Journal articles: 'Interferon Gamma CXCL10'

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Hameed, Ruaa Salim. "Upregulated CXCL10 gene Expression in SARS-CoV-2 Infected people." BASRA JOURNAL OF SCIENCE 40, no. 2 (September 1, 2022): 357–65. http://dx.doi.org/10.29072/basjs.20220208.

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Interferon and interferon-induced genes play a crucial role in early-stage post-infection virus defense. C-X-C10, also known as interferon gamma-induced protein 10 or small-inducible cytokine B10, is encoded by the CXCL10 gene and is essential for T-helper cell recruitment. The purpose of this study was to assess the gene expression of CXCL10 in SARS-CoV-2-positive and -negative individuals using qPCR. The results demonstrated a 35-fold increase in CXCL10 expression in SARS-CoV-2-positive individuals vs to negative samples. In conclusion, the elevated gene expression of CXCL10 in SARS-CoV-2 patients is a signal for the immune system to respond to the invading virus and may be taken into account in the design of future vaccines.

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Lim, JaeHyun, Steven C. Derrick, Kristopher Kolibab, Amy Li Yang, Steven Porcelli, William R. Jacobs, and Sheldon L. Morris. "Early Pulmonary Cytokine and Chemokine Responses in Mice Immunized with Three Different Vaccines against Mycobacterium tuberculosis Determined by PCR Array." Clinical and Vaccine Immunology 16, no. 1 (November 26, 2008): 122–26. http://dx.doi.org/10.1128/cvi.00359-08.

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ABSTRACT In this study, the early pulmonary cytokine and chemokine responses in mice immunized with either BCG vaccine, a ΔsecA2 mutant of Mycobacterium tuberculosis, or a DNA vaccine expressing an ESAT6-antigen 85B fusion protein and then aerogenically challenged with a low dose of M. tuberculosis were evaluated by PCR array. The cellular immune responses at day 10 postchallenge were essentially equivalent in the lungs of mice immunized with either the highly immunogenic BCG vaccine or the ΔsecA2 M. tuberculosis mutant strain. Specifically, 12 immune biomolecules (including gamma interferon [IFN-γ], interleukin-21 [IL-21], IL-27, IL-17f, CXCL9, CXCL10, and CXCL11) were differentially regulated, relative to the levels for naïve controls, in the lungs of vaccinated mice at this time point. Although the vaccine-related immune responses evoked in mice immunized with the DNA vaccine were relatively limited at 10 days postinfection, upregulation of IFN-γ RNA synthesis as well as increased expression levels of CXCL9, CXCL10, and CXCL11 chemokines were detected.

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Schnabel, Christiane L., Susanna Babasyan, Heather Freer, and Bettina Wagner. "CXCL10 production in equine monocytes is stimulated by interferon-gamma." Veterinary Immunology and Immunopathology 207 (January 2019): 25–30. http://dx.doi.org/10.1016/j.vetimm.2018.11.016.

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Zaph, Colby, and Phillip Scott. "Interleukin-12 Regulates Chemokine Gene Expression during the Early Immune Response to Leishmania major." Infection and Immunity 71, no. 3 (March 2003): 1587–89. http://dx.doi.org/10.1128/iai.71.3.1587-1589.2003.

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ABSTRACT Following infection with Leishmania major, the chemokines XCL1, CXCL10, and CCL2 were preferentially expressed in draining lymph nodes of resistant mice. Neutralization of interleukin 12 (IL-12) or gamma interferon in resistant mice resulted in decreased chemokine expression, while administration of IL-12 to susceptible mice resulted in an increase in the level of chemokine gene expression.

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Colvin, Richard A., Gabriele S. V. Campanella, Lindsay A. Manice, and Andrew D. Luster. "CXCR3 Requires Tyrosine Sulfation for Ligand Binding and a Second Extracellular Loop Arginine Residue for Ligand-Induced Chemotaxis." Molecular and Cellular Biology 26, no. 15 (August 1, 2006): 5838–49. http://dx.doi.org/10.1128/mcb.00556-06.

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ABSTRACT CXCR3 is a G-protein-coupled seven-transmembrane domain chemokine receptor that plays an important role in effector T-cell and NK cell trafficking. Three gamma interferon-inducible chemokines activate CXCR3: CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-TAC). Here, we identify extracellular domains of CXCR3 that are required for ligand binding and activation. We found that CXCR3 is sulfated on its N terminus and that sulfation is required for binding and activation by all three ligands. We also found that the proximal 16 amino acid residues of the N terminus are required for CXCL10 and CXCL11 binding and activation but not CXCL9 activation. In addition, we found that residue R216 in the second extracellular loop is required for CXCR3-mediated chemotaxis and calcium mobilization but is not required for ligand binding or ligand-induced CXCR3 internalization. Finally, charged residues in the extracellular loops contribute to the receptor-ligand interaction. These findings demonstrate that chemokine activation of CXCR3 involves both high-affinity ligand-binding interactions with negatively charged residues in the extracellular domains of CXCR3 and a lower-affinity receptor-activating interaction in the second extracellular loop. This lower-affinity interaction is necessary to induce chemotaxis but not ligand-induced CXCR3 internalization, further suggesting that different domains of CXCR3 mediate distinct functions.

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Scollard, David M., Meher V. Chaduvula, Alejandra Martinez, Natalie Fowlkes, Indira Nath, Barbara M. Stryjewska, Michael T. Kearney, and Diana L. Williams. "Increased CXC Ligand 10 Levels and Gene Expression in Type 1 Leprosy Reactions." Clinical and Vaccine Immunology 18, no. 6 (April 20, 2011): 947–53. http://dx.doi.org/10.1128/cvi.00042-11.

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ABSTRACTType 1 reaction (T1R) is a systemic inflammatory syndrome causing substantial morbidity in leprosy. T1R results from spontaneously enhanced cellular immunity in borderline types of leprosy, but there are no established laboratory markers for the reaction. Preliminary studies have identified elevated circulating CXC ligand 10 (CXCL10) during T1R. Correlation of CXCL10 with clinical T1R was studied in repeated serum specimens obtained before, during, and after T1R. CXCL10 gene expression was assessed in biopsy specimens taken before and during T1R, and sections were stained for the cytokine using monoclonal antibodies. Sequential serum specimens revealed elevation of circulating CXCL10 associated with episodes of T1R (P= 0.0001) but no evidence of an earlier, predictive change in the level of the chemokine. Reverse transcriptase (RT)-PCR revealed elevated expression of CXCL10 transcripts during T1R, but not in patients who did not have T1R. No significant correlation between CXCL10 and gamma interferon (IFN-γ) mRNA levels was observed. Immunohistochemical staining of the skin biopsy specimens suggested an overall increase in CXCL10 but did not identify a particular strongly staining population of leukocytes. Increased CXCL10 in lesions and serum is characteristic of T1R. CXCL10 measurement offers new possibilities for laboratory diagnosis and monitoring of T1R. Studies of the regulation of CXCL10 may provide insight into the mechanisms of T1R and identify potential new drug targets for treatment.

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Chai, Qingqing, Ruiping She, Ying Huang, and Zhen F. Fu. "Expression of Neuronal CXCL10 Induced by Rabies Virus Infection Initiates Infiltration of Inflammatory Cells, Production of Chemokines and Cytokines, and Enhancement of Blood-Brain Barrier Permeability." Journal of Virology 89, no. 1 (October 22, 2014): 870–76. http://dx.doi.org/10.1128/jvi.02154-14.

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It has been shown that enhancement of blood-brain barrier (BBB) permeability is modulated by the expression of chemokines/cytokines and reduction of tight junction (TJ) proteins in the brains of mice infected with rabies virus (RABV). Since CXCL10 was found to be the most highly expressed chemokine, its temporal and spatial expression were determined in the present study. The expression of the chemokine CXCL10 was initially detected in neurons as early as 3 days postinfection (p.i.) in the brains of RABV-infected mice, after which it was detected in microglia (6 days p.i.) and astrocytes (9 days p.i.). Neutralization of CXCL10 by treatment with anti-CXCL10 antibodies reduced gamma interferon (IFN-γ) production and Th17 cell infiltration, as well as restoring TJ protein expression and BBB integrity. Together, these data suggest that it is the neuronal CXCL10 that initiates the cascade that leads to the activation of microglia/astrocytes, infiltration of inflammatory cells, expression of chemokines/cytokines, reduction of TJ protein expression, and enhancement of the BBB permeability.

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Svensson, Mattias, Soombul Zubairi, Asher Maroof, Fatima Kazi, Masaru Taniguchi, and Paul M. Kaye. "Invariant NKT Cells Are Essential for the Regulation of Hepatic CXCL10 Gene Expression during Leishmania donovani Infection." Infection and Immunity 73, no. 11 (November 2005): 7541–47. http://dx.doi.org/10.1128/iai.73.11.7541-7547.2005.

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ABSTRACT Gamma interferon (IFN-γ)-regulated chemokines of the CXC family have been implicated as key regulators of a variety of T-cell-dependent inflammatory processes. However, the cellular source(s) of IFN-γ that regulates their early expression has rarely been defined. Here, we have directly addressed this question in mice after Leishmania donovani infection. Comparison of CXCL10 mRNA accumulation in normal and IFN-γ-deficient mice confirmed an absolute requirement for IFN-γ for sustained (24 h) expression of CXCL10 mRNA accumulation in this model. In normal mice, IFN-γ was produced by both CD3int NK1.1+ NKT cells and CD3− NK1.1+ NK cells, as detected by intracellular flow cytometry. Strikingly, B6.Jα281−/− mice lacking NKT cells that express the invariant Vα14Jα18 T-cell-receptor α chain, although retaining a significant population of IFN-γ-producing NK cells and NKT cells, were unable to sustain CXCL10 mRNA accumulation. These data indicate that invariant NKT cells are indispensable for the regulation of hepatic CXCL10 gene expression during L. donovani infection.

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Jauregui, Catherine E., Qian Wang, Christopher J. Wright, Hiroki Takeuchi, Silvia M. Uriarte, and Richard J. Lamont. "Suppression of T-Cell Chemokines by Porphyromonas gingivalis." Infection and Immunity 81, no. 7 (April 15, 2013): 2288–95. http://dx.doi.org/10.1128/iai.00264-13.

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ABSTRACTPorphyromonas gingivalisis a major pathogen in periodontal disease and is associated with immune dysbiosis. In this study, we found thatP. gingivalisdid not induce the expression of the T-cell chemokine IP-10 (CXCL10) from neutrophils, peripheral blood mononuclear cells (PBMCs), or gingival epithelial cells. Furthermore,P. gingivalissuppressed gamma interferon (IFN-γ)-stimulated release of IP-10, ITAC (CXCL11), and Mig (CXCL9) from epithelial cells and inhibited IP-10 secretion in a mixed infection with the otherwise stimulatoryFusobacterium nucleatum. Inhibition of chemokine expression occurred at the level of gene transcription and was associated with downregulation of interferon regulatory factor 1 (IRF-1) and decreased levels of Stat1. Ectopic expression of IRF-1 in epithelial cells relievedP. gingivalis-induced inhibition of IP-10 release. Direct contact betweenP. gingivalisand epithelial cells was not required for IP-10 inhibition. These results highlight the immune-disruptive potential ofP. gingivalis. Suppression of IP-10 and other Th1-biasing chemokines byP. gingivalismay perturb the balance of protective and destructive immunity in the periodontal tissues and facilitate the pathogenicity of oral microbial communities.

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Asensio, Valérie C., Joachim Maier, Richard Milner, Kaan Boztug, Carrie Kincaid, Maxime Moulard, Curtis Phillipson, et al. "Interferon-Independent, Human Immunodeficiency Virus Type 1 gp120-Mediated Induction of CXCL10/IP-10 Gene Expression by Astrocytes In Vivo and In Vitro." Journal of Virology 75, no. 15 (August 1, 2001): 7067–77. http://dx.doi.org/10.1128/jvi.75.15.7067-7077.2001.

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ABSTRACT The CXC chemokine gamma interferon (IFN-γ)-inducible protein CXCL10/IP-10 is markedly elevated in cerebrospinal fluid and brain of individuals infected with human immunodeficiency virus type 1 (HIV-1) and is implicated in the pathogenesis of HIV-associated dementia (HAD). To explore the possible role of CXCL10/IP-10 in HAD, we examined the expression of this and other chemokines in the central nervous system (CNS) of transgenic mice with astrocyte-targeted expression of HIV gp120 under the control of the glial fibrillary acidic protein (GFAP) promoter, a murine model for HIV-1 encephalopathy. Compared with wild-type controls, CNS expression of the CC chemokine gene CCL2/MCP-1 and the CXC chemokine genes CXCL10/IP-10 and CXCL9/Mig was induced in the GFAP-HIV gp120 mice. CXCL10/IP-10 RNA expression was increased most and overlapped the expression of the transgene-encoded HIV gp120 gene. Astrocytes and to a lesser extent microglia were identified as the major cellular sites for CXCL10/IP-10 gene expression. There was no detectable expression of any class of IFN or their responsive genes. In astrocyte cultures, soluble recombinant HIV gp120 protein was capable of directly inducing CXCL10/IP-10 gene expression a process that was independent of STAT1. These findings highlight a novel IFN- and STAT1-independent mechanism for the regulation of CXCL10/IP-10 expression and directly link expression of HIV gp120 to the induction of CXCL10/IP-10 that is found in HIV infection of the CNS. Finally, one function of IP-10 expression may be the recruitment of leukocytes to the CNS, since the brain of GFAP-HIV gp120 mice had increased numbers of CD3+ T cells that were found in close proximity to sites of CXCL10/IP-10 RNA expression.

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Mauldin, Ileana S., Ena Wang, Donna H. Deacon, Walter C. Olson, Yongde Bao, and Craig L. Slingluff. "TLR2/6 agonists and interferon-gamma induce human melanoma cells to produce CXCL10." International Journal of Cancer 137, no. 6 (May 29, 2015): 1386–96. http://dx.doi.org/10.1002/ijc.29515.

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Antonelli, Alessandro, Silvia Martina Ferrari, Poupak Fallahi, Emiliano Ghiri, Clara Crescioli, Paola Romagnani, Paolo Vitti, Mario Serio, and Ele Ferrannini. "Interferon-alpha, -beta and -gamma induce CXCL9 and CXCL10 secretion by human thyrocytes: Modulation by peroxisome proliferator-activated receptor-gamma agonists." Cytokine 50, no. 3 (June 2010): 260–67. http://dx.doi.org/10.1016/j.cyto.2010.01.009.

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Neujahr, D. C., S. D. Perez, A. Mohammed, O. Ulukpo, E. C. Lawrence, F. Fernandez, A. Pickens, et al. "Cumulative Exposure to Gamma Interferon-Dependent Chemokines CXCL9 and CXCL10 Correlates with Worse Outcome After Lung Transplant." American Journal of Transplantation 12, no. 2 (December 7, 2011): 438–46. http://dx.doi.org/10.1111/j.1600-6143.2011.03857.x.

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Trifilo, Matthew J., Cynthia Montalto-Morrison, Linda N. Stiles, Kelley R. Hurst, Jenny L. Hardison, Jerry E. Manning, Paul S. Masters, and Thomas E. Lane. "CXC Chemokine Ligand 10 Controls Viral Infection in the Central Nervous System: Evidence for a Role in Innate Immune Response through Recruitment and Activation of Natural Killer Cells." Journal of Virology 78, no. 2 (January 15, 2004): 585–94. http://dx.doi.org/10.1128/jvi.78.2.585-594.2004.

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ABSTRACT How chemokines shape the immune response to viral infection of the central nervous system (CNS) has largely been considered within the context of recruitment and activation of antigen-specific lymphocytes. However, chemokines are expressed early following viral infection, suggesting an important role in coordinating innate immune responses. Herein, we evaluated the contributions of CXC chemokine ligand 10 (CXCL10) in promoting innate defense mechanisms following coronavirus infection of the CNS. Intracerebral infection of RAG1−/− mice with a recombinant CXCL10-expressing murine coronavirus (mouse hepatitis virus) resulted in protection from disease and increased survival that correlated with a significant increase in recruitment and activation of natural killer (NK) cells within the CNS. Accumulation of NK cells resulted in a reduction in viral titers that was dependent on gamma interferon secretion. These results indicate that CXCL10 expression plays a pivotal role in defense following coronavirus infection of the CNS by enhancing innate immune responses.

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Walsh, Kevin B., Melissa B. Lodoen, Robert A. Edwards, Lewis L. Lanier, and Thomas E. Lane. "Evidence for Differential Roles for NKG2D Receptor Signaling in Innate Host Defense against Coronavirus-Induced Neurological and Liver Disease." Journal of Virology 82, no. 6 (December 19, 2007): 3021–30. http://dx.doi.org/10.1128/jvi.02032-07.

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ABSTRACT Infection of SCID mice with a recombinant murine coronavirus (mouse hepatitis virus [MHV]) expressing the T-cell chemoattractant CXC chemokine ligand 10 (CXCL10) resulted in increased survival and reduced viral burden within the brain and liver compared to those of mice infected with an isogenic control virus (MHV), supporting an important role for CXCL10 in innate immune responses following viral infection. Enhanced protection in MHV-CXCL10-infected mice correlated with increased gamma interferon (IFN-γ) production by infiltrating natural killer (NK) cells within the brain and reduced liver pathology. To explore the underlying mechanisms associated with protection from disease in MHV-CXCL10-infected mice, the functional contributions of the NK cell-activating receptor NKG2D in host defense were examined. The administration of an NKG2D-blocking antibody to MHV-CXCL10-infected mice did not reduce survival, dampen IFN-γ production in the brain, or affect liver pathology. However, NKG2D neutralization increased viral titers within the liver, suggesting a protective role for NKG2D signaling in this organ. These data indicate that (i) CXCL10 enhances innate immune responses, resulting in protection from MHV-induced neurological and liver disease; (ii) elevated NK cell IFN-γ expression in the brain of MHV-CXCL10-infected mice occurs independently of NKG2D; and (iii) NKG2D signaling promotes antiviral activity within the livers of MHV-infected mice that is not dependent on IFN-γ and tumor necrosis factor alpha secretion.

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Slingluff, Craig L., Gina R. Petroni, Lynn Dengel, David W. Mullins, William W. Grosh, Geoffrey R. Weiss, Robert M. Strieter, et al. "Evaluation of the safety and immunogenicity of intratumoral injection of interferon gamma (IFNg) during vaccination in patients with subcutaneous or cutaneous metastases of melanoma (Mel51; NCT00977145)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): TPS3118. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.tps3118.

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TPS3118^ Background: One mechanism to improve immunologic outcomes of vaccine therapy, and other immune therapies, is to optimize T cell trafficking to sites of tumor. CXCR3 is expressed by Th1 and Tc1 T cells and directs them to sites of inflammation by following the chemokine gradient. The ligands for CXCR3 (CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC)) are induced by interferon gamma (IFNg). This protocol tests whether administering peptide vaccine activates circulating tumor antigen-specific CD8+ CXCR3+ T cells, followed by intratumoral IFNg to increase CXCR3 ligands (CXCL9-11) at the tumor site and thus to recruit the CXCR3+T cells. Methods: This pilot clinical trial is enrolling patients (n=14) with subcutaneous or cutaneous metastases of melanoma (stage IIIB-IV), who have adequate accessible tumor in 1-4 lesions to provide 100-300 mm3 tumor on each of the three biopsy days, and with at least one lesion amenable to intratumoral IFNg injection. Patients must also express HLA-A1, A2, A3, or A11. Patients undergo tumor biopsy d1, then are vaccinated days 1, 8, and 15 with a multipeptide vaccine. A biopsy day 22 provides information on the effect of vaccination alone on T cell infiltration into tumor. IFNg (up to 2 million units) is injected into at least 1 metastasis, which is biopsied day 24. Additional vaccines are given days 24, 43, and 64. Primary goals are to determine the safety of intratumoral interferon gamma (IFNg) plus a multipeptide melanoma vaccine, and to evaluate the biological effects of vaccine plus IFN-g at the tumor site, to include expression of CXCR3 ligands (CXCL9, CXCL10 & CXCL11) and the magnitude of infiltration of CD8+ CXCR3+ T cells and vaccine-specific T cells. Secondary goals include evaluating effects of vaccine on CXCR3 expression by circulating antigen-experienced CD4 and CD8 T cells, estimating the effects of vaccine plus IFNg on changes in the percentage of FoxP3+ CD25hi CD4+(putative regulatory T cells, Tregs) among tumor infiltrating T cells and to obtain preliminary data on the clinical response of cutaneous or subcutaneous metastases of melanoma to the proposed combination regimen. Clinical trial information: NCT00977145.

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Hardison, Jenny L., Ruth A. Wrightsman, Philip M. Carpenter, Thomas E. Lane, and Jerry E. Manning. "The Chemokines CXCL9 and CXCL10 Promote a Protective Immune Response but Do Not Contribute to Cardiac Inflammation following Infection with Trypanosoma cruzi." Infection and Immunity 74, no. 1 (January 2006): 125–34. http://dx.doi.org/10.1128/iai.74.1.125-134.2006.

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ABSTRACT The expression of chemokines within the heart during experimental infection of susceptible mice with the Colombiana strain of Trypanosoma cruzi was characterized in an attempt to determine a functional role for these molecules in both host defense and disease. Analysis of chemokine transcripts revealed that CXC chemokine ligand 9 (CXCL9) and CXCL10, as well as CC chemokine ligand 2 (CCL2) and CCL5, were prominently expressed during acute disease, whereas transcripts for CXCL9, CXCL10, and CCL5 remained elevated during chronic infection. Inflammatory macrophages present within the heart were the primary cellular source of these chemokines following T. cruzi infection. Peak chemokine expression levels coincided with increased gamma interferon expression and inflammation within the heart, suggesting a role for these molecules in both host defense and disease. Indeed, simultaneous treatment of T. cruzi-infected mice with neutralizing antibodies specific for CXCL9 and CXCL10 resulted in an increased parasite burden that was sustained out to 50 days p.i. Antibody targeting either CXCL10 or CCL5 did not change either T. cruzi burden within the heart nor attenuate the severity of cardiac inflammation at any time point examined, while targeting CXCL9 in combination with CXCL10 resulted in increased parasite burden. Collectively, these studies imply that CXCL9 and CXCL10 signaling enhances immune responses following parasite infection. However, antibody targeting of CXCL9 and CXCL10, or CXCL10 alone, or CCL5 alone does not directly modulate the inflammatory response within the heart, suggesting that other proinflammatory factors are able to regulate inflammation in this tissue in response to T. cruzi infection.

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Vasquez, Rene E., and Lynn Soong. "CXCL10/Gamma Interferon-Inducible Protein 10-Mediated Protection against Leishmania amazonensis Infection in Mice." Infection and Immunity 74, no. 12 (September 18, 2006): 6769–77. http://dx.doi.org/10.1128/iai.01073-06.

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ABSTRACT Leishmania amazonensis can cause progressive disease in most inbred strains of mice. We have previously shown that L. amazonensis-infected C57BL/6 mice have profound impairments in expression of proinflammatory cytokines and chemokines and in activation of antigen-specific CD4+ T cells. These impairments are independent of interleukin-4 (IL-4) but partially due to IL-10 production. The precise mechanism of pathogenesis associated with L. amazonensis infection remains largely unresolved. Since chemokines are essential mediators of leukocyte recruitment and effector cell function, we hypothesized that these molecules are important for the initiation of early responses locally and for the eventual control of the infection. In this study, we examined the roles of CXCL10/gamma interferon-inducible protein 10 (IP-10) and CCL2/monocyte chemoattractant protein 1 (MCP-1) in the activation of the macrophage effector function in vitro and their efficacy in ameliorating infection in vivo. Bone marrow-derived macrophages of both BALB/c and C57BL/6 mice were treated with increasing concentrations of recombinant chemokines prior to infection with either stationary-phase promastigotes or tissue-derived amastigotes. We found that treatment with IP-10 or MCP-1 significantly reduced parasite burdens, in a dose-dependent manner, and triggered nitric oxide production. When susceptible C57BL/6 mice were injected locally with IP-10 following L. amazonensis infection, there was a significant delay in lesion development and a reduction in parasite burdens, accompanied by 7- and 3.5-fold increases in gamma interferon and IL-12 secretion, respectively, in restimulated lymph node cells. This study confirms that IP-10 plays a protective role in promoting the reduction of intracellular parasites and thereby opens new avenues for therapeutic control of nonhealing cutaneous leishmaniasis in the New World.

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Vasquez, René E., Lijun Xin, and Lynn Soong. "Effects of CXCL10 on Dendritic Cell and CD4+ T-Cell Functions during Leishmania amazonensis Infection." Infection and Immunity 76, no. 1 (November 12, 2007): 161–69. http://dx.doi.org/10.1128/iai.00825-07.

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ABSTRACT Leishmania amazonensis can cause progressive disease in most inbred strains of mice. We have previously reported that treatment with CXCL10 activates macrophage (MΦ) effector function(s) in parasite killing and significantly delays lesion development in susceptible C57BL/6 mice via enhanced gamma interferon (IFN-γ) and interleukin 12 (IL-12) secretion; however, the mechanism underlying this enhanced immunity against L. amazonensis infection remains largely unresolved. In this study, we utilized stationary promastigotes to infect bone marrow-derived dendritic cells (DCs) of C57BL/6 mice and assessed the activation of DC subsets and the capacity of these DC subsets to prime CD4+ T cells in vitro. We found that CXCL10 induced IL-12 p40 production but reduced IL-10 production in uninfected DCs. Yet L. amazonensis-infected DCs produced elevated levels of IL-10 despite CXCL10 treatment. Elimination of endogenous IL-10 led to increased IL-12 p40 production in DCs as well as increased proliferation and IFN-γ production by in vitro-primed CD4+ T cells. In addition, CXCL10-treated CD4+ T cells became more responsive to IL-12 via increased expression of the IL-12 receptor β2 chain and produced elevated levels of IFN-γ. This report indicates the utility of CXCL10 in generating a Th1-favored, proinflammatory response, which is a prerequisite for controlling Leishmania infection.

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Gerlza, Tanja, Michael Nagele, Martha Gschwandtner, Sophie Winkler, and Andreas Kungl. "Designing an improved T-cell mobilising CXCL10 mutant through enhanced GAG binding affinity." Protein Engineering, Design and Selection 32, no. 8 (August 2019): 367–73. http://dx.doi.org/10.1093/protein/gzz043.

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Abstract The chemokine CXCL10 is released by a plethora of cells, including immune and metastatic cancer cells, following stimulation with interferon-gamma. It acts via its GPC receptor on T-cells attracting them to various target tissues. Glycosaminoglycans (GAGs) are regarded as co-receptors of chemokines, which enable the establishment of a chemotactic gradient for target cell migration. We have engineered human CXCL10 towards improved T-cell mobilisation by implementing a single site-directed mutation N20K into the protein, which leads to a higher GAG binding affinity compared to the wild type. Interestingly, this mutation not only increased T-cell migration in a transendothelial migration assay, the mutant intensified T-cell chemotaxis also in a Boyden chamber set-up thereby indicating a strong role of T-cell-localised GAGs on leukocyte migration. A CXCL10 mutant with increased GAG-binding affinity could therefore potentially serve as a T-cell mobiliser in pathological conditions where the immune surveillance of the target tissue is impaired, as is the case for most solid tumors.

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Workman, Michael J., Elissa Troisi, Stephan R. Targan, Clive N. Svendsen, and Robert J. Barrett. "Modeling Intestinal Epithelial Response to Interferon-γ in Induced Pluripotent Stem Cell-Derived Human Intestinal Organoids." International Journal of Molecular Sciences 22, no. 1 (December 30, 2020): 288. http://dx.doi.org/10.3390/ijms22010288.

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Human intestinal organoids (HIOs) are increasingly being used to model intestinal responses to various stimuli, yet few studies have confirmed the fidelity of this modeling system. Given that the interferon-gamma (IFN-γ) response has been well characterized in various other cell types, our goal was to characterize the response to IFN-γ in HIOs derived from induced pluripotent stem cells (iPSCs). To achieve this, iPSCs were directed to form HIOs and subsequently treated with IFN-γ. Our results demonstrate that IFN-γ phosphorylates STAT1 but has little effect on the expression or localization of tight and adherens junction proteins in HIOs. However, transcriptomic profiling by microarray revealed numerous upregulated genes such as IDO1, GBP1, CXCL9, CXCL10 and CXCL11, which have previously been shown to be upregulated in other cell types in response to IFN-γ. Notably, “Response to Interferon Gamma” was determined to be one of the most significantly upregulated gene sets in IFN-γ-treated HIOs using gene set enrichment analysis. Interestingly, similar genes and pathways were upregulated in publicly available datasets contrasting the gene expression of in vivo biopsy tissue from patients with IBD against healthy controls. These data confirm that the iPSC-derived HIO modeling system represents an appropriate platform to evaluate the effects of various stimuli and specific environmental factors responsible for the alterations in the intestinal epithelium seen in various gastrointestinal conditions such as inflammatory bowel disease.

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Helbig, Karla J., Andrew Ruszkiewicz, Robert E. Lanford, Mark D. Berzsenyi, Hugh A. Harley, Shaun R. McColl, and Michael R. Beard. "Differential Expression of the CXCR3 Ligands in Chronic Hepatitis C Virus (HCV) Infection and Their Modulation by HCV In Vitro." Journal of Virology 83, no. 2 (November 5, 2008): 836–46. http://dx.doi.org/10.1128/jvi.01388-08.

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ABSTRACT To investigate chemokine expression networks in chronic hepatitis C virus (HCV) infection, we used microarray analysis to determine chemokine expression in human infection and in chimpanzees experimentally infected with HCV. The CXCR3 chemokine family was highly expressed in both human and chimpanzee infection. CXCL10 was the only CXCR3 chemokine elevated in the serum, suggesting that it may neutralize any CXCR3 chemokine gradient established between the periphery and liver by CXCL11 and CXCL9. Thus, CXCR3 chemokines may not be responsible for recruitment of T lymphocytes but may play a role in positioning these cells within the liver. The importance of the CXCR3 chemokines, in particular CXCL11, was highlighted by replicating HCV (JFH-1) to selectively upregulate its expression in response to gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α). This selective upregulation was confirmed at the transcriptional level by using the CXCL11 promoter driving the luciferase reporter gene. This synergistic increase in expression was not a result of HCV protein expression but the nonspecific innate response to double-stranded RNA (dsRNA), as both in vitro-transcribed HCV RNA and the dsRNA analogue poly(I:C) increased CXCL11 expression and promoter activity. Furthermore, we show that CXCL11 is an IRF3 (interferon regulatory factor 3) response gene whose expression is selectively enhanced by IFN-γ and TNF-α. In conclusion, the CXCR3 chemokines are the most significantly expressed chemokines in chronic hepatitis C and most likely play a role in positioning T cells in the liver. Furthermore, HCV can selectively increase CXCL11 expression in response to IFN-γ and TNF-α stimulation that may play a role in the pathogenesis of HCV-related liver disease.

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Cheeran, Maxim C. J., Shuxian Hu, Wen S. Sheng, Phillip K. Peterson, and James R. Lokensgard. "CXCL10 Production from Cytomegalovirus-Stimulated Microglia Is Regulated by both Human and Viral Interleukin-10." Journal of Virology 77, no. 8 (April 15, 2003): 4502–15. http://dx.doi.org/10.1128/jvi.77.8.4502-4515.2003.

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ABSTRACT Glial cells orchestrate immunocyte recruitment to focal areas of viral infection within the brain and synchronize immune cell functions through a regulated network of cytokines and chemokines. Since recruitment of T lymphocytes plays a critical role in resolving cytomegalovirus (CMV) infection, we investigated the production of a T-cell chemoattractant, CXCL10 (gamma interferon-inducible protein 10) in response to viral infection of human glial cells. Infection with CMV was found to elicit the production of CXCL10 from primary microglial cells but not from astrocytes. This CXCL10 expression was not dependent on secondary protein synthesis but did require the phosphorylation of p38 mitogen-activated protein (MAP) kinase. In addition, migration of activated lymphocytes toward supernatants from CMV-stimulated microglial cells was partially suppressed by anti-CXCL10 antibodies. Since regulation of central nervous system inflammation is essential to allow viral clearance without immunopathology, microglial cells were then treated with anti-inflammatory cytokines. CMV-induced CXCL10 production from microglial cells was suppressed following treatment with interleukin-10 (IL-10) and IL-4 but not following treatment with transforming growth factor β. The IL-10-mediated inhibition of CXCL10 production was associated with decreased CMV-induced NF-κB activation but not decreased p38 MAP kinase phosphorylation. Finally, CMV infection of fully permissive astrocytes resulted in mRNA expression for the viral homologue to human IL-10 (i.e., cmvIL-10 [UL111a]) in its spliced form and conditioned medium from CMV-infected astrocytes inhibited virus-induced CXCL10 production from microglial cells through the IL-10 receptor. These findings present yet another mechanism through which CMV may subvert host immune responses.

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Bussmeyer, Uta, Arup Sarkar, Kirsten Broszat, Tanja Lüdemann, Sonja Möller, Ger van Zandbergen, Christian Bogdan, et al. "Impairment of Gamma Interferon Signaling in Human Neutrophils Infected with Anaplasma phagocytophilum." Infection and Immunity 78, no. 1 (October 26, 2009): 358–63. http://dx.doi.org/10.1128/iai.01005-09.

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ABSTRACT Anaplasma phagocytophilum, the causative agent of tick-borne human granulocytic anaplasmosis (HGA), is an intracellular bacterium which survives and multiplies inside polymorphonuclear neutrophil granulocytes (PMN). Increased bacterial burden in gamma interferon (IFN-γ)-deficient mice suggested a major role of IFN-γ in the control of A. phagocytophilum. Here we investigated whether infection of human PMN with A. phagocytophilum impairs IFN-γ signaling thus facilitating intracellular survival of the bacterium. The secretion of the IFN-γ-inducible chemokines IP-10/CXCL10 and MIG/CXCL9 was markedly inhibited in infected neutrophils. Molecular analyses revealed that, compared to uninfected PMN, A. phagocytophilum decreased the expression of the IFN-γ receptor α-chain CD119, diminished the IFN-γ-induced phosphorylation of STAT1, and enhanced the expression of SOCS1 and SOCS3 in PMN. Since IFN-γ activates various antibacterial effector mechanisms of PMN, the impaired IFN-γ signaling in infected cells likely contributes to the survival of A. phagocytophilum inside PMN and to HGA disease development.

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Lin, Adora A., Pulak K. Tripathi, Allyson Sholl, Michael B. Jordan, and David A. Hildeman. "Gamma Interferon Signaling in Macrophage Lineage Cells Regulates Central Nervous System Inflammation and Chemokine Production." Journal of Virology 83, no. 17 (June 10, 2009): 8604–15. http://dx.doi.org/10.1128/jvi.02477-08.

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ABSTRACT Intracranial (i.c.) infection of mice with lymphocytic choriomeningitis virus (LCMV) results in anorexic weight loss, mediated by T cells and gamma interferon (IFN-γ). Here, we assessed the role of CD4+ T cells and IFN-γ on immune cell recruitment and proinflammatory cytokine/chemokine production in the central nervous system (CNS) after i.c. LCMV infection. We found that T-cell-depleted mice had decreased recruitment of hematopoietic cells to the CNS and diminished levels of IFN-γ, CCL2 (MCP-1), CCL3 (MIP-1α), and CCL5 (RANTES) in the cerebrospinal fluid (CSF). Mice deficient in IFN-γ had decreased CSF levels of CCL3, CCL5, and CXCL10 (IP-10), and decreased activation of both resident CNS and infiltrating antigen-presenting cells (APCs). The effects of IFN-γ signaling on macrophage lineage cells was assessed using transgenic mice, called “macrophages insensitive to interferon gamma” (MIIG) mice, that express a dominant-negative IFN-γ receptor under the control of the CD68 promoter. MIIG mice had decreased levels of CCL2, CCL3, CCL5, and CXCL10 compared to controls despite having normal numbers of LCMV-specific CD4+ T cells in the CNS. MIIG mice also had decreased recruitment of infiltrating macrophages and decreased activation of both resident CNS and infiltrating APCs. Finally, MIIG mice were significantly protected from LCMV-induced anorexia and weight loss. Thus, these data suggest that CD4+ T-cell production of IFN-γ promotes signaling in macrophage lineage cells, which control (i) the production of proinflammatory cytokines and chemokines, (ii) the recruitment of macrophages to the CNS, (iii) the activation of resident CNS and infiltrating APC populations, and (iv) anorexic weight loss.

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Prizant, Hen, Nilesh Patil, Seble Negatu, Alexandra Livingston, Scott Leddon, Andrew D. Luster, and Deborah J. Fowell. "CXCL10+ perivascular clusters nucleate Th1 cell tissue entry and activation in the inflamed skin." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 220.9. http://dx.doi.org/10.4049/jimmunol.204.supp.220.9.

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Abstract Efficient recruitment and correct positioning of T cells within infected peripheral tissues are crucial for pathogen clearance. Using a dual-chemokine reporter (Groom et Al. Immunity, 2012) mouse and intra-vital imaging, we identified a preferred tissue entry and accumulation site for effector Th1 cells, defined by clusters of CXCL9 and CXCL10 expressing hematopoietic cells, enriched with MHC-class-II+ cells, in restricted perivascular spaces within the inflamed dermis. Unbiased computational analysis of motility dynamics of antigen-specific Th1 cells within these clusters, revealed cell confinement characteristics. CXCR3 on Th1 cells and presence of cognate antigen were critical for persistence within clusters and T cell activation. Newly recruited Th1 cells strongly amplified CXCL9 and CXCL10 expression, mainly within skin monocyte-derived dendritic cells, in an antigen- and interferon-gamma-dependent manner, resulting in augmented chemokine clusters. Our data suggest a CXCR3-mediated mechanism of intrinsic amplification loop for optimal Th1 cell recruitment, positioning and activation in restricted antigen presentation sites within the inflamed skin.

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Karimabad, Mojgan Noroozi, Nicholas G. Kounis, Gholamhossein Hassanshahi, Farzaneh Hassanshahi, Virginia Mplani, Ioanna Koniari, Ming-Yow Hung, and Ali Esmaeili Nadimi. "The Involvement of CXC Motif Chemokine Ligand 10 (CXCL10) and Its Related Chemokines in the Pathogenesis of Coronary Artery Disease and in the COVID-19 Vaccination: A Narrative Review." Vaccines 9, no. 11 (October 21, 2021): 1224. http://dx.doi.org/10.3390/vaccines9111224.

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Coronary artery disease (CAD) and coronary heart disease (CHD) constitute two of the leading causes of death in Europe, USA and the rest of the world. According to the latest reports of the Iranian National Health Ministry, CAD is the main cause of death in Iranian patients with an age over 35 years despite a significant reduction in mortality due to early interventional treatments in the context of an acute coronary syndrome (ACS). Inflammation plays a fundamental role in coronary atherogenesis, atherosclerotic plaque formation, acute coronary thrombosis and CAD establishment. Chemokines are well-recognized mediators of inflammation involved in several bio-functions such as leucocyte migration in response to inflammatory signals and oxidative vascular injury. Different chemokines serve as chemo-attractants for a wide variety of cell types including immune cells. CXC motif chemokine ligand 10 (CXCL10), also known as interferon gamma-induced protein 10 (IP-10/CXLC10), is a chemokine with inflammatory features whereas CXC chemokine receptor 3 (CXCR3) serves as a shared receptor for CXCL9, 10 and 11. These chemokines mediate immune responses through the activation and recruitment of leukocytes, eosinophils, monocytes and natural killer (NK) cells. CXCL10, interleukin (IL-15) and interferon (IFN-g) are increased after a COVID-19 vaccination with a BNT162b2 mRNA (Pfizer/BioNTech) vaccine and are enriched by tumor necrosis factor alpha (TNF-α) and IL-6 after the second vaccination. The aim of the present study is the presentation of the elucidation of the crucial role of CXCL10 in the patho-physiology and pathogenesis of CAD and in identifying markers associated with the vaccination resulting in antibody development.

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Horiguchi, Kotaro, Ken Fujiwara, Takehiro Tsukada, Saishu Yoshida, Masashi Higuchi, Kozue Tateno, Rumi Hasegawa, et al. "CXCL10/CXCR3 signaling mediates inhibitory action by interferon-gamma on CRF-stimulated adrenocorticotropic hormone (ACTH) release." Cell and Tissue Research 364, no. 2 (November 14, 2015): 395–404. http://dx.doi.org/10.1007/s00441-015-2317-2.

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Raza, Ali, Sadaf Firasat, Shagufta Khaliq, Tahir Aziz, Muhammed Mubarak, Syed Ali Anwar Naqvi, Syed Qasim Mehdi, Syed Adib-ul-Hasan Rizvi, and Aiysha Abid. "The association of urinary interferon-gamma inducible protein-10 (IP10/CXCL10) levels with kidney allograft rejection." Inflammation Research 66, no. 5 (February 28, 2017): 425–32. http://dx.doi.org/10.1007/s00011-017-1025-7.

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Tribouillard-Tanvier, Déborah, James F. Striebel, Karin E. Peterson, and Bruce Chesebro. "Analysis of Protein Levels of 24 Cytokines in Scrapie Agent-Infected Brain and Glial Cell Cultures from Mice Differing in Prion Protein Expression Levels." Journal of Virology 83, no. 21 (August 26, 2009): 11244–53. http://dx.doi.org/10.1128/jvi.01413-09.

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ABSTRACT Activation of microglia and astroglia is seen in many neurodegenerative diseases including prion diseases. Activated glial cells produce cytokines as a protective response against certain pathogens and as part of the host inflammatory response to brain damage. In addition, cytokines might also exacerbate tissue damage initiated by other processes. In the present work using multiplex assays to analyze protein levels of 24 cytokines in scrapie agent-infected C57BL/10 mouse brains, we observed elevation of CCL2, CCL5, CXCL1, CXCL10, granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma interferon (IFN-γ), interleukin 1α (IL-1α), IL-1β, IL-6, and IL-12p40. Scrapie agent-infected wild-type mice and transgenic mice expressing anchorless prion protein (PrP) had similar cytokine responses in spite of extensive differences in neuropathology. Therefore, these responses may be primarily a reaction to brain damage induced by prion infection rather than specific inducers of a particular type of pathology. To study the roles of astroglia and microglia in these cytokine responses, primary glial cultures were exposed to scrapie agent-infected brain homogenates. Microglia produced only IL-12p40 and CXCL10, whereas astroglia produced these cytokines plus CCL2, CCL3, CCL5, CXCL1, G-CSF, IL-1β, IL-6, IL-12p70, and IL-13. Glial cytokine responses from wild-type mice and transgenic mice expressing anchorless PrP differed only slightly, but glia from PrP-null mice produced only IL-12p40, indicating that PrP expression was required for scrapie agent induction of other cytokines detected. The difference in cytokine response between microglia and astroglia correlated with 20-fold-higher levels of PrP expression in astroglia versus microglia, suggesting that high-level PrP expression on astroglia might be important for induction of certain cytokines.

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Popik, Waldemar, Atanu K. Khatua, Noyna F. Fabre, James E. K. Hildreth, and Donald J. Alcendor. "BK Virus Replication in the Glomerular Vascular Unit: Implications for BK Virus Associated Nephropathy." Viruses 11, no. 7 (June 27, 2019): 583. http://dx.doi.org/10.3390/v11070583.

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Background: BK polyomavirus (BKV) reactivates from latency after immunosuppression in renal transplant patients, resulting in BKV-associated nephropathy (BKVAN). BKVAN has emerged as an important cause of graft dysfunction and graft loss among transplant patients. BKV infection in kidney transplant patients has increased over recent decades which correlates with the use of more potent immunosuppressive therapies. BKV infection of the Glomerular Vascular Unit (GVU) consisting of podocytes, mesangial cells, and glomerular endothelial cells could lead to glomerular inflammation and contribute to renal fibrosis. The effects of BKV on GVU infectivity have not been reported. methods: We infected GVU cells with the Dunlop strain of BKV. Viral infectivity was analyzed by microscopy, immunofluorescence, Western blot analysis, and quantitative RT-PCR (qRT-PCR). The expression of specific proinflammatory cytokines induced by BKV was analyzed by qRT-PCR. Results: BKV infection of podocytes, mesangial cells, and glomerular endothelial cells was confirmed by qRT-PCR and positive staining with antibodies to the BKV VP1 major capsid protein, or the SV40 Large T-Antigen. The increased transcriptional expression of interferon gamma-induced protein 10 (CXCL10/IP-10) and interferon beta (IFNβ) was detected in podocytes and mesangial cells at 96 h post-infection. conclusions: All cellular components of the GVU are permissive for BKV replication. Cytopathic effects induced by BKV in podocytes and glomerular endothelial cells and the expression of CXCL10 and IFNβ genes by podocytes and mesangial cells may together contribute to glomerular inflammation and cytopathology in BKVAN.

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Bakmiwewa, Supun M., Silvia Weiser, Meredith Grey, Benjamin Heng, Gilles J. Guillemin, Helen J. Ball, and Nicholas H. Hunt. "Synergistic induction of CXCL10 by interferon-gamma and lymphotoxin-alpha in astrocytes: Possible role in cerebral malaria." Cytokine 78 (February 2016): 79–86. http://dx.doi.org/10.1016/j.cyto.2015.11.024.

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Xagoraris, Ioanna, Georgia Kokaraki, Christina Plastira, Konstantina Stathopoulou, Vasiliki Leventaki, Elias Drakos, Jeffrey Medeiros, Anders Österborg, and George Z. Rassidakis. "The NPM-ALK Oncogenic Kinase Suppresses CGAS-Sting-Associated Anti-Tumor Immune Responses through STAT3 Activation in Anaplastic Large Cell Lymphoma (ALCL)." Blood 138, Supplement 1 (November 5, 2021): 1338. http://dx.doi.org/10.1182/blood-2021-149257.

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Abstract Background: ALK+ anaplastic large cell lymphoma (ALCL) is a distinct T-cell non-Hodgkin lymphoma type that frequently carries the t(2;5) resulting in overexpression and activation of NPM-ALK chimeric kinase, which activates multiple oncogenic pathways including JAK-STAT3 pathway. The presence of cytosolic DNA of either exogenous or endogenous origin activates the cyclic GMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor, which activates the adaptor protein STING. The latter then activates the TBK1 and IKK kinases, which activate through phosphorylation the transcription factors IRF3 and NF-κB, respectively. IRF3 and NF-κB induce expression of interferons (e.g. IFN-β) and cytokines leading to activation of innate immune responses. The potential role of NPM-ALK oncogenic kinase in cGAS-STING-related anti-tumor immune responses in ALK+ ALCL is unknown to date. Therefore, the present study aimed to investigate the biologic impact of NPM-ALK on cGAS-STING activation status and expression of relevant interferon genes in ALK+ ALCL. Methods: The in vitro system included 5 ALK+ (Karpas 299, SUPM2, DEL, SUDHL1, L82) and 2 ALK- (Mac-1, Mac-2a) ALCL cell lines, as well as Ba/F3 cells stably transfected with NPM-ALK (Ba/F3-NPM-ALK) or a control (Ba/F3-MIG) plasmid. Expression and activation (phosphorylation) of cGAS-STING pathway proteins at baseline and experimental conditions were analysed by RT-PCR and Western blot at the RNA and protein level, respectively. Inhibition of ALK and STAT3 activity was performed using Crizotinib and the selective XIII STAT3 inhibitor, respectively. Silencing of ALK gene was performed using transient transfection with ALK siRNA and the Amaxa Nucleofector Technology. A STING agonist and TBK inhibitor (Amlexanox) were also used alone or in combination with other agents. The cGAS-STING-associated anti-tumor immune responses were evaluated by assessing the RNA levels of interferon beta (IFN-β), CXCL10, and interferon gamma (IFN-γ), as well as a control gene (GAPDH), with quantitative RT-PCR. The patient study group included 38 previously untreated patients with ALK+ ALCL. Immunohistochemical analysis for STING protein expression was performed using a monoclonal antibody (Cell Signaling) and standard protocols. An arbitrary 10% cutoff was used to define positivity. Results: STING gene was highly expressed at both the mRNA and protein level in ALK+ and ALK- ALCL cell lines, however, cGAS-STING pathway proteins were activated at a variable level among ALCL cell lines as shown in immunoblots. STING was highly expressed in 36 of 38 (95%) ALK+ ALCL tumors, highlighting its biologic significance in this lymphoma type. Inhibition of ALK activity by Crizotinib resulted in significant increase in IFN-β and CXCL10 gene expression linked to activation/phosphorylation of TBK1 indicating cGAS-STING pathway activation in ALK+ ALCL and Ba/F3-NPM-ALK cells. Silencing of ALK gene with specific ALK siRNA also resulted in a dramatic increase in the CXCL10 gene expression (mRNA level). Similarly, treatment of ALK+ ALCL cells with the XIII STAT3 inhibitor resulted in significantly increased IFN-β and CXCL10 gene expression associated with activation of the cGAS-STING pathway proteins in ALK+ ALCL cells but also in the ALK- ALCL cell line, Mac-1. Incubation of ALK+ ALCL cells with a STING agonist alone led to further activation of the cGAS-STING pathway in ALK+ ALCL cells. Conclusion: NPM-ALK suppresses STING-associated, anti-tumor immune responses in ALK+ ALCL, through STAT3 activation and regulation of gene expression of type-1 interferons (IFN-β, CXCL10). Thus, combined ALK inhibition (ALK inhibitors) and STING stimulation (STING agonists) may represent a novel investigational therapeutic strategy for these patients. Disclosures No relevant conflicts of interest to declare.

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Zeng, Xianying, Thomas A. Moore, Michael W. Newstead, Jane C. Deng, Steven L. Kunkel, Andrew D. Luster, and Theodore J. Standiford. "Interferon-Inducible Protein 10, but Not Monokine Induced by Gamma Interferon, Promotes Protective Type 1 Immunity in Murine Klebsiella pneumoniae Pneumonia." Infection and Immunity 73, no. 12 (December 2005): 8226–36. http://dx.doi.org/10.1128/iai.73.12.8226-8236.2005.

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ABSTRACT CXC chemokines that lack the ELR motif, including interferon-inducible protein 10 [IP-10 (CXCL10)] and monokine induced by gamma interferon (IFN-γ) [MIG (CXCL9)], have been shown to mediate the generation of type 1 immune responses. In this study, we found that intrapulmonary administration of the gram-negative bacterium Klebsiella pneumoniae resulted in the local and systemic expression of IP-10, followed sequentially by MIG expression. MIG mRNA expression in the lungs of Klebsiella-infected mice required the endogenous production of IFN-γ, whereas IP-10 was expressed in both an IFN-γ-dependent and an IFN-γ-independent fashion. Antibody-mediated neutralization of IP-10 resulted in reduced bacterial clearance and decreased survival, whereas bacterial clearance was unaltered in mice treated with anti-MIG antibody. Impaired bacterial clearance in anti-IP-10 antibody-treated mice was associated with significant reductions in the number and/or activational status of NK and NK-T cells, CD4+ T cells, and γδ T cells, as well as a reduction in the expression of IFN-γ. Conversely, the transient transgenic expression of murine IP-10 using adenovirus-mediated gene transfer resulted in improved bacterial clearance when IP-10 adenovirus was given concomitant with intrapulmonary bacterial challenge. These results indicate that IP-10 is an important component of innate immunity against extracellular bacterial pathogens of the lung and may represent a candidate molecule for immunotherapy in the setting of severe respiratory tract infection.

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Nakata, Katsuya, Luis J. Espinoza, Makoto Onizuka, Takahiro Fukuda, Takakazu Kawase, Eriko Morishita, Yoshihisa Kodera, et al. "The Association of a Single Nucleotide Polymorphism in the Chemokine CXCL10 Gene with Transplant Outcomes After HLA-Matched Unrelated Bone Marrow Transplantation for Low Risk Hematologic Malignancies." Blood 118, no. 21 (November 18, 2011): 2048. http://dx.doi.org/10.1182/blood.v118.21.2048.2048.

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Abstract Abstract 2048 CXCL10, also known as interferon gamma inducible protein 10, is a chemokine secreted by several cell types including monocytes, endothelial cells and fibroblasts that plays important roles in the stimulation and migration of natural killer cells and T cells. The single nucleotide polymorphism (SNP) rs3921 located in the 3'-untranslated region of the CXCL10 gene has been reportedly associated with acute GVHD and with invasive aspergillosis after allogenic stem-cell transplantation. In this study, we analyzed the impact of rs3921 polymorphism on transplant outcomes in patients undergoing unrelated HLA-matched myeloablative bone marrow transplantation (BMT) through the Japan Marrow Donation Program. The CXCL10 genotypes were retrospectively analyzed in a cohort of 652 pairs of patients with hematologic malignancies and their unrelated donors. The genotype frequencies of GG, CG and CC were 1%, 13% and 86% in recipients and 1%, 12% and 87% in donors (P=0.62). The recipient GG or CG genotype was associated with significantly better overall survival (OS; P=0.02; Fig1). No difference was noted in transplant-related mortality, disease relapse or graft-versus-host disease in relation to the recipients' polymorphism. The multivariate analysis showed that in patients with low risk disease, the recipient GG or GC genotype remained statistically significant for better OS (hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.30 to 1.01; P=0.05). The donor CXCL10 genotypes did not significantly influence the transplant outcomes. These results suggest an association of the recipient GG or GC genotypes with better transplant outcomes after unrelated HLA-matched BMT. These findings could therefore be useful in creating therapeutic strategies such as risk-adapted management of transplanted patients. Disclosures: No relevant conflicts of interest to declare.

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Hokeness, Kirsten L., Elizabeth S. Deweerd, Michael W. Munks, Casey A. Lewis, Ronald P. Gladue, and Thais P. Salazar-Mather. "CXCR3-Dependent Recruitment of Antigen-Specific T Lymphocytes to the Liver during Murine Cytomegalovirus Infection." Journal of Virology 81, no. 3 (November 15, 2006): 1241–50. http://dx.doi.org/10.1128/jvi.01937-06.

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ABSTRACT Innate inflammatory events promoting antiviral defense in the liver against murine cytomegalovirus (MCMV) infection have been characterized. However, the mechanisms that regulate the selective recruitment of inflammatory T lymphocytes to the liver during MCMV infection have not been defined. The studies presented here demonstrate the expression of monokine induced by gamma interferon (IFN-γ; Mig/CXCL9) and IFN-γ-inducible protein 10 (IP-10/CXCL10) in liver leukocytes and correlate their production with the infiltration of MCMV-specific CD8 T cells into the liver. Antibody-mediated neutralization of CXCL9 and CXCL10 and studies using mice deficient in CXCR3, the primary known receptor for these chemokines, revealed that CXCR3-dependent mechanisms promote the infiltration of virus-specific CD8 T cells into the liver during acute infection with MCMV. Furthermore, CXCR3 functions augmented the hepatic accumulation of CD8 T-cell IFN-γ responses to MCMV. Evaluation of protective functions demonstrated enhanced pathology that overlapped with transient increases in virus titers in CXCR3-deficient mice. However, ultimate viral clearance and survival were not compromised. Thus, CXCR3-mediated signals support the accumulation of MCMV-specific CD8 T cells that contribute to, but are not exclusively required for, protective responses in a virus-infected tissue site.

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Widney, Daniel P., Yan Hu, Amy K. Foreman-Wykert, Kim C. Bui, Tam T. Nguyen, Bao Lu, Craig Gerard, Jeff F. Miller, and Jeffrey B. Smith. "CXCR3 and Its Ligands Participate in the Host Response to Bordetella bronchiseptica Infection of the Mouse Respiratory Tract but Are Not Required for Clearance of Bacteria from the Lung." Infection and Immunity 73, no. 1 (January 2005): 485–93. http://dx.doi.org/10.1128/iai.73.1.485-493.2005.

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ABSTRACT Intranasal inoculation of mice with Bordetella bronchiseptica produces a transient pneumonia that is cleared over several weeks in a process known to require both neutrophils and lymphocytes. In this study, we evaluated the roles of the chemokines MIG (CXCL9), IP-10 (CXCL10), and I-TAC (CXCL11) and their common receptor, CXCR3. Following bacterial inoculation, message expression of interleukin-1 (IL-1), IL-6, and the neutrophil-attracting chemokines KC, LIX, and MIP-2 was rapidly induced, with maximal expression found at 6 h. In contrast, message expression of gamma interferon, MIG, IP-10, and I-TAC peaked at 2 days. Expression of all of these chemokines and cytokines returned to near baseline by 5 days, despite the persistence of high levels of live bacteria at this time. Induced MIG, IP-10, and I-TAC protein expression was localized in areas of inflammation at 2 to 3 days and was temporally associated with increased levels of CXCR3+ lymphocytes in bronchoalveolar lavage fluid. There was no increase in mortality in mice lacking CXCR3. However, the clearance of bacteria from the lung and trachea was delayed, and the recruitment of lymphocytes and NK cells was slightly decreased, for CXCR3−/− mice relative to CXCR3+/+ mice. We conclude that the CXCR3 receptor-ligand system contributes to pulmonary host defense in B. bronchiseptica infection by recruiting lymphocytes and NK cells into the lung.

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Lee, Silvia, Julius Varano, James P. Flexman, Wendy Cheng, Mark W. Watson, Enrico Rossi, Leon A. Adams, Max Bulsara, and Patricia Price. "Decreased IP-10 and Elevated TGFβ1 Levels are Associated with Viral Clearance Following Therapy in Patients with Hepatitis C Virus." Disease Markers 28, no. 5 (2010): 273–80. http://dx.doi.org/10.1155/2010/706984.

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The role of pro-fibrogenic cytokines in the outcome of infections with hepatitis C virus (HCV) and the response to treatment with pegylated interferon-alpha (pegIFNα) and ribavirin remains unclear. To address this issue, we assessed hepatic fibrosis and plasma markers pertinent to T-cell mediated fibrogenesis and inflammation at the start of treatment. Levels of soluble (s)CD30, interleukin-13 receptor alpha 2 (IL-13Rα2), total and active transforming growth factor-beta 1 (TGFβ1), interleukin-18 (IL-18) and interferon-gamma inducible protein-10 (IP-10, CXCL10) were correlated with the severity of fibrosis and with treatment outcome using multiple logistic regression modelling. The Hepascore algorithm was confirmed as a marker of fibrosis, but was a poor predictor of treatment outcome. Inclusion of all immunological markers improved prediction based on Hepascore alone (p= 0.045), but optimal prediction was achieved with an algorithm (“TIPscore”) based on TGFβ1 (total), IP-10, age, sex and HCV genotype (p= 0.003 relative to Hepascore). Whilst this was only marginally more effective than predictions based on HCV genotype age and sex (p= 0.07), it associates high TGFβ1 and low IP-10 levels with a failure of therapy.

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Zaidi, Wahaj, Lawrence J. Saubermann, Victor M. Morales, Keely R. Parisian, and Gianni Harris. "W1140 Differentiation Between Ulcerative Colitis and Crohn's Disease Based On Longitudinal Measurement of Interferon-Gamma Inducible CXCL10 Chemokine Serum Levels." Gastroenterology 134, no. 4 (April 2008): A—642. http://dx.doi.org/10.1016/s0016-5085(08)62994-7.

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Milush, Jeffrey M., Kelly Stefano-Cole, Kimberli Schmidt, Andre Durudas, Ivona Pandrea, and Donald L. Sodora. "Mucosal Innate Immune Response Associated with a Timely Humoral Immune Response and Slower Disease Progression after Oral Transmission of Simian Immunodeficiency Virus to Rhesus Macaques." Journal of Virology 81, no. 12 (April 11, 2007): 6175–86. http://dx.doi.org/10.1128/jvi.00042-07.

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ABSTRACT Mucosal transmission is the predominant mode of human immunodeficiency virus (HIV) infection worldwide, and the mucosal innate interferon response represents an important component of the earliest host response to the infection. Our goal here was to assess the changes in mRNA expression of innate mucosal genes after oral simian immunodeficiency virus (SIV) inoculation of rhesus macaques (Macaca mulatta) that were followed throughout their course of disease progression. The SIV plasma viral load was highest in the macaque that progressed rapidly to simian AIDS (99 days) and lowest in the macaque that progressed more slowly (>700 days). The mRNA levels of six innate/effector genes in the oral mucosa indicated that slower disease progression was associated with increased expression of these genes. This distinction was most evident when comparing the slowest-progressing macaque to the intermediate and rapid progressors. Expression levels of alpha and gamma interferons, the antiviral interferon-stimulated gene product 2′-5′ oligoadenylate synthetase (OAS), and the chemokines CXCL9 and CXCL10 in the slow progressor were elevated at each of the three oral mucosal biopsy time points examined (day 2 to 4, 14 to 21, and day 70 postinfection). In contrast, the more rapidly progressing macaques demonstrated elevated levels of these cytokine/chemokine mRNA at lymph nodes, coincident with decreased levels at the mucosal sites, and a decreased ability to elicit an effective anti-SIV antibody response. These data provide evidence that a robust mucosal innate/effector immune response is beneficial following lentiviral exposure; however, it is likely that the anatomical location and timing of the response need to be coordinated to permit an effective immune response able to delay progression to simian AIDS.

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Ganesan, Priya, Larissa Bohn, and Lauren O’Donnell. "Failure to control measles virus spread in the neonatal CNS despite immune cell infiltration and cytokine production." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 217.24. http://dx.doi.org/10.4049/jimmunol.196.supp.217.24.

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Abstract Viral infections in the central nervous system (CNS) are associated with devastating neurological consequences in newborns. This may be due, in part, to deficiencies in the immature innate and adaptive immune response. To study viral CNS infections in neonates, we use a transgenic mouse model of neuronally-restricted measles virus (MV) infection (NSE-CD46 mice), where the human isoform of CD46, a MV receptor, is expressed under the control of the neuron-specific enolase promoter. Adult CD46+ mice survive infection and clear MV in an interferon gamma (IFNg)- and T cell-dependent manner. In contrast, neonatal CD46+ mice succumb to the infection despite T cell infiltration into the brain parenchyma. Neonatal mice lacking IFNg succumb more rapidly than wildtype pups despite higher T cell infiltration, equivalent natural killer cell infiltration, and microglial activation. Quantitative RT-PCR analysis demonstrated upregulation of pro-inflammatory cytokines and chemokines such as IFNg, IL-1β, and CXCL10, as well as the anti-inflammatory interleukin 1 receptor antagonist in infected adults and neonates. IL-12β, IL-23, CCL2, and TNF were significantly upregulated in infected neonates only. These results suggest the neonates are capable of cytokine production with a Th1-like profile within the CNS, but that the cytokine milieu is ineffective at controlling MV spread. Current experiments aim to inhibit inflammatory mediators such as CXCL10 and CCL2 that are expressed in an age-dependent manner during infection to determine if there is an improvement in neuropathology and survival of neonates.

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Verzijl, Dennis, Carlos P. Fitzsimons, Marie van Dijk, James P. Stewart, Henk Timmerman, Martine J. Smit, and Rob Leurs. "Differential Activation of Murine Herpesvirus 68- and Kaposi's Sarcoma-Associated Herpesvirus-Encoded ORF74 G Protein-Coupled Receptors by Human and Murine Chemokines." Journal of Virology 78, no. 7 (April 1, 2004): 3343–51. http://dx.doi.org/10.1128/jvi.78.7.3343-3351.2004.

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ABSTRACT Infection of mice with murine gammaherpesvirus 68 (MHV-68) is a well-characterized small animal model for the study of gammaherpesvirus infection. MHV-68 belongs to the same herpesvirus family as herpesvirus saimiri (HVS) of New World squirrel monkeys and human herpesvirus 8 (HHV-8) (also referred to as Kaposi's sarcoma-associated herpesvirus [KSHV]). The open reading frame ORF74 of HVS, KSHV, and MHV-68 encodes a protein with homology to G protein-coupled receptors and chemokine receptors in particular. ORF74 of KSHV (human ORF74 [hORF74]) is highly constitutively active and has been implicated in the pathogenesis of Kaposi's sarcoma. MHV-68-encoded ORF74 (mORF74) is oncogenic and has been implicated in viral replication and reactivation from latency. Here, we show that mORF74 is a functional chemokine receptor. Chemokines with an N-terminal glutamic acid-leucine-arginine (ELR) motif (e.g., KC and macrophage inflammatory protein 2) act as agonists on mORF74, activating phospholipase C, NF-κB, p44/p42 mitogen-activated protein kinase, and Akt signaling pathways and inhibiting formation of cyclic AMP. Using 125I-labeled CXCL1/growth-related oncogene α as a tracer, we show that murine CXCL10/gamma interferon-inducible protein 10 binds mORF74, and functional assays show that it behaves as an antagonist for this virally encoded G protein-coupled receptor. Profound differences in the upstream activation of signal transduction pathways between mORF74 and hORF74 were found. Moreover, in contrast to hORF74, no constitutive activity of mORF74 could be detected.

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Smit, Martine J., Dennis Verzijl, Paola Casarosa, Marjon Navis, Henk Timmerman, and Rob Leurs. "Kaposi's Sarcoma-Associated Herpesvirus-Encoded G Protein-Coupled Receptor ORF74 Constitutively Activates p44/p42 MAPK and Akt via Gi and Phospholipase C-Dependent Signaling Pathways." Journal of Virology 76, no. 4 (February 15, 2002): 1744–52. http://dx.doi.org/10.1128/jvi.76.4.1744-1752.2002.

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ABSTRACT The G protein-coupled receptor encoded by Kaposi's sarcoma-associated herpesvirus, also referred to as ORF74, has been shown to stimulate oncogenic and angiogenic signaling pathways in a constitutively active manner. The biochemical routes linking ORF74 to these signaling pathways are poorly defined. In this study, we show that ORF74 constitutively activates p44/p42 mitogen-activated protein kinase (MAPK) and Akt via Gi- and phospholipase C (PLC)-mediated signaling pathways. Activation of Akt by ORF74 appears to be phosphatidylinositol 3-kinase (PI3-K) dependent but, interestingly, is also mediated by activation of protein kinase C (PKC) and p44/p42 MAPK. ORF74 may signal to Akt via p44/p42 MAPK, which can be activated by Gi, through activation of PI3-K or through PKC via the PLC pathway. Signaling of ORF74 to these proliferative and antiapoptotic signaling pathways can be further modulated positively by growth-related oncogene (GROα/CXCL1) and negatively by human gamma interferon-inducible protein 10 (IP-10/CXCL10), thus acting as an agonist and an inverse agonist, respectively. Despite the ability of the cytomegalovirus-encoded chemokine receptor US28 to constitutively activate PLC, this receptor does not increase phosphorylation of p44/p42 MAPK or Akt in COS-7 cells. Hence, ORF74 appears to signal through a larger diversity of G proteins than US28, allowing it to couple to proliferative and antiapoptotic signaling pathways. ORF74 can therefore be envisioned as an attractive target for novel treatment of Kaposi's sarcoma.

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Abel, Kristina, Lisa La Franco-Scheuch, Tracy Rourke, Zhong-Min Ma, Veronique de Silva, Beth Fallert, Laurel Beckett, Todd A. Reinhart, and Christopher J. Miller. "Gamma Interferon-Mediated Inflammation Is Associated with Lack of Protection from Intravaginal Simian Immunodeficiency Virus SIVmac239 Challenge in Simian-Human Immunodeficiency Virus 89.6-Immunized Rhesus Macaques." Journal of Virology 78, no. 2 (January 15, 2004): 841–54. http://dx.doi.org/10.1128/jvi.78.2.841-854.2004.

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ABSTRACT Although gamma interferon (IFN-γ) is a key mediator of antiviral defenses, it is also a mediator of inflammation. As inflammation can drive lentiviral replication, we sought to determine the relationship between IFN-γ-related host immune responses and challenge virus replication in lymphoid tissues of simian-human immunodeficiency virus 89.6 (SHIV89.6)-vaccinated and unvaccinated rhesus macaques 6 months after challenge with simian immunodeficiency virus SIVmac239. Vaccinated-protected monkeys had low tissue viral RNA (vRNA) levels, vaccinated-unprotected animals had moderate tissue vRNA levels, and unvaccinated animals had high tissue vRNA levels. The long-term challenge outcome in vaccinated monkeys was correlated with the relative balance between SIV-specific IFN-γ T-cell responses and nonspecific IFN-γ-driven inflammation. Vaccinated-protected monkeys had slightly increased tissue IFN-γ mRNA levels and a high frequency of IFN-γ-secreting T cells responding to in vitro SIVgag peptide stimulation; thus, it is likely that they could develop effective anti-SIV cytotoxic T lymphocytes in vivo. In contrast, both high tissue IFN-γ mRNA levels and strong in vitro SIV-specific IFN-γ T-cell responses were detected in lymphoid tissues of vaccinated-unprotected monkeys. Unvaccinated monkeys had increased tissue IFN-γ mRNA levels but weak in vitro anti-SIV IFN-γ T-cell responses. In addition, in lymphoid tissues of vaccinated-unprotected and unvaccinated monkeys, the increased IFN-γ mRNA levels were associated with increased Mig/CXCL9, IP-10/CXCL10, and CXCR3 mRNA levels, suggesting that increased Mig/CXCL9 and IP-10/CXCL10 expression resulted in recruitment of CXCR3+ activated T cells. Thus, IFN-γ-driven inflammation promotes SIV replication in vaccinated-unprotected and unvaccinated monkeys. Unlike all unvaccinated monkeys, most monkeys vaccinated with SHIV89.6 did not develop IFN-γ-driven inflammation, but they did develop effective antiviral CD8+-T-cell responses.

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Antonelli, Alessandro, Mario Rotondi, Poupak Fallahi, Paola Romagnani, Silvia Martina Ferrari, Lucio Barani, Ele Ferrannini, and Mario Serio. "Increase of interferon-gamma-inducible CXC chemokine CXCL10 serum levels in patients with active Graves' disease, and modulation by methimazole therapy." Clinical Endocrinology 64, no. 2 (February 2006): 189–95. http://dx.doi.org/10.1111/j.1365-2265.2006.02447.x.

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Chen, Jun, Yuk Fai Lau, Elaine W. Lamirande, Christopher D. Paddock, Jeanine H. Bartlett, Sherif R. Zaki, and Kanta Subbarao. "Cellular Immune Responses to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection in Senescent BALB/c Mice: CD4+ T Cells Are Important in Control of SARS-CoV Infection." Journal of Virology 84, no. 3 (November 11, 2009): 1289–301. http://dx.doi.org/10.1128/jvi.01281-09.

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ABSTRACT We characterized the cellular immune response to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in 12- to 14-month-old BALB/c mice, a model that mimics features of the human disease. Following intranasal administration, the virus replicated in the lungs, with peak titers on day 2 postinfection. Enhanced production of cytokines (tumor necrosis factor alpha [TNF-α] and interleukin-6 [IL-6]) and chemokines (CXCL10, CCL2, CCL3, and CCL5) correlated with migration of NK cells, macrophages, and plasmacytoid dendritic cells (pDC) into the lungs. By day 7, histopathologic evidence of pneumonitis was seen in the lungs when viral clearance occurred. At this time, a second wave of enhanced production of cytokines (TNF-α, IL-6, gamma interferon [IFN-γ], IL-2, and IL-5), chemokines (CXCL9, CXCL10, CCL2, CCL3, and CCL5), and receptors (CXCR3, CCR2, and CCR5), was detected in the lungs, associated with an influx of T lymphocytes. Depletion of CD8+ T cells at the time of infection did not affect viral replication or clearance. However, depletion of CD4+ T cells resulted in an enhanced immune-mediated interstitial pneumonitis and delayed clearance of SARS-CoV from the lungs, which was associated with reduced neutralizing antibody and cytokine production and reduced pulmonary recruitment of lymphocytes. Innate defense mechanisms are able to control SARS-CoV infection in the absence of CD4+ and CD8+ T cells and antibodies. Our findings provide new insights into the pathogenesis of SARS, demonstrating the important role of CD4+ but not CD8+ T cells in primary SARS-CoV infection in this model.

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Ganesan, Priya, Alison M. Kuhn, Abigail A. Dunphy, and Lauren A. O’Donnell. "Role of innate immunity in neonates during a viral CNS infection." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 214.10. http://dx.doi.org/10.4049/jimmunol.198.supp.214.10.

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Abstract Viral infections in the central nervous system (CNS) are associated with devastating neurological consequences in newborns. This may be due, in part, to deficiencies in the immature innate and adaptive immune response. To study viral CNS infections in neonates, we use a transgenic mouse model of neuronally-restricted measles virus (MV) infection (NSE-CD46 mice), where the human isoform of CD46, a MV receptor, is expressed under the control of the neuron-specific enolase promoter. Adult CD46+ mice survive infection and control MV in an interferon gamma (IFNg)- and T cell-dependent manner. In contrast, neonatal CD46+ mice succumb to the infection despite T cell infiltration into the brain parenchyma. CD46+/RAG2-KO neonates, which lack T- and B-cells, experience less severe disease, prolonged survival, and lower viral load compared to CD46+ neonates. CD46+/RAG2-KO neonates also show greater infiltration of neutrophils and natural killer cells and higher expression of the pathogen recognition receptors melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIGI) during infection. Both CD46+ and CD46+/RAG2-KO neonates upregulate IFNg but CD46+/RAG2-KO neonates show higher expression of IFN-beta. CXCL10, a IFNg inducible chemokine, is also upregulated in CD46+ neonates (84-fold) and CD46+/RAG2-KO neonates (771-fold). Current studies aim to explore the role of IFN-beta in early viral control in the neonates and explore the contribution of CXCL10 in the infiltration of innate immune cells in the CNS. Supported by 1R15NS087606-01A1.

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Fuller, Craig L., JoAnne L. Flynn, and Todd A. Reinhart. "In Situ Studyof Abundant Expression of Proinflammatory Chemokines and Cytokines inPulmonary Granulomas That Develop in Cynomolgus MacaquesExperimentally Infected with Mycobacteriumtuberculosis." Infection and Immunity 71, no. 12 (December 2003): 7023–34. http://dx.doi.org/10.1128/iai.71.12.7023-7034.2003.

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ABSTRACT Tuberculosis remains a major public health problem worldwide. Chemokines and cytokines organize and direct infiltrating cells to sites of infection, and these molecules likely play crucial roles in granuloma formation and maintenance. To address this issue, we used in situ hybridization (ISH) to measure chemokine and cytokine mRNA expression levels and patterns directly in lung tissues from cynomolgus macaques (Macaca fascicularis) experimentally infected with a low dose of virulent Mycobacterium tuberculosis. We examined more than 300 granulomas and observed abundant expression of gamma interferon (IFN-γ)-inducible chemokine mRNAs (CXCL9/monokine induced by IFN-γ, CXCL10/IFN-γ-inducible protein, and CXCL11/IFN-γ-inducible T-cell α-chemoattractant) within solid and caseous granulomas, and there was only minimal expression in nongranulomatous regions of tissue. The mRNA expression patterns of IFN-γ and tumor necrosis factor alpha were examined in parallel, and the results revealed that cytokine mRNA+ cells were abundant and generally localized to the granulomas. Mycobacterial 16S rRNA expression was also measured by ISH, and the results revealed that there was localization predominantly to the granulomas and that the highest signal intensity was in caseous granulomas. We observed several granulomatous lesions with exceptionally high levels of RNA for mycobacterial 16S rRNA, IFN-γ, and IFN-γ-inducible chemokines, suggesting that the local presence of mycobacteria is partially responsible for the upregulation of IFN-γ-inducible chemokines and recruitment of CXCR3+ cells, which were also abundant in granulomatous lesions. These results suggest that expression of CXCR3 ligands and the subsequent recruitment of CXCR3+ cells are involved in granuloma formation and maintenance.

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Thapa, Manoj, and Daniel J. J. Carr. "CXCR3 Deficiency Increases Susceptibility to Genital Herpes Simplex Virus Type 2 Infection: Uncoupling of CD8+ T-Cell Effector Function but Not Migration." Journal of Virology 83, no. 18 (July 8, 2009): 9486–501. http://dx.doi.org/10.1128/jvi.00854-09.

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ABSTRACT CXCR3 is a G-protein-coupled receptor preferentially expressed by activated T cells, NK cells, and dendritic cells. Signaling through gamma interferon-regulated chemokines CXCL9, CXCL10, CXCL11, and CXCR3 plays a critical role in the immune response of many viral pathogens. However, the relevance of CXCR3 for optimal T-cell activation and the induction of regulatory transcription factors (i.e., T-bet and eomesodermin) relative to host immune defense against genital herpes simplex virus type 2 (HSV-2) infection have been poorly defined. In this study, we evaluated the requirement of CXCR3 expression during genital HSV-2 infection using mice deficient in CXCR3 (CXCR3−/−) along with wild-type (WT) controls, assessing the resistance of mice to viral infection and focusing on the cytokine/chemokine response, phenotypic analysis of recruited leukocytes, and functional analysis of CD8+ T cells. CXCR3−/− mice showed a heightened sensitivity to infection compared to WT animals in terms of the viral burden in infected tissues as well as elevated mortality. The poor response of CXCR3−/− mice to viral infection was associated with reduced cytotoxic T-lymphocyte activity through the impairment of T-bet, perforin, and granzyme B expression by CD8+ T cells. Corresponding with the defective cytolytic activity, a reduction in recruitment of plasmacytoid dendritic cells and CD80 expression in CD11c+ dendritic cells in the draining lymph nodes of CXCR3−/− mice were detected. Collectively, the results provide a new perspective to CXCR3 signaling for the appropriate activation of CD8+ T cells required for host defense against genital HSV-2 infection.

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Cernetich, Amy, Lindsey S. Garver, Anne E. Jedlicka, Pamela W. Klein, Nirbhay Kumar, Alan L. Scott, and Sabra L. Klein. "Involvement of Gonadal Steroids and Gamma Interferon in Sex Differences in Response to Blood-Stage Malaria Infection." Infection and Immunity 74, no. 6 (June 2006): 3190–203. http://dx.doi.org/10.1128/iai.00008-06.

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ABSTRACT To examine the hormonal and immunological mechanisms that mediate sex differences in susceptibility to malaria infection, intact and gonadectomized (gdx) C57BL/6 mice were inoculated with Plasmodium chabaudi AS-infected erythrocytes, and the responses to infection were monitored. In addition to reduced mortality, intact females recovered from infection-induced weigh loss and anemia faster than intact males. Expression microarrays and real-time reverse transcription-PCR revealed that gonadally intact females exhibited higher expression of interleukin-10 (IL-10), IL-15Rα, IL-12Rβ, Gadd45γ, gamma interferon (IFN-γ), CCL3, CXCL10, CCR5, and several IFN-inducible genes in white blood cells and produced more IFN-γ than did intact males and gdx females, with these differences being most pronounced during peak parasitemia. Intact females also had higher anti-P. chabaudi immunoglobulin G (IgG) and IgG1 responses than either intact males or gdx females. To further examine the effector mechanisms mediating sex differences in response to P. chabaudi infection, responses to infection were compared among male and female wild-type (WT), T-cell-deficient (TCRβδ−/−), B-cell-deficient (μMT), combined T- and B-cell-deficient (RAG1), and IFN-γ knockout (IFN-γ−/−) mice. Males were 3.5 times more likely to die from malaria infection than females, with these differences being most pronounced among TCRβδ−/−, μMT, and RAG1 mice. Male mice also exhibited more severe weight loss, anemia, and hypothermia, and higher peak parasitemia than females during infection, with WT, RAG1, TCRβδ−/−, and μMT mice exhibiting the most pronounced sexual dimorphism. The absence of IFN-γ reduced the sex difference in mortality and was more detrimental to females than males. These data suggest that differential transcription and translation of IFN-γ, that is influenced by estrogens, may mediate sex differences in response to malaria.

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Journal articles on the topic 'Interferon Gamma CXCL10'

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