Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Cutaneous leishmaniasis is a chronic disease characterized by ulcerating and disfiguring skin lesions. Infection with different species of Leishmania parasites is responsible for the initiation of this disease, yet most of the pathology observed is mediated by an unregulated immune response. The work presented in this thesis investigated the roles of IL-22 and the skin microbiota in regulating immune mediated pathology during cutaneous leishmaniasis. We found that IL-22, a cytokine important in wound repair in the skin, was required to limit pathology when mice were infected with L. major. In order to promote lesion resolution, IL-22 induced keratinocyte migration and decreased IL-1α and IL-1β production, both important stages in tissue repair. Interestingly, this protective role for IL-22 was only observed with a high dose of infection, suggesting a threshold of inflammation is required for IL-22 to limit pathology. We also found that the L. major infection in mice, as well as, L. braziliensis infection in humans caused a dysbiosis in the skin microbiota on lesional skin and nearby skin sites, characterized by a dominance of Staphylococcus spp. or Streptococcus spp. Interestingly, this dysbiotic microbiota was also transmissible to co-housed na�ve skin and exacerbated skin inflammation during L. major infection and during an acute contact hypersensitivity model. These data are the first to demonstrate that a dysbiotic skin microbiota can be transmitted to non-inflamed tissue and demonstrate how a naturally occurring dysbiosis can worsen disease during cutaneous leishmaniasis. Work presented in this thesis demonstrates that both IL-22 and the skin microbiota have distinct roles during cutaneous leishmaniasis. Future studies will be aimed at how these factors can be regulated to aid in the treatment of the disease.
Gimblet-Ochieng, Ciara, "Regulating Immune Mediated Pathology In Cutaneous Leishmaniasis: Roles For Il-22 And Skin Microbiota" (2017). Publicly Accessible Penn Dissertations. 2305.