Impaired immune activation following Leishmania mexicana infection

Effective immune responses against Leishmania parasites rely on the generation of a robust Th1 response in the absence of strong immunosuppression, ultimately resulting in the induction of parasite killing by macrophages at the site of infection. However, some species of Leishmania including L. mexicana elicit chronic, non-healing responses in mouse strains known to mount protective Th1 responses against other species such as L. major. The goal of this project has been to identify major factors responsible for the inadequate immune response observed against L. mexicana in mice fully capable of controlling infection with L. major. The first part of this thesis identifies dramatic defects in lymph node (LN) expansion and Th1 differentiation of responding T cells induced by L. mexicana. In the second part of this thesis, we uncover a defect in DC activation that may underlie a partial defect in T cell priming. We find that DCs exposed to the intracellular amastigote form of L. mexicana fail to respond appropriately to stimuli associated with Toll-like receptor 9 (TLR9) such as CpG DNA. The last section of this thesis examines the potential role for TLR9 signaling during in vivo infection with Leishmania. DNA isolated from different Leishmania species are capable of directly activating DCs, suggesting that inhibition of TLR9-dependent DC activation may allow L. mexicana parasites to actively suppress immune responses to Leishmania infection itself. Therefore, the capacity to inhibit TLR9 signaling by L. mexicana may have evolved as a strategy to ensure parasite survival by interfering with innate immune recognition of parasite infection. However, even in L. mexicana, TLR9 appears to play a role later during infection, and we have found that high dose administration of CpG is sufficient to elicit a healing response to L. mexicana infection. Together, these data suggest that L. mexicana may limit curative Th1 responses by blocking low-level TLR9-associated activation of DCs or other cells during the natural course of infection with Leishmania; however, our experiments also reveal a potential strategy to overcome this inhibition, which may benefit future studies seeking to establish and maintain stronger immunity against infection with L. mexicana