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1.
J Virol ; 86(11): 6010-22, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22438562

ABSTRACT

Mutations in the genes that encode Fas or Fas ligand (FasL) can result in poor restraints on lymphocyte activation and in increased susceptibility to autoimmune disorders. Because these mutations portend a continuously activated immune state, we hypothesized that they might in some cases confer resistance to infection. To examine this possibility, the immune response to, morbidity caused by, and clearance of vaccinia virus (VACV) Western Reserve was examined in 5- to 7-week-old Fas mutant (lpr) mice, before an overt lymphoproliferative disorder was observable. On day 6 after VACV infection, C57BL/6-lpr (B6-lpr) mice had decreased morbidity, decreased viral titers, and an increased percentage and number of CD4(+) and CD8(+) T cells. As early as day 2 after infection, B6-lpr mice had decreased liver and spleen viral titers and increased numbers of and increased gamma interferon (IFN-γ) production by several different effector cell populations. Depletion of individual effector cell subsets did not inhibit the resistance of B6-lpr mice. Uninfected B6-lpr mice also had increased numbers of NK cells, γδ(+) T cells, and CD44(+) CD4(+) and CD44(+) CD8(+) T cells compared to uninfected B6 mice. Antibody to IFN-γ resulted in increased virus load in both B6 and B6-lpr mice and eliminated the differences in viral titers between them. These results suggest that IFN-γ produced by multiple activated leukocyte populations in Fas-deficient hosts enhances resistance to some viral infections.


Subject(s)
Disease Resistance , Lymphoproliferative Disorders/complications , Vaccinia virus/pathogenicity , Vaccinia/mortality , Vaccinia/virology , fas Receptor/deficiency , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Interferon-gamma/metabolism , Liver/virology , Lymphocyte Subsets/immunology , Lymphoproliferative Disorders/genetics , Mice , Mice, Inbred C57BL , Spleen/virology , Survival Analysis , Vaccinia/immunology , Vaccinia virus/immunology , Viral Load
2.
J Virol ; 83(8): 3528-39, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19193795

ABSTRACT

The bacillus Calmette-Guerin (BCG) strain of Mycobacterium bovis is used in many parts of the world as a vaccine against Mycobacterium tuberculosis. Some epidemiological evidence has suggested that BCG immunization may have unpredicted effects on resistance to other pathogens. We show here in a mouse model that BCG immunization followed by antibiotic treatment to clear the host of the pathogen rendered three strains of mice partially resistant to infection with vaccinia virus (VV) but not to lymphocytic choriomeningitis virus (LCMV). VV-challenged BCG-immune mice developed a striking splenomegaly and elevated CD4 and CD8 T-cell responses by 6 days postinfection (p.i.). However, resistance to VV infection could be seen as early as 1 to 2 days p.i. and was lost after antibody depletion of CD4 T-cell populations. BCG- but not LCMV-immune memory phenotype CD4 T cells preferentially produced gamma interferon (IFN-gamma) in vivo after VV challenge. In contrast, LCMV-immune CD8 T cells preferentially produced IFN-gamma in vivo in response to VV infection. In BCG-immune mice the resistance to VV infection and VV-induced CD4 T-cell IFN-gamma production were ablated by cyclosporine A, which inhibits signaling through the T-cell receptor. This study therefore demonstrates CD4 T-cell-mediated heterologous immunity between a bacterium and virus. Further, it poses the question of whether BCG immunization of humans alters resistance to unrelated pathogens.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Immunity, Innate , Mycobacterium bovis/immunology , Vaccinia virus/immunology , Vaccinia/immunology , Animals , Anti-Bacterial Agents/therapeutic use , CD8-Positive T-Lymphocytes/immunology , Cross Reactions , Cyclosporine/pharmacology , Female , Immunologic Factors/pharmacology , Interferon-gamma/metabolism , Lymphocyte Count , Lymphocytic choriomeningitis virus/immunology , Mice , Mice, Inbred C57BL , Mycobacterium bovis/drug effects , Receptors, Antigen, T-Cell/antagonists & inhibitors , Splenomegaly , Vaccinia/prevention & control
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