Journal articles: 'Anti-mycobacterial Effectors'

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Driss, Virginie, Fanny Legrand, Emmanuel Hermann, Sylvie Loiseau, Yann Guerardel, Laurent Kremer, Estelle Adam, Gaëtane Woerly, David Dombrowicz, and Monique Capron. "TLR2-dependent eosinophil interactions with mycobacteria: role of α-defensins." Blood 113, no. 14 (April 2, 2009): 3235–44. http://dx.doi.org/10.1182/blood-2008-07-166595.

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AbstractPeripheral blood and tissue eosinophilia are a prominent feature in allergic diseases and during helminth infections. Eosinophil recruitment also frequently occurs upon mycobacterial infections, particularly in lung granuloma. However, the mechanism by which eosinophils interact with mycobacteria remains largely unknown. Because eosinophils recently have been shown to be involved in innate immune responses, we investigated the direct interactions of eosinophils with Mycobacterium bovis BCG as a study model. We show that live BCG attracts human eosinophils and induces reactive oxygen species (ROS) synthesis, granule protein release, and tumor necrosis factor (TNF)–α secretion. Using anti-TLR2 neutralizing antibodies before exposure of eosinophils to BCG, we showed a critical role of TLR2 signaling in ROS and eosinophil peroxidase release. BCG-induced eosinophil activation is mediated through the p38 mitogen-activated protein (MAP) kinase and nuclear factor (NF)–κB pathways. In addition, a mycobacterial wall component, lipomannan, induced a TLR2-dependent eosinophil activation. In addition, we showed that eosinophils express and produce α-defensins upon stimulation with BCG and lipomannan and that α-defensins could inhibit mycobacterial growth in synergy with eosinophil cationic protein. These results suggest a role for human eosinophils as direct effectors in TLR2-mediated innate immunity against mycobacteria and confer to these cells potent cytotoxic functions through defensin and eosinophil cationic protein production.

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Sano, Keisuke, Haruaki Tomioka, Katsumasa Sato, Chiaki Sano, Hideyuki Kawauchi, Shanshan Cai, and Toshiaki Shimizu. "Interaction of Antimycobacterial Drugs with the Anti-Mycobacterium avium Complex Effects of Antimicrobial Effectors, Reactive Oxygen Intermediates, Reactive Nitrogen Intermediates, and Free Fatty Acids Produced by Macrophages." Antimicrobial Agents and Chemotherapy 48, no. 6 (June 2004): 2132–39. http://dx.doi.org/10.1128/aac.48.6.2132-2139.2004.

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ABSTRACT The profiles of the interaction of antimycobacterial drugs with macrophage (MΦ) antimicrobial mechanisms have yet to be elucidated in detail. We examined the effects of various antimycobacterial drugs on the anti-Mycobacterium avium complex (MAC) antimicrobial activity of reactive oxygen intermediates (ROIs), especially of an H2O2-halogen (H2O2-Fe2+-NaI)-mediated bactericidal system, reactive nitrogen intermediates (RNIs), and free fatty acids (FFAs), which are known as central antimicrobial effectors of host MΦs against mycobacterial pathogens. We have found that certain drugs, such as rifampin (RIF), rifabutin (RFB), isoniazid (INH), clofazimine (CLO), and some fluoroquinolones, strongly or moderately reduced the anti-MAC activity of the H2O2-Fe2+-NaI system, primarily by inhibiting the generation of hypohalite ions and in part by interfering with the halogenation reaction of bacterial cell components due to the H2O2-Fe2+-NaI system. This phenomenon is specific to the H2O2-Fe2+-NaI system, since these drugs did not reduce the anti-MAC activity of RNIs and FFAs. From the perspective of the chemotherapy of MAC infections, the present findings indicate an important possibility that certain antimycobacterial drugs, such as rifamycins (RIF and RFB), INH, CLO, and also some types of fluoroquinolones, may interfere with the ROI-mediated antimicrobial mechanisms of host MΦs against intracellular MAC organisms.

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Mattila, Joshua, Olabisi Ojo, Philana Lin, and JoAnne Flynn. "Macrophages and neutrophils in necrotic granulomas from cynomolgus macaques and humans localize to distinct microenvironments and express nitric oxide synthase and arginase enzymes. (117.11)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 117.11. http://dx.doi.org/10.4049/jimmunol.188.supp.117.11.

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Abstract Macrophages are abundant in granulomas, the hallmark lesion of tuberculosis (TB), where they engage in activities critical for mycobacterial control. The assortment of macrophage functions, ranging from being the primary anti-mycobacterial effector cell to the primary mycobacterial host cell, underscores the complexity of macrophages in this system. Despite their importance, the molecular phenotypes and functions of granuloma macrophages in human TB are not well understood. In this study, we examined a variety of macrophage markers in non-human primate and human granulomas to better describe macrophage diversity and spatial organization. We identified three myeloid cell markers, including CD68, CD163, and HAM56, that stained populations of macrophages occupying discrete positions in necrotic granulomas that may be relevant to granuloma function. Neutrophils expressed high levels of calprotectin, a small bacteriostatic protein sometimes associated with macrophages, and also localized to specific positions in necrotic granulomas. In addition to phenotypic markers, we identified cell-specific expression of nitric oxide synthase isoforms (iNOS and eNOS) and arginase isoforms (arg1 and arg2) expression in granulomas by biochemical, molecular and immunohistochemical techniques. Both macrophages and neutrophils were determined to express NOS and arg enzymes, including co-expression, suggesting these enzymes with opposing effects act in concert to maintain mycobacterial control.

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Huang, Shouxiong, Manju Sharma, Shuangmin Zhang, Liang Niu, and Xiang Zhang. "Innate-like activation of mucosal-associated invariant T cells in mycobacterial infection." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 114.12. http://dx.doi.org/10.4049/jimmunol.200.supp.114.12.

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Abstract Unlike conventional T cells, mucosal-associated invariant T (MAIT) T cells respond to microbial riboflavin precursor metabolites presented by major histocompatibility complex (MHC)-like molecule MHC-related protein 1 (MR1). Recently, a high percentage of CD8+ T cells reactive to Mycobacterium tuberculosis in humans were identified as MAIT cells instead of conventional MHC class I-restricted T cells. To understand the activation mechanism and effector functions of MAIT cells in mycobacterial infections, we used mycobacterial-incubated human dendritic cells and MR1-overexpressed cells to stimulate primary and clonal human MAIT cells. As a result, the enzyme-linked immunospot assay showed a quick activation kinetics of MAIT cells within hours of mycobacterial stimulation in an MR1-dependent manner. Flow cytometry analysis demonstrated that mycobacterial-incubated antigen presenting cells quickly stimulated primary human MAIT cells to develop a dominant CD69+CD26+phenotype. Activated MAIT cells displayed an enhanced expression of cytokines TNFa, IFNg, IL-17, and granulysin, demonstrating a potential to induce pro-inflammatory and cytolytic responses. Further transcriptomic analysis of the CD69+CD26+subset revealed an integrated activation pathway from conventional CD8+ T cells and natural killer (NK) cells. Especially, activated MAIT cells showed an enhanced gene expression of mitogen-activated protein kinase (MAPK) signaling molecules, NF-kB, T-bet, RORg, and PLZF transcription factors, and pro-inflammatory cytokines and cytolytic molecules. Taken together, our data support that MAIT cells are quickly activated through an innate-like activation mechanism to induce anti-mycobacterial responses.

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Moni, Esther Del florence Ndedi, Patrick Hervé Diboue Betote, Christelle Wayoue Kom, Chimène Félicite Mekoulou Benga, Armelle Deutou Tchamgoue, and Maximilienne Ascension Nyegue. "Inhibitory effects of hydroethanolic extracts from three Cameroonian medicinal plants on proteins inflammation and growth of multi-resistant strains of Mycobacterium tuberculosis." Journal of Drug Delivery and Therapeutics 11, no. 4-S (August 15, 2021): 15–21. http://dx.doi.org/10.22270/jddt.v11i4-s.4930.

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The present work aimed to determine the phytochemical components and evaluate the in vitro anti-inflammatory and anti-mycobacterial effects of hydroethanolic extracts of Allium sativum L bulbs, Drypetes gossweileri S. MOORE stem-barks and Pentadiplandra brazzeana Baill roots against several resistant strains of Mycobacterium tuberculosis. The phytochemical screenings of extracts were carried out according the colorimetric and precipitation tests to reveal the presence of phytochemical compounds. The anti-inflammatory effects of extracts were evaluated using in vitro Bovine Serum Albumin denaturation and proteinase inhibitory action assays. The inhibitory parameters of hydro-ethanol extracts were evaluated by the microdilution method agaisnt Mycobacterium tuberculosis. The phytochemical screening of hydro-ethanol extracts revealed the presence of phenols, polyphenols, flavonoids, alkaloids, cathechic tannins, triterpens, steroids, anthocyanins and leucoanthocyanins. The anti-inflammatory activity of hydro-ethanol extracts of D. gossweileri, P. brazzeana and A. sativum have shown the inhibitory concentrations 50 (IC50) values ranging from 356.70, 183.30 and 226.30 mg/mL for BSA denaturation and 31.92, 33.62 and 56.93 mg/mL for proteinase inhibitory action respectively. The hydroethanolic extracts of D. gossweileri, P. brazzeana and A. sativum exhibited moderate and weak anti-mycobacterial activities with the minimum inhibitory concentrations (MICs) ranging from 312.5 to 2500 μg/mL. A. sativum hydro-ethanol extract has shown the highest anti-mycobacterial activity with MIC of 312.5 μg/mL against isoniazid resistant of M. tuberculosis and extremely resistant drug strain of M. tuberculosis. These results suggest that hydro-ethanol extracts of A. sativum, D. gossweileri and P. brazzeana are efficient against tuberculosis caused by multi-resistant Mycobacterium tuberculosis strains and are able to resorb the inflammation induced during infection. Keywords: Anti-inflammatory activity, Anti-mycobacterial effect, Hydroethanolic extracts, Medicinal plants, Phytochemical screening.

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Hong, Min-Sun, Eun-Soon Son, Sung-Joong Lee, Sun-Kyoung Lee, Ye-Jin Lee, Sun-Dae Song, Sang-Nae Cho, Clifton E. III Barry, and Seok-Yong Eum. "Anti-mycobacterial Effects of the Extract of Humulus japonicus." Korean Journal of Food Science and Technology 46, no. 1 (February 28, 2014): 94–99. http://dx.doi.org/10.9721/kjfst.2014.46.1.94.

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Kirman, Joanna, Kathy McCoy, Sarah Hook, Melanie Prout, Brett Delahunt, Ian Orme, Anthony Frank, and Graham Le Gros. "CTLA-4 Blockade Enhances the Immune Response Induced by Mycobacterial Infection but Does Not Lead to Increased Protection." Infection and Immunity 67, no. 8 (August 1, 1999): 3786–92. http://dx.doi.org/10.1128/iai.67.8.3786-3792.1999.

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ABSTRACT The murine immune response to a pulmonary mycobacterial infection is slow to develop, allowing bacterial numbers to increase in the lung for several weeks after infection. We sought to enhance the protective immune response induced during Mycobacterium bovis BCG infection by administering an antibody that blocks the interaction of CTLA-4 with its ligands, CD80 and CD86. We found that injection of anti-CTLA-4 monoclonal antibody (MAb) greatly enhanced and accelerated the immune response, as measured by increased cellularity of the draining mediastinal lymph nodes, and enhanced antigen-inducible proliferation and gamma interferon production by mediastinal lymphocytes in vitro. However, despite the apparently enhanced immune response in the mediastinal lymph node following treatment with anti-CTLA-4 MAb, there was no improvement in clearance of mycobacteria in the lungs, liver, or spleen. Examination of the primary site of infection, the lung, revealed that CTLA-4 blockade had no effect on the number or function of lymphocytes infiltrating the infected lung tissue. Taken together, these data suggest that in vivo CTLA-4 blockade enhances mycobacterial-infection-induced lymphocyte expansion and effector cell cytokine production in the draining lymph node but does not alter the number or function of lymphocytes at the primary site of infection and therefore does not lead to enhanced clearance of the infection.

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Spencer, Charles T., Getahun Abate, Azra Blazevic, and Daniel F. Hoft. "Mycobacteria Induce Protective Effector Functions in a Subset of Nonprotective Phosphoantigen-reactive γ9δ2 T cells (43.21)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S40. http://dx.doi.org/10.4049/jimmunol.178.supp.43.21.

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Abstract Human γ9δ2 T cells expand and produce protective cytokine and cytolytic responses during mycobacterial infection. γ9δ2 T cells are also stimulated by nonpeptidic phosphoantigens (i.e-IPP, HMB-PP), expressed by intracellular mycobacteria and infected cells. Therefore, purified phosphoantigens could be useful components of new vaccines or immunotherapeutics by stimulating protective γ9δ2 T cells. However, it is unclear whether γ9δ2 T cells induced by phosphoantigens can protect against mycobacterial replication. We show that while BCG-expanded γ9δ2 T cells potently inhibit intracellular mycobacterial growth, IPP/HMB-PP-expanded γ9δ2 T cells fail to inhibit intracellular mycobacteria, although both lyse Daudi targets. TLR co-stimulation during IPP expansion also failed to induce anti-mycobacterial γ9δ2 T cells. TCR spectratyping and CDR3 sequencing demonstrated that BCG-expanded γ9δ2 T cells expressed significantly less TCR sequence diversity than IPP-expanded γ9δ2 T cells. BCG-expanded γ9δ2 T cells respond similarly to BCG- and IPP-stimulation, while IPP-expanded γ9δ2 T cells responded poorly to BCG. BCG appears to stimulate an antigen-specific focusing event in γ9δ2 T cells while IPP acts like a mitogen with broad γ9δ2 T cell reactivity. The antigens and/or co-stimulatory signals required to induce protective γ9δ2 T cells remain to be identified. Support: NIH R01-AI-48391, VTEU NO1-AI-25464

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Shurygina, A. P. S., N. V. Zabolotnykh, T. I. Vinogradova, K. A. Vasilyev, Zh V. Buzitskaya, and M. A. Stukova. "Lung memory T-cell response in mice following intranasal immunization with influenza vector expressing mycobacterial proteins." Russian Journal of Infection and Immunity 10, no. 3 (August 7, 2020): 506–14. http://dx.doi.org/10.15789/2220-7619-iol-1232.

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Improving specific prevention of tuberculosis continues to be a top priority in phthisiology. “Prime-boost” vaccination schemes aim to maintain adequate levels of specific immunity while forming long-term protection. They are based on sequential use of BCG vaccine and new vaccine candidates expressing protective mycobacterial proteins. The development of new tuberculosis prevention approaches requires an understanding of how the anti-tuberculosis immune response forms and which mechanisms provide TB protection. Since tuberculosis is an airborne infection, vaccine effectiveness largely depends on mucosal immunity based on the formation of long-lived, functionally-active memory T-lymphocytes in the respiratory tract. We have previously shown that the influenza vector expressing ESAT-6 and Ag85A mycobacterial proteins (Flu/ESAT-6_Ag85A) in vaccination scheme of intranasal boost immunization resulted in significant increase of BCG's protective effect according to key indicators aggregate data in experimental tuberculosis infection. The aim of this work was to study the effect of intranasal immunization with the Flu/ESAT-6_Ag85A influenza vector on the formation of antigen-specific central and effector memory T cells and the cytokine-producing activity of effector T cells (TEM) in BCG standard and “BCG prime — influenza vector boost” vaccination schemes in mice. Intranasal immunization with the influenza vector has been shown to increase the proportion of antigen-specific CD4+ central memory T cells (TCM) in the pool of activated lymphocytes of lung and spleen reaching significant differences from the BCG group in the percentage of spleen CD4+ TCM (p < 0.01). In contrast to BCG, vaccination with the studied vaccine candidate was accompanied by accumulation of highly differentiated CD8 effector cells in lung, the target organ during tuberculosis infection. Comparative evaluation of the cell-mediated, post-vaccine immune response after immunization with influenzavector-based vaccine candidate (intranasal/mucosal) or BCG vaccine (subcutaneous) showed advantages in the mucosal group: in formation of functionally active subpopulations of effector CD4 and CD8 T lymphocytes (CD44highCD62Llow) in lungs secreting IL-2 as well as polyfunctional cells capable of coproducing two cytokines (IFNγ/TNFα or IFNγ/IL-2) or three cytokines (IFNγ/TNFα/IL-2). Due to their more pronounced effector function, polyfunctional T-lymphocytes can be considered to be potential immunological markers of protective immunity in tuberculosis.

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Via, L. E., R. A. Fratti, M. McFalone, E. Pagan-Ramos, D. Deretic, and V. Deretic. "Effects of cytokines on mycobacterial phagosome maturation." Journal of Cell Science 111, no. 7 (April 1, 1998): 897–905. http://dx.doi.org/10.1242/jcs.111.7.897.

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One of the major mechanisms permitting intracellular pathogens to parasitize macrophages is their ability to alter maturation of the phagosome or affect its physical integrity. These processes are opposed by the host innate and adaptive immune defenses, and in many instances mononuclear phagocytes can be stimulated with appropriate cytokines to restrict the growth of the microorganisms within the phagosomal compartment. Very little is known about the effects that cytokines have on phagosome maturation. Here we have used green fluorescent protein (GFP)-labeled mycobacteria and a fixable acidotropic probe, LysoTracker Red DND-99, to monitor maturation of the mycobacterial phagosome. The macrophage compartments that stained with the LysoTracker probe were examined first. This dye was found to colocalize preferentially with the late endosomal and lysosomal markers rab7 and Lamp1, and with a fluid phase marker chased into the late endosomal compartments. In contrast, LysoTracker showed only a minor overlap with the early endosomal marker rab5. Pathogenic mycobacteria are believed to reside in nonacidified vacuoles sequestered away from late endosomal compartments as a part of their intracellular survival strategy. We examined the status of mycobacterial phagosomes in macrophages from IL-10 knockout mice, in quiescent cells, and in mononuclear phagocytes stimulated with the macrophage-activating cytokine IFN-(gamma). When macrophages were derived from the bone marrow of transgenic IL-10 mice lacking this major deactivating cytokine, colocalization of GFP-fluorescing mycobacteria with the LysoTracker staining appeared enhanced, suggestive of increased acidification of the mycobacterial phagosome relative to macrophages from normal mice. When bone marrow-derived macrophages from normal mice or a J774 murine macrophage cell line were stimulated with IFN-(gamma) and LPS, this resulted in increased colocalization of mycobacteria and LysoTracker, but no statistically significant enhancement was observed in IL-10 transgenic animals. These studies are consistent with the interpretation that proinflammatory and anti-inflammatory cytokines affect maturation of mycobacterial phagosomes. Although multiple mechanisms are likely to be at work, we propose the existence of a direct link between cytokine effects on the host cell and phagosome maturation in the macrophage.

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Mejia, Oscar Rosas, Amanda Williams, and Richard Robinson. "IL12RB1 allelic expression imbalance in polarized human TH cells." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 76.16. http://dx.doi.org/10.4049/jimmunol.204.supp.76.16.

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Abstract Allelic Expression Imbalance (AEI) occurs when two alleles of a given gene are expressed at different levels, either due to epigenetic inactivation and/or genetic variation in regulatory regions. Human autosomal genes are widely presumed to be equally expressed from both alleles (biallelic expression); this is not always the case, however, as AEI affects expression of odorant receptor and adhesin genes in neurons, as well as immunoglobulin (Ig) and T-cell receptor (TCR) genes in lymphocytes. Ig and TCR gene AEI is an important regulator of immune development and disease resistance; therefore, it is reasonable to believe AEI of other immune receptors may similarly impact immune development and disease resistance. Here we demonstrate that the human cytokine receptor gene Interleukin 12 Receptor Beta 1 (IL12RB1) exhibits AEI in differentiated T cells, as measured by a significant deviation of the allelic mRNA expression ratios from that of the allelic gDNA ratios. Specifically, naïve human CD4+ T cells were purified from healthy adult donors and incubated with polarizing cytokines to drive their differentiation into specific T helper subsets (e.g. TH0 cocktail: IL-2. TH1 cocktail: IL-2, anti-IL-4, IL-12. TH17 cocktail: IL-2, IL-1b, TGF-b1, IL-23, anti-IFNg, anti-IL-4). The extent of IL12RB1 AEI was then quantified and related to T cell expression of IFNg (TH1) and IL17 (TH17). Collectively, our data suggest that IL12RB1 AEI associates with the expression of anti-mycobacterial effector genes in T cells. Future experiments will determine the epigenetic or molecular mechanism behind IL12RB1 AEI.

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Lane, Daniel Scot, Priyanka Talukdar, Beth Fallert Junecko, and Joshua T. Mattila. "Inhibiting glycolysis by targeting the enzyme PFKFB3 restricts macrophage anti-mycobacterial activity and neutrophil phagocytosis of Mycobacterium tuberculosis." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 110.03. http://dx.doi.org/10.4049/jimmunol.208.supp.110.03.

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Abstract Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB), a leading cause of infectious disease-related mortality around the world. Myeloid cells are important in TB as Mtb host cells and anti-Mtb effector cells but the factors that differentiate these roles are not clearly defined. Immunometabolism is a driver of immune function and may be an important determinant of this interaction and represents a potential target for host-directed therapies against TB. To better understand how immunometabolism relates to TB, we incubated macrophages and neutrophils from Mtb-infected macaques with a panel of metabolic inhibitors and measured how this affected cellular responses to Mtb infection. Specifically, we targeted glycolysis, oxidative phosphorylation, and fatty acid oxidation and measured how this affected macrophage and neutrophil phagocytosis, macrophage control over Mtb viability and replication, and neutrophil production of extracellular traps. We found that targeting glycolysis by inhibiting PFKFB3, a rate-limiting enzyme in glycolysis, reduced macrophage anti-Mtb activity and neutrophil phagocytosis, while inhibition with the glucose analog 2-DG did not. In contrast, incubating cell-free mycobacteria with PFKFB3 inhibitors severely inhibited their growth, suggesting that these bacteria use different metabolic pathways in cells and culture to survive. Inhibiting oxidative phosphorylation with metformin or fatty acid oxidation with etomoxir did not change how macrophages or neutrophils responded to Mtb or affect mycobacterial growth in culture. These results indicate a role for immunometabolism in myeloid responses to Mtb and may inform efforts for development of metabolism-targeted therapies for TB. Supported by grants from NIH (R01AI134183)

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Adekambi, Toidi, Chris Ibegbu, Stephanie Cagle, Susan Ray, and Jyothi Rengarajan. "High frequencies of Caspase-3-expressing M. tuberculosis-specific CD4 T cells are associated with active tuberculosis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 54.8. http://dx.doi.org/10.4049/jimmunol.196.supp.54.8.

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Abstract Background The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluations and detection of Mycobacterium tuberculosis (Mtb) in the patients’ sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes 3–6 weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that frequencies of Mtb-specific CD4+IFN-g+ T cells expressing caspase-3 would decrease following anti-TB treatment. Caspase-3, a member of cysteine proteases’ family, is highly expressed in CD4 effector T cells and has been shown to regulate T cell activation, cell cycle entry, proliferation and apoptosis. Methods Using polychromatic flow cytometry, we evaluated the expression of the active form of caspase-3 on Mtb-specific CD4+ T cells from individuals with asymptomatic latent Mtb infection (LTBI) (n=22), ATB (n=18), and from ATB patients undergoing anti-TB treatment (n=7). Results Frequencies of Mtb-specific IFN-g+CD4+ T cells that expressed active caspase-3 were higher in individuals with ATB compared to those with LTBI suggesting that apoptotic pathways are operant during pulmonary ATB. This marker also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment. Conclusion We have identified caspase-3 on Mtb-specific CD4+ T cells as a marker that distinguishes ATB and LTBI and may provide a tool for monitoring treatment response and cure.

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Saxena, Amit. "Synthesis, antibacterial, antifungal and anti-mycobacterial effects of 5-substituted oxindole-3-amino-2-phenyl quinazoline." Advances in Biomedicine and Pharmacy 03, no. 02 (April 1, 2016): 94–100. http://dx.doi.org/10.19046/abp.v03i02.03.

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Hawthorne, G., H. Mujakperuo, S. Lax, L. McGowan, H. Kunst, D. Thickett, and A. Turner. "S4 Anti-Inflammatory Effects of Vitamin D Are Influenced More by Genetic Background Than Mycobacterial Infection." Thorax 67, Suppl 2 (November 19, 2012): A5.1—A5. http://dx.doi.org/10.1136/thoraxjnl-2012-202678.010.

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Endsley, Janice J., Alison Hogg, Lis J. Shell, Martin McAulay, Tracey Coffey, Chris Howard, Charles F. Capinos Scherer, et al. "Mycobacterium bovis BCG vaccination induces memory CD4+ T cells characterized by effector biomarker expression and anti-mycobacterial activity." Vaccine 25, no. 50 (December 2007): 8384–94. http://dx.doi.org/10.1016/j.vaccine.2007.10.011.

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Qasem, Ahmad, Abed Elrahman Naser, and Saleh A. Naser. "The alternate effects of anti-TNFα therapeutics and their role in mycobacterial granulomatous infection in Crohn’s disease." Expert Review of Anti-infective Therapy 15, no. 7 (May 17, 2017): 637–43. http://dx.doi.org/10.1080/14787210.2017.1328276.

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Edholm, Eva-Stina, Jules Park, and Jacques Robert. "Two different nonclassical MHC class I-restricted invariant T cell lineages with non-overlapping antiviral and anti-mycobacterial immune functions in the amphibian Xenopus." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 200.16. http://dx.doi.org/10.4049/jimmunol.196.supp.200.16.

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Abstract Unconventional T cells, including disparate populations of MHC class Ib-reactive innate T (iT) cells are emerging as key factors in the immune system partly due to their public antigen specificities and rapid effector responses. The biological relevance and evolutionary conservation of iT cells have, over the past few years, been strengthened by studies in the amphibian Xenopus, which have revealed an overrepresentation of several invariant TCRs in tadpoles and identified a prominent subset of iT cells (invariant Vα6 [iVα6]) restricted by the nonclassical MHC class Ib molecule XNC10. Recently, we showed that similar to CD1d restricted iNKT cells in humans and mice Xenopus iVα6 T cells are critical for early antiviral immunity. Here, using RNAi loss-of-function by transgenesis targeting another Xenopus nonclassical gene, XNC4, we have identified a different XNC4-dependent iT cell population expressing one of the 6 previously identified overrepresented TCRα rearrangements (TRAV45 joined to TRAJ1.14). We show that this invariant Vα45 [iVα45] T cell population is critical for antibacterial immunity against Mycobacterium marinum. These data suggest that functionally distinct populations of MHC class Ib-reactive iT cell populations play a prominent role in amphibian immune defense and as such may represent a more primordial immune cell type that previously thought.

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Javed, Sadia, and Zainab Akmal. "Hepatic Adverse Effects of Anti-Mycobacterium Tuberculosis Drugs and Their Associations with Various Genetic Variants." Precision Medicine Communications 2, no. 01 (June 30, 2022): 59–78. http://dx.doi.org/10.55627/pmc.002.001.0053.

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Tuberculosis is a significant healthcare burden, especially in the developing world. Current first-line therapies for tuberculosis treatment (isoniazid, pyrazinamide, rifampicin, and ethambutol) have significant efficacy but they all have the potential to cause hepatotoxicity. Effects produced by these drugs may be asymptomatic with increased levels of aminotransferases in some patients or the development of severe hepatotoxicity in others. On the other hand, it can also lead to hepatic failure in some patients. In this review, we evaluated the studies on genetic variants showing associations with drug-induced hepatic injury in tuberculosis patients. Several studies on important genes such as NAT2, AADAC, CYP2E1, HLA, CYP7A1, ALDH1A1, NFkB, PXR, HMOX1, SLCO1B1, UGT1A1, NRF2, and MAFF were reviewed and discussed for utilizing them as predictors of hepatic injury in tuberculosis patients. Recommendations are made on the potential of some of these genetic variants as a screening tool for determining patients most likely to experience hepatic adverse effects after receiving standard first-line anti-mycobacterial tuberculosis treatment.

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Zorzella-Pezavento, Sofia Fernanda Gonçalves, Clara Pires Fujiara Guerino, Fernanda Chiuso-Minicucci, Thais Graziela Donegá França, Larissa Lumi Watanabe Ishikawa, Ana Paula Masson, Célio Lopes Silva, and Alexandrina Sartori. "BCG and BCG/DNAhsp65 Vaccinations Promote Protective Effects without Deleterious Consequences for Experimental Autoimmune Encephalomyelitis." Clinical and Developmental Immunology 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/721383.

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A prime-boost strategy conserving BCG is considered the most promising vaccine to control tuberculosis. A boost with a DNA vaccine containing the mycobacterial gene of a heat shock protein (pVAXhsp65) after BCG priming protected mice against experimental tuberculosis. However, anti-hsp65 immunity could worsen an autoimmune disease due to molecular mimicry. In this investigation, we evaluated the effect of a previous BCG or BCG/pVAXhsp65 immunization on experimental autoimmune encephalomyelitis (EAE) development. Female Lewis rats were immunized with BCG or BCG followed by pVAXhsp65 boosters. The animals underwent EAE induction and were daily evaluated for weight loss and clinical score. They were euthanized during recovery phase to assess immune response and inflammatory infiltration at the central nervous system. Previous immunization did not aggravate or accelerate clinical score or weight loss. In addition, this procedure clearly decreased inflammation in the brain. BCG immunization modulated the host immune response by triggering a significant reduction in IL-10 and IFN-γlevels induced by myelin basic protein. These data indicated that vaccination protocols with BCG or BCG followed by boosters with pVAXhsp65 did not trigger a deleterious effect on EAE evolution.

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Lang, F., M. A. Peyrat, P. Constant, F. Davodeau, J. David-Ameline, Y. Poquet, H. Vié, J. J. Fournié, and M. Bonneville. "Early activation of human V gamma 9V delta 2 T cell broad cytotoxicity and TNF production by nonpeptidic mycobacterial ligands." Journal of Immunology 154, no. 11 (June 1, 1995): 5986–94. http://dx.doi.org/10.4049/jimmunol.154.11.5986.

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Abstract Human V gamma 9V delta 2 T cells were shown recently to respond to nonpeptidic phosphorylated molecules of mycobacterial origin (previously referred to as TUBag). To investigate the early events of V gamma 9V delta 2 T cell activation, we have analyzed induction of cytotoxicity and TNF production of T cell clones by these molecules. We showed that within minutes after exposure, TUBag induced cytotoxicity of V gamma 9V delta 2 CTL (but not of CTL expressing other TCR V gamma/V delta or V alpha/V beta regions) against a broad set of target cells, including effector cells themselves. Induction of V gamma 9V delta 2 cytotoxicity by TUBag was blocked by anti-TCR mAbs and was abrogated after dephosphorylation of TUBag. Similarly, TUBag, but not dephosphorylated TUBag, induced massive TNF production by V gamma 9V delta 2 T cell clones only, which already was significant 20 min after exposure. Of note, only basal amounts of TNF were produced when cells were maintained in suspension in the presence of TUBag, indicating that efficient activation of TNF production induced by these compounds required a cell-to-cell contact. Finally, preincubation experiments allowed us to demonstrate that activation of V gamma 9V delta 2 T cells was strictly dependent on the presence of TUBag because preincubation of the targets with TUBag followed by a single wash abrogated the activation. Taken together, these results strongly suggest that activation of V gamma 9V delta 2 cells by TUBag occurs after binding of these compounds to (a) yet unidentified, highly conserved, and broadly distributed molecule(s). The results also suggest either that TUBag induces a very rapid and transient expression of a V gamma 9V delta 2 TCR ligand or, more likely, that TUBag is a low affinity component of a complex recognized by the V gamma 9V delta 2 TCR.

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Herbath, Melinda, Sarah Marcus, Zsuzsanna Fabry, and Matyas Sandor. "Renewal rates of CD4 and CD11b cells in mycobacterial granulomas." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.40. http://dx.doi.org/10.4049/jimmunol.202.supp.190.40.

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Abstract Granulomas are the central feature of mycobacterial infections. The majority of granuloma cells are monocytes/macrophages but T cells also play an important role in regulating these lesions. The effector cells in the granuloma have a relatively short life time. Therefore, they must be continuously replaced from the blood. However, the rate of monocyte and T cell recruitment into Mtb-induced lung granulomas is not known and the focus of our work is to measure this rate using intravascular staining. C57Bl/6 mice were infected via the aerosol route with 200 CFU Mtb H37Rv, expressing tdTomato. Four weeks post infection, the mice were IV injected with anti-CD45 antibody conjugated with BV421, A488 and A647, 24 hours, 4 hours and 3 minutes prior to harvest, respectively. Lung sections were labelled for CD4 and CD11b to test granuloma homing of the stained cells from the blood. A significant fraction of granuloma cells was labelled indicating an access of blood cells to these lesions and a fast turnover of monocytes and CD4 T cells in the granuloma. The cellular turnover differs between different regions, with a higher replacement rate for CD4+ cells (23% in 24 h, from which 16% occurred in the last 4 h) and a slower renewal for CD11b+ cells (19% in 24 h). The rapid cell renewal we observed suggests a therapeutic potential for cell migration blockers in the reduction of Mtb-induced granulomatous pathology. We examine the effect of VEGFR1 and CCR2 blocker treatments on short-term changes in cellular composition and cell distribution in Mtb-induced lung granulomas to demonstrate that this technology offers an approach to study the mechanism of cellular replacement in granulomatous lesions.

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Palacios, Jacqueline Barrios, Jorge Barrios-Payán, Dulce Mata-Espinosa, Jacqueline V. Lara-Espinosa, Juan Carlos León-Contreras, Gerald H. Lushington, Tonatiuh Melgarejo, and Rogelio Hernández-Pando. "In Vitro, In Vivo and In Silico Assessment of the Antimicrobial and Immunomodulatory Effects of a Water Buffalo Cathelicidin (WBCATH) in Experimental Pulmonary Tuberculosis." Antibiotics 12, no. 1 (December 31, 2022): 75. http://dx.doi.org/10.3390/antibiotics12010075.

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Tuberculosis (TB) is considered the oldest pandemic in human history. The emergence of multidrug-resistant (MDR) strains is currently considered a serious global health problem. As components of the innate immune response, antimicrobial peptides (AMPs) such as cathelicidins have been proposed to have efficacious antimicrobial activity against Mycobacterium tuberculosis (Mtb). In this work, we assessed a cathelicidin from water buffalo, Bubalus bubalis, (WBCATH), determining in vitro its antitubercular activity (MIC), cytotoxicity and the peptide effect on bacillary loads and cytokines production in infected alveolar macrophages. Our results showed that WBCATH has microbicidal activity against drug-sensitive and MDR Mtb, induces structural mycobacterial damage demonstrated by electron microscopy, improves Mtb killing and induces the production of protective cytokines by murine macrophages. Furthermore, in vivo WBCATH showed decreased bacterial loads in a model of progressive pulmonary TB in BALB/c mice infected with drug-sensitive or MDR mycobacteria. In addition, a synergistic therapeutic effect was observed when first-line antibiotics were administered with WBCATH. These results were supported by computational modeling of the potential effects of WBCATH on the cellular membrane of Mtb. Thus, this water buffalo-derived cathelicidin could be a promising adjuvant therapy for current anti-TB drugs by enhancing a protective immune response and potentially reducing antibiotic treatment duration.

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Denis, M. "Tat protein from HIV-1 binds to Mycobacterium avium via a bacterial integrin. Effects on extracellular and intracellular growth." Journal of Immunology 153, no. 5 (September 1, 1994): 2072–81. http://dx.doi.org/10.4049/jimmunol.153.5.2072.

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Abstract We examined the interaction between HIV-1 Tat protein and the opportunistic pathogen Mycobacterium avium. AIDS-associated strains of M. avium were shown to bind Tat protein quite avidly in an attachment assay. The attachment of M. avium to Tat was shown to occur via the integrin alpha 5 beta 1 present on the mycobacterial cell surface. M. avium strains were shown to bind the viral Tat protein with high affinity in a specific fashion (600 binding sites with a Kd of 1 to 5 nM). M. avium coated with Tat protein were shown to be more infective for human alveolar macrophages than untreated M. avium. Other HIV-1 Ags had no such effects (e.g., p24, p17). Examination of the cytokine profile of infected macrophages showed that M. avium-Tat complexes induced higher levels of TGF beta-1 (TGF beta 1) than M. avium alone or M. avium that had been in contact with other viral proteins. Conditioned media from HIV-1-infected H9 cells released a factor that enhanced M. avium intramacrophage growth, and was partially neutralized by an anti-Tat Ab. Finally, Tat protein (purified or present in conditioned media from infected cells) moderately enhanced the growth of M. avium strains in extracellular media, and exposure of M. avium to Tat protein in the presence of IL-6 enhanced the growth of AIDS-associated strains. These data argue for an interaction between the Tat viral product and the opportunistic pathogen M. avium which may contribute to the exquisite susceptibility of AIDS subjects to this pathogen.

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Yankai, Zhang, Yan Rong, He Yi, Liu Wentao, Cao Rongyue, Yan Ming, Li Taiming, Liu Jingjing, and Wu Jie. "Ten tandem repeats of β-hCG 109–118 enhance immunogenicity and anti-tumor effects of β-hCG C-terminal peptide carried by mycobacterial heat-shock protein HSP65." Biochemical and Biophysical Research Communications 345, no. 4 (July 2006): 1365–71. http://dx.doi.org/10.1016/j.bbrc.2006.05.022.

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Gramegna, Andrea, Andrea Lombardi, Nicola I. Lorè, Francesco Amati, Ivan Barone, Cecilia Azzarà, Daniela Cirillo, Stefano Aliberti, Andrea Gori, and Francesco Blasi. "Innate and Adaptive Lymphocytes in Non-Tuberculous Mycobacteria Lung Disease: A Review." Frontiers in Immunology 13 (June 28, 2022). http://dx.doi.org/10.3389/fimmu.2022.927049.

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Non-tuberculous mycobacteria (NTM) are ubiquitous environmental microorganisms capable of a wide range of infections that primarily involve the lymphatic system and the lower respiratory tract. In recent years, cases of lung infection sustained by NTM have been steadily increasing, due mainly to the ageing of the population with underlying lung disease, the enlargement of the cohort of patients undergoing immunosuppressive medications and the improvement in microbiologic diagnostic techniques. However, only a small proportion of individuals at risk ultimately develop the disease due to reasons that are not fully understood. A better understanding of the pathophysiology of NTM pulmonary disease is the key to the development of better diagnostic tools and therapeutic targets for anti-mycobacterial therapy. In this review, we cover the various types of interactions between NTM and lymphoid effectors of innate and adaptive immunity. We also give a brief look into the mechanism of immune exhaustion, a phenomenon of immune dysfunction originally reported for chronic viral infections and cancer, but recently also observed in the setting of mycobacterial diseases. We try to set the scene to postulate that a better knowledge of immune exhaustion can play a crucial role in establishing prognostic/predictive factors and enabling a broader investigation of immune-modulatory drugs in the experimental treatment of NTM pulmonary disease.

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Sharma, Manju, Liang Niu, Xiang Zhang, and Shouxiong Huang. "Comparative transcriptomes reveal pro-survival and cytotoxic programs of mucosal-associated invariant T cells upon Bacillus Calmette–Guérin stimulation." Frontiers in Cellular and Infection Microbiology 13 (April 6, 2023). http://dx.doi.org/10.3389/fcimb.2023.1134119.

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Mucosal-associated invariant T (MAIT) cells are protective against tuberculous and non-tuberculous mycobacterial infections with poorly understood mechanisms. Despite an innate-like nature, MAIT cell responses remain heterogeneous in bacterial infections. To comprehensively characterize MAIT activation programs responding to different bacteria, we stimulated MAIT cells with E. coli to compare with Bacillus Calmette-Guérin (BCG), which remains the only licensed vaccine and a feasible tool for investigating anti-mycobacterial immunity in humans. Upon sequencing mRNA from the activated and inactivated CD8+ MAIT cells, results demonstrated the altered MAIT cell gene profiles by each bacterium with upregulated expression of activation markers, transcription factors, cytokines, and cytolytic mediators crucial in anti-mycobacterial responses. Compared with E. coli, BCG altered more MAIT cell genes to enhance cell survival and cytolysis. Flow cytometry analyses similarly displayed a more upregulated protein expression of B-cell lymphoma 2 and T-box transcription factor Eomesodermin in BCG compared to E.coli stimulations. Thus, the transcriptomic program and protein expression of MAIT cells together displayed enhanced pro-survival and cytotoxic programs in response to BCG stimulation, supporting BCG induces cell-mediated effector responses of MAIT cells to fight mycobacterial infections.

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Pandya, Keyur M., Janki Patel, Arpan H. Patel, Navin B. Patel, and P. S. Desai. "Substituted Imidazole-pyrazole clubbed scaffolds: Microwave assisted Synthesis and Examined their In-vitro Antimicrobial and Antituberculosis Effects." Letters in Organic Chemistry 17 (August 19, 2020). http://dx.doi.org/10.2174/1570178617999200819164729.

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A series of substituted imidazole-pyrazole fused compounds were designed & fused synthesized by employing Debus-Radziszewski one-pot synthesis reaction. Azoles are an extensive and comparatively new class of synthetic com-pounds including imidazoles and pyrazoles.The current clinical treatment uses compounds of azole framework. Azoles act by inhibiting ergosterol synthesis path way (a principal component of the fungal cell wall). In addition, a literature review shows that the compounds that include imidazoles and pyrazoles have significant anti-bacterial and anti-mycobacterial ef-fects. In light of the above findings, a series of compounds with imidazole and pyrazole scaffolds were sketched and devel-oped to examine anti-bacterial, antifungal and anti-mycobacterial activity. The structures of the synthesized compounds were characterized using 1HNMR, 13CNMR, elemental analysis, and MS spectral data. The target compounds were screened for their in-vitro antimicrobial activity against gram-positive and gram-negative bacterial species by disc diffusion method according to the NCCLS (National Committee for Clinical Laboratory Standards) and anti-mycobacterial activity against the Mycobacterium tuberculosis H37Rv strain.The results revealed that imidazole-pyrazole fused scaffold compounds have po-tential anti-bacterial, antifungal and anti-mycobacterial activity which can be further optimized to get a lead compound.

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Ahmad, Faraz, Mohd Saad Umar, Nazoora Khan, Fauzia Jamal, Pushpa Gupta, Swaleha Zubair, Umesh Datta Gupta, and Mohammad Owais. "Immunotherapy With 5, 15-DPP Mediates Macrophage M1 Polarization and Modulates Subsequent Mycobacterium tuberculosis Infectivity in rBCG30 Immunized Mice." Frontiers in Immunology 12 (October 29, 2021). http://dx.doi.org/10.3389/fimmu.2021.706727.

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Tuberculosis (TB) is a significant and continuing problem worldwide, with a death toll of around 1.5 million human lives annually. BCG, the only vaccine against TB, offers a varied degree of protection among human subjects in different regions and races of the world. The majority of the population living near the tropics carries a varying degree of tolerance against BCG due to the widespread prevalence of non-tuberculous mycobacteria (NTM). Interestingly, ≈90% of the Mycobacterium tuberculosis (Mtb) infected population restrain the bacilli on its own, which strengthens the notion of empowering the host immune system to advance the protective efficacy of existing mycobacterial vaccines. In general, Mtb modulates IL-10/STAT3 signaling to skew host mononuclear phagocytes toward an alternatively activated, anti-inflammatory state that helps it thrive against hostile immune advances. We hypothesized that modulating the IL-10/STAT3 driven anti-inflammatory effects in mononuclear cells may improve the prophylactic ability of TB vaccines. This study investigated the immunotherapeutic ability of a porphyrin based small molecule inhibitor of IL-10/STAT3 axis, 5, 15-diphenyl porphyrin (DPP), in improving anti-TB immunity offered by second generation recombinant BCG30 (rBCG30-ARMF-II®) vaccine in mice. The DPP therapy potentiated vaccine induced anti-TB immunity by down-modulating anti-inflammatory responses, while simultaneously up-regulating pro-inflammatory immune effector responses in the immunized host. The employed DPP based immunotherapy led to the predominant activation/proliferation of pro-inflammatory monocytes/macrophages/DCs, the concerted expansion of CD4+/CD8+ effector and central memory T cells, alongside balanced Th17 and Treg cell amplification, and conferred augmented resistance to aerosol Mtb challenge in rBCG30 immunized BALB/c mice.

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Bilham, Kirstin, Amy C. Boyd, Stephen G. Preston, Christina D. Buesching, Chris Newman, David W. Macdonald, and Adrian L. Smith. "Badger macrophages fail to produce nitric oxide, a key anti-mycobacterial effector molecule." Scientific Reports 7, no. 1 (April 6, 2017). http://dx.doi.org/10.1038/srep45470.

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Adankwah, Ernest, Jean Harelimana, Difery Minadzi, Wilfred Aniagyei, Mohammed K. Abass, Linda Batsa Debrah, Dorcas Owusu, Ertan Mayatepek, Richard O. Phillips, and Marc Jacobsen. "Lower Monocyte Interleukin-7 Receptor Expression Impairs Anti-Mycobacterial Effector Functions in Tuberculosis Patients." SSRN Electronic Journal, 2020. http://dx.doi.org/10.2139/ssrn.3710619.

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Ku, Min Wen, Pierre Authié, Fabien Nevo, Philippe Souque, Maryline Bourgine, Marta Romano, Pierre Charneau, and Laleh Majlessi. "Lentiviral vector induces high-quality memory T cells via dendritic cells transduction." Communications Biology 4, no. 1 (June 10, 2021). http://dx.doi.org/10.1038/s42003-021-02251-6.

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AbstractWe report a lentiviral vector harboring the human β2-microglobulin promoter, with predominant expression in immune cells and minimal proximal enhancers to improve vector safety. This lentiviral vector efficiently transduces major dendritic cell subsets in vivo. With a mycobacterial immunogen, we observed distinct functional signatures and memory phenotype in lentiviral vector- or Adenovirus type 5 (Ad5)-immunized mice, despite comparable antigen-specific CD8+ T cell magnitudes. Compared to Ad5, lentiviral vector immunization resulted in higher multifunctional and IL-2-producing CD8+ T cells. Furthermore, lentiviral vector immunization primed CD8+ T cells towards central memory phenotype, while Ad5 immunization favored effector memory phenotype. Studies using HIV antigens in outbred rats demonstrated additional clear-cut evidence for an immunogenic advantage of lentiviral vector over Ad5. Additionally, lentiviral vector provided enhance therapeutic anti-tumor protection than Ad5. In conclusion, coupling lentiviral vector with β2-microglobulin promoter represents a promising approach to produce long-lasting, high-quality cellular immunity for vaccinal purposes.

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Park, Hyun-Eui, Wonsik Lee, Min-Kyoung Shin, and Sung Jae Shin. "Understanding the Reciprocal Interplay Between Antibiotics and Host Immune System: How Can We Improve the Anti-Mycobacterial Activity of Current Drugs to Better Control Tuberculosis?" Frontiers in Immunology 12 (June 28, 2021). http://dx.doi.org/10.3389/fimmu.2021.703060.

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, remains a global health threat despite recent advances and insights into host-pathogen interactions and the identification of diverse pathways that may be novel therapeutic targets for TB treatment. In addition, the emergence and spread of multidrug-resistant Mtb strains led to a low success rate of TB treatments. Thus, novel strategies involving the host immune system that boost the effectiveness of existing antibiotics have been recently suggested to better control TB. However, the lack of comprehensive understanding of the immunomodulatory effects of anti-TB drugs, including first-line drugs and newly introduced antibiotics, on bystander and effector immune cells curtailed the development of effective therapeutic strategies to combat Mtb infection. In this review, we focus on the influence of host immune-mediated stresses, such as lysosomal activation, metabolic changes, oxidative stress, mitochondrial damage, and immune mediators, on the activities of anti-TB drugs. In addition, we discuss how anti-TB drugs facilitate the generation of Mtb populations that are resistant to host immune response or disrupt host immunity. Thus, further understanding the interplay between anti-TB drugs and host immune responses may enhance effective host antimicrobial activities and prevent Mtb tolerance to antibiotic and immune attacks. Finally, this review highlights novel adjunctive therapeutic approaches against Mtb infection for better disease outcomes, shorter treatment duration, and improved treatment efficacy based on reciprocal interactions between current TB antibiotics and host immune cells.

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Vivekanandan, Monika M., Ernest Adankwah, Wilfred Aniagyei, Isaac Acheampong, Difery Minadzi, Augustine Yeboah, Joseph F. Arthur, et al. "Impaired T-cell response to phytohemagglutinin (PHA) in tuberculosis patients is associated with high IL-6 plasma levels and normalizes early during anti-mycobacterial treatment." Infection, January 18, 2023. http://dx.doi.org/10.1007/s15010-023-01977-1.

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Abstract Purpose Human tuberculosis is characterized by immunopathology that affects T-cell phenotype and functions. Previous studies found impaired T-cell response to phytohemagglutinin (PHA) in patients with acute tuberculosis. However, the influence of disease severity, affected T-cell subsets, and underlying mechanisms remain elusive. Methods Here we investigated PHA-induced and antigen-specific T-cell effector cytokines in tuberculosis patients (n = 55) as well as in healthy asymptomatic contacts (n = 32) from Ghana. Effects of Mycobacterium (M.) tuberculosis sputum burden and treatment response were analyzed and compared during follow-up. Finally, cytokine characteristics of the aberrant plasma milieu in tuberculosis were analyzed as a potential cause for impaired PHA response. Results PHA-induced IFN-γ expression was significantly lower in sputum-positive tuberculosis patients as compared to both, contacts and paucibacillary cases, and efficiently discriminated the study groups. T-cell responses to PHA increased significantly early during treatment and this was more pronounced in tuberculosis patients with rapid treatment response. Analysis of alternative cytokines revealed distinct patterns and IL-22, as well as IL-10, showed comparable expression to IFN-γ in response to PHA. Finally, we found that high IL-6 plasma levels were strongly associated with impaired IFN-γ and IL-22 response to PHA. Conclusion We conclude that impaired T-cell response to PHA stimulation in acute tuberculosis patients (i) was potentially caused by the aberrant plasma milieu, (ii) affected differentially polarized T-cell subsets, (iii) normalized early during treatment. This study shed light on the mechanisms of impaired T-cell functions in tuberculosis and yielded promising biomarker candidates for diagnosis and monitoring of treatment response.

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Dalhoff, Axel. "Are antibacterial effects of non-antibiotic drugs random or purposeful because of a common evolutionary origin of bacterial and mammalian targets?" Infection, December 15, 2020. http://dx.doi.org/10.1007/s15010-020-01547-9.

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Abstract Purpose Advances in structural biology, genetics, bioinformatics, etc. resulted in the availability of an enormous pool of information enabling the analysis of the ancestry of pro- and eukaryotic genes and proteins. Methods This review summarizes findings of structural and/or functional homologies of pro- and eukaryotic enzymes catalysing analogous biological reactions because of their highly conserved active centres so that non-antibiotics interacted with bacterial targets. Results Protease inhibitors such as staurosporine or camostat inhibited bacterial serine/threonine or serine/tyrosine protein kinases, serine/threonine phosphatases, and serine/threonine kinases, to which penicillin-binding-proteins are linked, so that these drugs synergized with β-lactams, reverted aminoglycoside-resistance and attenuated bacterial virulence. Calcium antagonists such as nitrendipine or verapamil blocked not only prokaryotic ion channels but interacted with negatively charged bacterial cell membranes thus disrupting membrane energetics and inducing membrane stress response resulting in inhibition of P-glycoprotein such as bacterial pumps thus improving anti-mycobacterial activities of rifampicin, tetracycline, fluoroquinolones, bedaquilin and imipenem-activity against Acinetobacter spp. Ciclosporine and tacrolimus attenuated bacterial virulence. ACE-inhibitors like captopril interacted with metallo-β-lactamases thus reverting carbapenem-resistance; prokaryotic carbonic anhydrases were inhibited as well resulting in growth impairment. In general, non-antibiotics exerted weak antibacterial activities on their own but synergized with antibiotics, and/or reverted resistance and/or attenuated virulence. Conclusions Data summarized in this review support the theory that prokaryotic proteins represent targets for non-antibiotics because of a common evolutionary origin of bacterial- and mammalian targets resulting in highly conserved active centres of both, pro- and eukaryotic proteins with which the non-antibiotics interact and exert antibacterial actions.

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Catozzi, Carlotta, Valentina Zamarian, Gabriele Marziano, Emanuela Dalla Costa, Alessandra Martucciello, Paola Serpe, Domenico Vecchio, Cristina Lecchi, Esterina De Carlo, and Fabrizio Ceciliani. "The effects of intradermal M. bovis and M. avium PPD test on immune-related mRNA and miRNA in dermal oedema exudates of water buffaloes (Bubalus bubalis)." Tropical Animal Health and Production 53, no. 2 (April 6, 2021). http://dx.doi.org/10.1007/s11250-021-02696-1.

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AbstractTuberculosis (TB) is a zoonotic disease primarily caused by pathogens belonging to the genus of Mycobacterium. Programs of control and eradication for bovine TB include a screening using single intradermal tuberculin (SIT) test with Mycobacterium bovis (M. bovis)-purified protein derivatives (PPD-B) single or concurrent with Mycobacterium avium (M. avium)-purified protein derivatives (PPD-A). This study aimed to determine the effects of intradermal PPD-B and PPD-A test on immune-related mRNA and microRNAs in dermal oedema exudates of water buffaloes (Bubalus bubalis). The investigation was carried out on RNA extracted from dermal oedema exudates of 36 animals, of which 24 were M. bovis positive (M. bovis+) and 12 M. avium positive (M. avium+). The lymphocyte polarization toward Th1, Th2, TReg, and Th17 lineages was addressed by measuring the abundance of the respective cytokines and transcription factors, namely TBET, STAT4, IFNγ, and IL1β for Th1; STAT5B, and IL4 for Th2; FOXP3 and IL10 for TReg; and RORC, STAT3, and IL17A for Th17. Due to the very low abundance of Th17-related genes, a digital PCR protocol was also applied. The abundance of microRNAs involved in the immune response against PPDs, including miR-122-5p, miR-148a-3p, miR30a, and miR-455-5p, was equally measured. Results showed that IFNγ (fold change = 2.54; p = 0.037) and miR-148a-3p (fold change = 2.54; p = 0.03) were upregulated in M. bovis+ as compared to M. avium+ samples. Our preliminary results supported the pivotal role of IFNγ in the local immune response related to PPD-B and highlighted the differential expression of miR-148a-3p, which downregulates the proinflammatory cytokines and the TLR4-mediated NF-κB activation, providing an anti-inflammation modulator in responses to mycobacterial infection.

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Journal articles on the topic 'Anti-mycobacterial Effectors'

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