Oral L-arginine cures arginase 1-dependent chronic cutaneous leishmaniasis by redirecting the T helper cell response

Abstract

Leishmania (L.) mexicana-induced cutaneous leishmaniasis (CL) is a neglected tropical disease characterized by localized chronic ulcers (LCL) and, in rare cases, by disseminated skin lesions (DCL). The therapeutic options for CL are currently limited, and the immune dysregulation leading to chronicity of disease is poorly understood. Here, we identified interleukin (IL)-10-dependent upregulation of arginase 1 (ARG1) in cutaneous CX3CR1+ myeloid cells as central immunometabolic determinant of chronic CL in L. mexicana-infected C57BL/6 wild-type (WT) mice. Deletion of Arg1 in myeloid cells (Arg1{Delta}Cx3cr1) enabled parasite control and clinical healing. Single-cell RNA sequencing revealed that ARG1, together with interferon-{gamma} produced by T-helper 1 (Th1) cells, caused pathologic differentiation of Ly6Chigh monocytes into inflammatory macrophages (iMACs) that simultaneously expressed ARG1, nitric oxide synthase type 2 (NOS2) and the chemokines CXCL9/10. These Arg1+Nos2+Cxcl9/10+iMACs induced a lasting depletion of L-arginine in the skin, served as parasite niche, and maintained a self-perpetuating cycle of host cell recruitment. In Arg1{Delta}Cx3cr1 mice, the ARG1+NOS2+ host cell niche for the parasite was diminished. Prophylactic or therapeutic oral L-arginine supplementation restored tissue arginine levels, reduced parasite burden, and prevented or resolved chronic disease. L-arginine-treated mice showed enhanced T cell expansion and Th1 differentiation, remained free of clinical relapses, and were resistant to reinfection. As skin lesion biopsies from L. mexicana-infected LCL and DCL patients demonstrated a similar pattern of Th1/Th2 cytokine, Arg1 and Nos2 mRNA expression as seen in mice, we suggest metabolic reprogramming by oral L-arginine as a promising and easy-to-apply host-directed therapy for human L. mexicana CL. ONE SENTENCE SUMMARYArginase 1-mediated arginine depletion accounts for chronic cutaneous leishmaniasis, which can be prevented and even cured by oral L-arginine therapy.