Evaluation of the Host-Parasite Interphase: Understanding the Impact of Vector-Host Interaction on Plasmodium Development and Innate Immunity in Parasitic Diseases

Each year, together, Leishmania and Plasmodium infect more than 500 million individuals and these infections result in the deaths of approximately 3 million, illustrating the drastic need for immunological research on these and other tropical diseases. Both Leishmania and Plasmodium are transmitted by the bite of an infected female hematophagus insect; Leishmania by sand flies, while Plasmodium by Anopheline mosquitoes. Studies have demonstrated the strong effects associated with saliva from hematophagous insects, like mosquitoes, sand flies, and ticks. Work has shown that the pathology associated with disease models, like LymeÌøåÀå_s disease and leishmaniasis, is exacerbated by the inclusion of saliva or salivary gland portions during introduction of infection. However, previous vaccination to uninfected vector saliva induces protection from severe pathology upon infection in the presence of saliva or salivary gland extract in the case of sand flies. Chapter 2 illustrates that a similar phenomenon also is present in the mosquito-Plasmodium model. Our study reveals that previous vaccination with uninfected mosquito bites induces interferon gamma (IFNg) systemically upon exposure to P. yoelii-infected mosquito bites. Chronic diseases such as leishmaniasis and malaria are able to induce immuno-suppression in their hosts. One recently characterized mechanism of immuno-suppression/ immuno-regulation by dendritic cells is the induction of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the tryptophan catabolism pathway. IDO limits growth of tryptophan auxotrophs. Chapter 3 demonstrates that IDO is induced in human dendritic cells in response to exposure to L. major, L.donovani, and P. falciparum. In the case of Leishmania infection, the IDO protein is active and inhibits a mixed lymphocyte reaction. Additionally, IDO is induced during an in vivo P. yoelii infection. Subversion of immune recognition is a mechanism by which different pathogens are able to gain a niche in a host. Two methods of inhibition of immune surveillance are discussed in Chapters 4 and 5. CD1, the group of molecules that dendritic cells utilize to present lipid antigen to T cells is expressed at significantly lower levels in Leishmania-infected human dendritic cells. Also, Leishmania-infected macrophages do not readily undergo apoptosis induced by cycloheximide via a strain- and phosphoglycan- dependent mechanism.