Date of Degree
PhD (Doctor of Philosophy)
Molecular and Cell Biology
Wilson, Mary E
First Committee Member
Second Committee Member
Third Committee Member
Fourth Committee Member
Fifth Committee Member
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.
Leishmaniasis is caused by infection with Leishmania species of parasites spread by sand flies that feed on mammals. Leishmaniasis is a serious global health problem and an estimated 12 million people are infected in 88 countries. Leishmaniasis, rather than a single disease is actually a group of diseases caused by distinct species of parasites with very different clinical symptoms. Immunity, our body’s response to infection and damage, and specifically inflammation, has different consequences in these different diseases. In visceral leishmaniasis parasites migrate from the skin, multiply in the liver and spleen, and eventually cause the patient’s entire immune system to be suppressed. This can be a fatal infection if left untreated. In cutaneous leishmaniasis parasites stay at the site of the sand fly bite and create a long-term skin ulcer. The damage from this disease is actually increased by a strong immune response to the parasite.
The immune pathways responding to Leishmania parasites are not fully understood. One family of proteins, the NLRs, are important in innate immunity (the body’s first line of defense against infection) and inflammation and this research is an investigation into their function in leishmaniasis. We used mice as models of both visceral and cutaneous leishmaniasis. Our results showed that in visceral leishmaniasis several members of the NLR family of proteins were needed for the parasites to grow as we expected in the liver and spleen. We also found that one NLR protein, NLRP10, was important in cutaneous leishmaniasis and it limited the size of the skin lesion and the damage caused by inflammation. This research helps us understand more about how different parts of our immune response change the outcome of Leishmaniasis as well as giving us insight into how members of the NLR family of proteins function.
Inflammasome, Leishmania, Leishmaniasis, NLR
xxii, 203 pages
Includes bibliographical references (pages 183-203).
Copyright © 2016 Gwendolyn Mary Clay
Clay, Gwendolyn Mary. "The role of NLR proteins in Leishmaniasis." PhD (Doctor of Philosophy) thesis, University of Iowa, 2016.