Regulation of Immunity to Visceral Leishmaniasis by Regulatory T cells (Tregs) and Hepatic Stellate Cells (HSCs)
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Leishmaniasis is a vector borne disease that spreads through the bite of an infected sandfly and is caused by the intracellular parasite-Leishmania. An estimated 10-15 million cases of leishmaniasis occur worldwide, presenting as one of the three forms: cutaneous (CL), mucocutaneous (MCL) or visceral leishmaniasis (VL). The occurrence of leishmaniasis is increasing due to global traveling, emergence of drug resistant species and Leishmania-HIV coinfection. Therefore, there is an urgent need for the development of new therapies or vaccines against leishmaniasis. Our laboratory previously showed that mice with an inactivating knock-in mutation in the p110δ gene (known as p110δD910A) are resistant to L. major (the causative agent of CL). Here, I demonstrate that signaling via the p110δ also regulates immunity to L. donovani (the causative agent of VL) resulting in hyper-resistance to experimental VL. This outcome is dependent on the impact of p110δ signaling on expansion and function of regulatory T cells (Tregs). I show for the first time that L. donovani can infect Hepatic Stellate Cells (HSCs) in vivo and in vitro and this infection leads to the production of cytokines that are known to induce Tregs. I also demonstrate that infection with L. donovani leads to dramatic expansion of HSCs in a PI3K-dependent manner, and this correlates with expansion of hepatic Tregs. I further show that L. donovani-infected HSCs can induce CD4+ T cells to become Tregs and this effect is dependent on p110δ signalling. Targeted depletion of HSCs during infection caused a dramatic reduction in liver Treg numbers and proliferation, which was associated with a more efficient parasite control. I also demonstrate that prophylactic and therapeutic administration of CAL-101 (a pharmacological inhibitor of p110δ signalling) is associated with significant reduction in parasite burden, Treg numbers and cytokine production in both experimental models of VL and CL. More importantly, combination of CAL-101 with sub-therapeutic dose of Amphotericin-B leads to full cure from VL. Collectively, these results provide novel understandings into the mechanisms involved in the development and regulation of protective immunity against VL, which could have direct implications for immunotherapy and drug/vaccine development against leishmaniasis.