Lymphocytic Choriomeningitis Virus Expands a Population of NKG2D+CD8+ T Cells That Exacerbates Disease in Mice Coinfected with Leishmania major.
Leishmaniasis is a significant neglected tropical disease that is associated with a wide range of clinical presentations and a lifelong persistent infection. Because of the chronic nature of the disease, there is a high risk for coinfection occurring in patients, and how coinfections influence the outcome of leishmaniasis is poorly understood. To address this issue, we infected mice with Leishmania major and 2 wk later with lymphocytic choriomeningitis virus (LCMV) and then monitored the course of infection. Leishmania parasites are controlled by production of IFN-γ, which leads to macrophage-mediated parasite killing. Thus, one might predict that coinfection with LCMV, which induces a strong systemic type 1 response, would accelerate disease resolution. However, we found that infection with LCMV led to significantly enhanced disease in L. major-infected animals. This increased disease correlated with an infiltration into the leishmanial lesions of NKG2D(+) CD8(+) T cells producing granzyme B, but surprisingly little IFN-γ. We found that depletion of CD8 T cells after viral clearance, as well as blockade of NKG2D, reversed the increased pathology seen in coinfected mice. Thus, this work highlights the impact a secondary infection can have on leishmaniasis and demonstrates that even pathogens known to promote a type 1 response may exacerbate leishmanial infections.
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
Erika J
EJ
Crosby
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
Megan
M
Clark
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and.
Fernanda O
FO
Novais
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
E John
EJ
Wherry
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and pscott@vet.upenn.edu.
Phillip
P
Scott
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060085:Coinfection / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D053804:Granzymes / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018320:Leishmania major / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000469:parasitology; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*
D016207:Cytokines; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse