existing T reg cells and are not derived from conventional ESAT-64-17-specific CD4+ T cells. Moreover, ESAT-64-17-specific T reg cells use a different profile of T cell receptors than effector CD4+ T cells. We hypothesize that the expansion of pathogen-specific T reg cells may not occur in all infections, but may be driven by Mtb to assist in establishing persistent infection.
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bhatt, kamlesh, Zhugong Liu, W. C. Gause, and P. Salgame. "Nippostrongylus brasiliensis infection modulates Mycobacterium tuberculosis induced Th1 response (43.45)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S45. http://dx.doi.org/10.4049/jimmunol.178.supp.43.45.
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Abstract Modulation of Th1 response generated against pathogens like M tuberculosis (Mtb) by helminths is an important, area of investigation, because of the prevalence of coinfections in TB endemic regions. In this study we have designed an approach to investigate how the Th1 response generated by Mtb is modulated by helminthic infection. We have used the ovalbumin – specific TCR transgenic adoptive transfer system, wherein the ability of Mtb-pulsed dendritic cells to initiate a Th1 response was studied on the background of a helminth infection. BALB/c mice were infected with N. brasiliensis, and groups of uninfected and infected mice were injected with CFSE labeled OVA-specific TCR transgenic T cells followed by intratracheal instillation of Mtb and ovalbumin peptide-pulsed bone marrow-derived dendritic cells. Analysis of the labeled transgenic T cells harvested from the draining lymph nodes indicated proliferation of T cells from both groups of mice. However, we observed significantly reduced level of IFNγ and a reciprocal increase in IL-4 in T cells derived form the helminth-infected mice. These findings indicate that helminth infection does not abrogate the priming ability of Mtb-pulsed DCs, but interferes with their ability to promote a Th1 response. The significance of the findings lies in the potential of helminth infections to modulate resistance to tuberculosis, and also to interfere with the efficacy of tuberculosis vaccines.
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Konstantynovska, Olha, Mariia Rekrotchuk, Ivan Hrek, Anton Rohozhyn, Nataliia Rudova, Petro Poteiko, Anton Gerilovych, Eric Bortz, and Oleksii Solodiankin. "Severe Clinical Outcomes of Tuberculosis in Kharkiv Region, Ukraine, Are Associated with Beijing Strains of Mycobacterium tuberculosis." Pathogens 8, no. 2 (June 10, 2019): 75. http://dx.doi.org/10.3390/pathogens8020075.
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Genotypic variation in Beijing lineages of Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis (TB), has been associated with hyper virulence and the spread of extensively and multiple drug (X/MDR) resistant MTB strains in Eastern Europe, Central Asia, and East Asia. The clinical outcomes of 215 new cases of TB among the population of the Kharkiv region of Eastern Ukraine were analyzed to uncover factors associated with severe infection. Infecting MTB strains were profiled by 5 locus exact tandem repeats (ETRs) and 15 locus mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) genotyping. Among diverse MTB genotypes discovered in Ukraine, the Beijing genotype (MIRU-VNTR 42425) was significantly associated with risk factors for severe outcomes of disease in the study population, including TB/HIV co-infection and treatment failure. Strain replacement (superinfection) was observed in 10 patients, suggesting repeated exposure to novel MTB strains in hospital or community settings. Inclusion of MTB genotyping data may identify at-risk patients and improve treatment adherence to prevent X/MDR development for effective public health response against tuberculosis in Ukraine.