Leishmaniasis is an important neglected tropical disease that occurs worldwide, and is caused by several different parasites with different characteristics. L. braziliensis infections are particularly distinct from other forms of leishmaniasis, since disease severity is not due to uncontrolled parasite replication, but rather t an exaggerated immune response. Thus, therapeutics designed to increase parasite killing are detrimental if they concomitantly enhance inflammatory responses. Our new data strongly suggests that optimal control of L. braziliensis requires a response that not only effectively eliminates the parasite, but also reduces the potential for immunopathology. We have made two unexpected observations demonstrating that CD8 T cells contribute to leishmanial immunopathology. First, we find that unregulated CD8 T cells mediate severe perforin-dependent pathology, which is associated with CD8 T cell killing of infected cells. Furthermore, we also find that CD8 T cells promote increased metastasis of the parasites, which provides a model to investigate the factors contributing to the development of metastatic lesions in patients. Second, we find that mice that have resolved an infection with lymphocytic choriomeningitis virus (LCMV) maintain an expanded CD8 pool and, when challenged with Leishmania, recruit large numbers of LCMV specific CD8 T cells to the lesions, with an associated increase in disease severity. In contrast to Leishmania-specific CD8 T cells that can kill Leishmania infected target cells, we hypothesize that these LCMV specific CD8 T cells (or bystander T cells) promote increased inflammation either due to non-specific lysis of target cells via an activating receptor known as NKG2D, or due to cytokine-induced release of granzyme B (GrzB). These findings suggest that control of the pathogenic activity of CD8 T cells might be a good approach for developing new immunotherapies for cutaneous leishmaniasis. We propose three specific aims to advance our understanding of the disease and provide a foundation for new therapeutic approaches.
In Aim 1 we will evaluate how the lesion environment influences CD8 function. We find that CD8 T cell function is determined by the cytokine milieu and we propose experiments to determine if pathogenic CD8 T cells can be converted to protective cells.
In Aim 2, we focus on defining how the bystander CD8 T cells promote increased disease, particularly focusing on the role of NKG2D and GzmB. Finally, in Aim 3 we will determine how CD8 T cells become protective following resolution of a primary infection. Taken together, these studies will provide new information about this disease that can be translated into new therapies.

Public Health Relevance

Leishmaniasis is a serious neglected tropical disease where destructive cutaneous lesions develop. These are caused both by the parasites and the immunopathologic response to infection. The studies in this proposal seek to define the mechanisms responsible for the pathology seen in cutaneous leishmaniasis, with the goal of designing new therapeutic approaches to lessening the impact of this disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Pathogenic Eukaryotes Study Section (PTHE)
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Wali, Tonu M
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University of Pennsylvania
Schools of Veterinary Medicine
United States
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Novais, Fernanda O; Wong, Andrea C; Villareal, Daniel O et al. (2018) CD8+ T Cells Lack Local Signals To Produce IFN-? in the Skin during Leishmania Infection. J Immunol 200:1737-1745
Gimblet, Ciara; Meisel, Jacquelyn S; Loesche, Michael A et al. (2017) Cutaneous Leishmaniasis Induces a Transmissible Dysbiotic Skin Microbiota that Promotes Skin Inflammation. Cell Host Microbe 22:13-24.e4
Novais, Fernanda O; Carvalho, Augusto M; Clark, Megan L et al. (2017) CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1? production. PLoS Pathog 13:e1006196
Weinkopff, Tiffany; Konradt, Christoph; Christian, David A et al. (2016) Leishmania major Infection-Induced VEGF-A/VEGFR-2 Signaling Promotes Lymphangiogenesis That Controls Disease. J Immunol 197:1823-31
Scott, Phillip; Novais, Fernanda O (2016) Cutaneous leishmaniasis: immune responses in protection and pathogenesis. Nat Rev Immunol 16:581-92
Davis, Kimberly M; Isberg, Ralph R (2016) Defining heterogeneity within bacterial populations via single cell approaches. Bioessays 38:782-90
Crosby, Erika J; Clark, Megan; Novais, Fernanda O et al. (2015) Lymphocytic Choriomeningitis Virus Expands a Population of NKG2D+CD8+ T Cells That Exacerbates Disease in Mice Coinfected with Leishmania major. J Immunol 195:3301-10
Novais, Fernanda O; Scott, Phillip (2015) CD8+ T cells in cutaneous leishmaniasis: the good, the bad, and the ugly. Semin Immunopathol 37:251-9
Gimblet, Ciara; Loesche, Michael A; Carvalho, Lucas et al. (2015) IL-22 Protects against Tissue Damage during Cutaneous Leishmaniasis. PLoS One 10:e0134698