Different Leishmania species protozoa localize in different body locations, leading to a variety of disease outcomes. L. chagasi, the protozoan causing visceral leishmaniasis in South America, causes manifestations ranging from asymptomatic infection to potentially fatal visceral leishmaniasis, with dissemination to the liver, bone marrow and spleen. Remarkable features of the Leishmania spp. are their ability to disseminate silently through infected hosts, their propensity to """"""""home"""""""" to particular tissues where they can replicate, and their propensity to persist in an asymptomatic form in mammalian tissues. Factors that regulate dissemination, homing, and persistence are not well understood. In particular, the way in which host immunity, including immunization-derived immunity, modifies the travels of parasites through the body is not known. The molecular mechanisms through which the parasite itself can modify the local immune factors are just beginning to be understood. We reason that both host and parasite factors must contribute to this trafficking of parasites through an infected host. Our ability to study Leishmania sp. infections in animal models have been hampered by difficulties in detecting the """"""""silent"""""""" stages of parasite infection. During this application we propose to explore the utility of bioluminescence in vitro imaging system (MS) to detect luminescent parasites as they infect a host. This method, and real time PCR as well as conventional microscopic methods, will be coupled with studies of immune modulation to follow the trafficking of parasite throughout infection. The overall hypothesis of this application is that both the local host immune microenvironment surrounding the invading parasite, and parasite factors influencing this immediate immune environment, will determine whether the parasite escapes from the site of inoculation, disseminates to visceral organs, and persists long-term in host tissues. Using MS to localize L. c/iagas/within the infected murine host, we will address the following aims: (1) Develop a model to track parasite dissemination and persistence in vivo, and test which host factors influence dissemination, localization, and long-term maintenance of L. chagasi infection. (2) Determine whether parasite factors that modulate local cytokines and macrophage activation influence the establishment and systemic dissemination of L. chagasi. (3) Determine the effects of immunization on the establishment and systemic dissemination of L. chagasi. Leishmaniasis is the result of a dynamic interaction between host and parasite, with each modifying the functions and survival of the other. Through studies described in this application we hope to delineate critical features that determine the ultimate outcome of the infection.
Showing the most recent 10 out of 70 publications
