HIF-α signaling regulates the macrophage inflammatory response during Leishmania major infection 4332

Abstract Description Cutaneous leishmaniasis (CL) contributes significantly to the global burden of neglected tropical diseases, with 12 million people infected with Leishmania parasites. CL encompasses a range of disease manifestations, from self-healing skin lesions to permanent disfigurations. Macrophage HIF-α-mediated lymphangiogenesis is necessary to achieve efficient wound resolution during murine L. major infection. Here, we investigate the role of macrophage HIF-α signaling independent of lymphangiogenesis. Macrophages from mice with intact HIF-α signaling or mice with deleted HIF-α signaling were subjected to RNASequencing after L. major infection and under pro-inflammatory stimulus. L. major infection alone is sufficient to induce some minor HIF-α-dependent transcriptomic changes, while infection with L. major in combination with pro-inflammatory stimuli induces numerous transcriptomic changes that are both dependent and independent of HIF-a signaling. We found HIF-α suppresses pathways involved in protein translation during L. major infection in a pro-inflammatory environment. Together, these findings show L. major induces a HIF-a-dependent transcriptomic program, but HIF-a only suppresses protein translation in a pro-inflammatory environment. Thus, this work reveals the host inflammatory response, rather than the parasite, largely contributes to myeloid HIF-α signaling during Leishmania infection. Funding Sources NIGMS P20-GM103625, NCATS TL1 TR003109 and UL1 TR003107, NIH T32 GM106999 NIGMS P20-GM121293, and NSF OIA-1946391. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)