Impaired responsiveness to gamma interferon of macrophages infected with lymphocytic choriomeningitis virus clone 13: susceptibility to histoplasmosis

Villarete, Lorelie; Fries, R de; Kolhekar, S. R.; Howard, Dexter H.; Ahmed, Rafi; Wu-Hsieh, Betty A.

doi:10.1128/iai.63.4.1468-1472.1995

Cited by 6 publications

(1 citation statement)

References 22 publications

(34 reference statements)

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“…These data support a role for CD8 T cells in protection when CD4 T cells are deficient. Macrophage-tropic LCMV clone 13 variant decreases the response of murine macrophage to IFN-␥ in vitro, resulting in the uncontrolled replication of Histoplasma capsulatum (50,52). Double infection with LCMV clone 13 and H. capsulatum is also associated with reduced antifungal immunity mediated by CD8 T cells (53).…”

Section: Cells Similarly Depletion Of T-cell Subsets During Latencymentioning

confidence: 99%

Virally Activated CD8 T Cells Home toMycobacterium bovisBCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

Hogan

Karman

et al. 2007

Infect Immun

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The effect of secondary infections on CD4 T-cell-regulated chronic granulomatous inflammation is not well understood. Here, we have investigated the effect of an acute viral infection on the cellular composition and bacterial protection in Mycobacterium bovis strain bacille Calmette-Guérin (BCG)-induced granulomas using an immunocompetent and a partially immunodeficient murine model. Acute lymphocytic choriomeningitis virus (LCMV) coinfection of C57BL/6 mice led to substantial accumulation of gamma interferon (IFN-␥)-producing LCMV-specific T cells in liver granulomas and increased local IFN-␥. Despite traffic of activated T cells that resulted in a CD8 T-cell-dominated granuloma, the BCG liver organ load was unaltered from control levels. In OT-1 T-cell-receptor (TCR) transgenic mice, ovalbumin (OVA) immunization or LCMV coinfection of BCG-infected mice induced CD8 T-cell-dominated granulomas containing large numbers of non-BCGspecific activated T cells. The higher baseline BCG organ load in this CD8 TCR transgenic animal allowed us to demonstrate that OVA immunization and LCMV coinfection increased anti-BCG protection. The bacterial load remained substantially higher than in mice with a more complete TCR repertoire. Overall, the present study suggests that peripherally activated CD8 T cells can be recruited to chronic inflammatory sites, but their contribution to protective immunity is limited to conditions of underlying immunodeficiency.Immune responses to chronic infections by intracellular pathogens include delayed-type hypersensitivity reactions such as granulomatous inflammation. Granuloma formation around infected macrophage prevents dissemination of the pathogen and protects surrounding healthy tissue from inflammatory infiltrates. Immunopathologies can arise from long-term deposition of extracellular matrix around the granuloma, leading to fibrosis and organ damage. CD4 T cells are essential for regulating the formation and ongoing function of granulomas induced in response to many infectious agents and, in the absence of these T cells, chronic infectious diseases, including tuberculosis and histoplasmosis, become widely disseminated (6,29,36).Very little research has been directed at understanding what effect, if any, secondary viral infections may have upon granuloma function. Specifically, we questioned what the role of virally activated CD8 T cells might be in augmenting or disrupting granuloma function in the presence or absence of immune deficiency. Over the course of a lifetime, the opportunities for coinfection with Mycobacterium and an unrelated viral infection are quite widespread (14). We used a mycobacterial model of Mycobacterium bovis strain bacille CalmetteGuérin (BCG) intraperitoneal (i.p.) infection of C57BL/6 mice to model chronic granuloma formation in the liver. At a stage when the infection is chronic, the mice were coinfected with lymphocytic choriomeningitis virus (LCMV) strain Armstrong to induce a dramatic virus-specific immune response. Our studies were designed to answer thre...

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Section: Cells Similarly Depletion Of T-cell Subsets During Latencymentioning

confidence: 99%

Virally Activated CD8 T Cells Home toMycobacterium bovisBCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

Hogan

Karman

et al. 2007

Infect Immun

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Murine Cytomegalovirus Infection Inhibits IFNγ-Induced MHC Class II Expression on Macrophages: The Role of Type I Interferon

et al. 1998

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Macrophage (M phi) activation, as measured by cell surface expression of MHC class II, was examined during infection of immunocompetent and immunocompromised mice with murine cytomegalovirus (MCMV). Intraperitoneal infection of CB17 SCID mice with 10(6) PFU of MCMV elicited a large population of M phi which expressed low levels of MHC class II. This was surprising since infection of SCID mice with lower doses (e.g., 10(4) PFU) of MCMV elicits M phi expressing high levels of MHC class II (M. T. Heise and H. W. Virgin, J. Virol. (1995) 69, 904-909). In vivo administration of recombinant mouse IFN gamma resulted in high levels of MHC class II expression on M phi from control but not MCMV-infected SCID mice, suggesting that MCMV infection generates a state in which IFN gamma is not effective at activating M phi. The effect of MCMV infection was MHC class II specific, since MHC class I and ICAM-1 levels were increased on M phi expressing low levels of MHC class II. Interference with IFN gamma action was not due to productive or abortive infection of M phi. This suggested that MCMV infection induces a soluble factor that alters M phi responsiveness to IFN gamma. Infection of SCID mice with 10(6) PFU of MCMV induced higher levels of serum IFN alpha beta (one candidate for inhibition of IFN gamma induction of MHC class II expression) than infection with 10(4) PFU. We therefore evaluated the role of MCMV-induced IFN alpha beta on IFN gamma responses of bone marrow-derived (BMM phi) or thioglycollate-elicited M phi in vitro. Infection of normal M phi with MCMV at a low m.o.i. (0.1 to 0.2) impaired IFN gamma-mediated induction of M phi MHC class II expression, but not MHC class I expression. Inhibition of IFN gamma responses was not observed in M phi from mice with a null mutation in the IFN alpha beta receptor (IFN alpha beta R-/-). To test the in vivo relevance of virus-induced IFN alpha beta to IFN gamma-mediated responses, the kinetics of MHC class II induction during MCMV infection of IFN alpha beta R-/- mice was evaluated. MCMV-infected IFN alpha beta R-/- mice mounted an earlier M phi MHC class II response than normal mice. We conclude that MCMV infection specifically impairs IFN gamma-mediated MHC class II expression on M phi and that induction of IFN alpha beta is one mechanism by which this inhibition occurs.

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Histoplasmosis

Kleiman¹

2009

Feigin and Cherry's Textbook of Pediatric Infectious Diseases

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Impaired responsiveness to gamma interferon of macrophages infected with lymphocytic choriomeningitis virus clone 13: susceptibility to histoplasmosis

Cited by 6 publications

References 22 publications

Virally Activated CD8 T Cells Home toMycobacterium bovisBCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

Virally Activated CD8 T Cells Home toMycobacterium bovisBCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

Murine Cytomegalovirus Infection Inhibits IFNγ-Induced MHC Class II Expression on Macrophages: The Role of Type I Interferon

Histoplasmosis

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