Grant: Project Grant

Leishmaniases are a group of infectious diseases caused by parasites that infect 12 million people worldwide with 1.3 million new cases every year. Like many neglected diseases, leishmaniasis is primarily endemic to developing nations and thus presents additional socioeconomic burdens to already impoverished people. Leishmania donovani-the focus of this project-causes visceral leishmaniasis with severe morbidity and mortality. There are no effective vaccines and current treatments have limited efficacy and significant toxicities. The mechanisms that enable intracellular pathogens such as leishmania to chronically infect macrophages -pivotal cells of the innate immune system- are a focus of intense interest. Research is proposed here to investigate two novel mechanisms of leishmania pathogenesis. The first mechanism relates to investigate the roles of small, non-coding RNAs (snRNAs) in immunity to intracellular infection. These snRNAs are found in both animals and plants and some viruses and are well conserved and recognized as a vital component of genetic regulation. snRNAs have been implicated in stress, cancer, infection and innate immunity. Our hypothesis is that leishmania uses small RNA-based effector mechanisms to establish chronic infection. Research relevant to the second novel mechanism of pathogenesis relates to exploitation of host cell signaling pathway-PI3K-Akt in particular- by leishmania to create an environment which is permissive to survive inside the host. Our hypothesis is that PI3K functions as a master regulator of innate immunity to leishmania and promotes chronic infection. We will study the molecular mechanism of PI3K-Akt regulation by leishmania. This research will greatly improve the current understanding of leishmania biology and pathogenesis, and has the potential to aid in the discovery and development of novel therapeutics and vaccines to both treat and prevent leishmania infection and disease.