Lymphocytic Choriomeningitis Virus Expands a Population of NKG2D+CD8+ T Cells That Exacerbates Disease in Mice Coinfected with Leishmania major

Abstract

Leishmaniasis is a significant neglected tropical disease that is associated with a wide range of clinical presentations and a life long persistent infection. Due to the chronic nature of the disease there is a high risk of co-infection occurring in patients, and how co-infections influence the outcome of leishmaniasis is poorly understood. To address this issue, we infected mice with Leishmania major and two weeks later with lymphocytic choriomeningitis virus (LCMV), and 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 co-infection 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 co-infected 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.

Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis

“…This phenotype was due to an increased inflammatory response induced by memory T cells not accompanied by an increased parasite burden. Similar results were observed when mice were first infected with L. major and only 2 wk later coinfected with LCMV (40). In this latter case, a transiently decreased anti-Leishmania immune response was observed 1 wk following LCMV coinfection.…”

Frontline Science: Leishmania mexicana amastigotes can replicate within neutrophils

“…were shown to survive within these cells [7,[36][37][38][39]. In addition, neutrophils are found later in infection within both human and mouse chronic cutaneous Leishmania inflammatory lesions [3,7,16,17,20,21,40]. Neutrophils, through the release of inflammatory mediators and the formation of NETs, can drive inflammation [41].…”

“…In addition, up-regulation of a pattern of neutrophil attracting chemokines was observed by transcriptional profiling of biopsy specimens with chronic dermal lesions as a result of infection with Leishmania panamensis and L. braziliensis, strongly suggesting the presence of neutrophils in these lesions [18,19]. In mice, the presence of neutrophils was reported in lesions of unhealing L. major LV39-infected BALB/c mice [3], in lesions of infected L. major Seidman C57BL/6 mice [20], and in unhealing lesions of C57BL/6 mice coinfected with L. major Friedlin and lymphocytic choriomeningitis virus [21]. Neutrophils were also observed in lesions of Leishmania chagasi-infected dogs [22].…”

Of Mice, Dirty Mice, and Men: Using Mice To Understand Human Immunology

“…Intentional pathogen experience in SPF mice resulted in unanticipated yet substantial effects on graft rejection (40), resistance to infection (41, 42), and de novo adaptive immune responses (43-45). Elegant studies comparing healthy monozygotic and dizygotic human twins revealed that variation in cell population frequencies, cytokine responses, and serum proteins were determined not only by genetics, but also substantially a consequence of non-heritable factors, consistent with the interpretation that environmental and microbial exposure drives much of the immune system variation among individuals (46, 47).…”