Document Type

Dissertation

Date of Degree

Spring 2016

Degree Name

PhD (Doctor of Philosophy)

Degree In

Molecular and Cell Biology

First Advisor

Mary E. Wilson

Abstract

Leishmania species are vector-borne protozoan parasites that cause a spectrum of human diseases, with an estimated 12 million people infected in 88 countries. Inflammation plays distinct roles in the different clinical syndromes. Visceral leishmaniasis, in which parasites migrate from the site of infection and proliferate in liver and spleen, is accompanied by systemic immune suppression. Cutaneous leishmaniasis, where parasites remain at the site of inoculation and create a long-term ulcer, is associated with vigorous systemic immunity to the parasite. The innate immune sensing pathways responding to Leishmania spp. parasites are not fully described.

NLR proteins are a class of structurally related cytosolic proteins. The most well described NLRs form inflammasome complexes that generate strong inflammatory responses to “danger” signals. Other NLRs do not form inflammasomes and have anti-inflammatory functions. While NLR proteins are known to be important in the immune response to many pathogens, the roles NLR proteins in leishmaniasis have only begun to be investigated. We hypothesized that NLR proteins affect the pathogenesis of leishmaniasis through their ability to modulate inflammatory responses. We hypothesized that inflammasome activation in cutaneous leishmaniasis would be detrimental, leading to greater disease pathology, and that the potential anti-inflammatory functions of the non-inflammasome NLRs, NLRP6, NLRP10, and NLRP12, would be protective, reducing tissue damage. In contrast, we hypothesized that in visceral leishmaniasis greater inflammation due to activation of the inflammasome would be protective and control parasite replication, while the anti-inflammatory NLRs would be permissive to parasite replication in the liver and spleen by contributing to the immunosuppressive strategy of the parasite. We used knockout mouse strains lacking the inflammasome adaptor protein ASC, and several non-inflammasome forming NLRs, to investigate NLR proteins in murine models of visceral or cutaneous leishmaniasis.

Our data showed that NLR proteins have important functions in visceral leishmaniasis, where they are essential for appropriate parasite homing and replication in the liver and spleen. In cutaneous leishmaniasis, we found that NLRP10 is essential for controlling inflammation in the skin, limiting lesion development and tissue damage at the site of infection. Taken together our findings show important functions for NLR proteins in leishmaniasis, influencing localized tissue specific inflammation, the adaptive immune responses, and clearance or long term residence of the parasite in the infected organs. This research underscores the importance of localized inflammation at the infection site to the pathogenesis and the course of leishmaniasis.

Keywords

Inflammasome, Leishmania, Leishmaniasis, NLR

Pages

xxii, 203 pages

Bibliography

Includes bibliographical references (pages 183-203).

Copyright

Copyright © 2016 Gwendolyn Mary Clay

Included in

Cell Biology Commons

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