IMMUNE REGULATION AND VACCINE DEVELOPMENT IN LEISHMANIASIS

National Institute Of Allergy And Infectious Diseases

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Abstract

Tissue-resident macrophages (TRMs) are critical for tissue homeostasis/repair, and their development is governed by tissue niche-specific signals. Although the importance of these nurturing signals for TRMs to perform tissue-specific functions has been extensively studied, it remain poorly addressed how TRMs maintain their homeostatic properties during inflammation, in particular infection-driven inflammation in the skin. We previously showed that IL-4 produced by eosinophils is critical to maintain the number and M2-like properties of dermal TRMs in the strong TH1 environment of the Leishmania major infected skin. Here, we show that TSLP receptor signaling is also required to maintain the number of dermal TRMs, as well as IL-5+ innate lymphoid cell 2 (ILC2s) in the infected skin. The severity of cutaneous disease was ameliorated in TSLP receptor deficient mice, and in mice conditionally depleted of IL-5+ ILC2s. By single cell RNA sequencing, the dermal TRMs were the sole source of TSLP in the infected skin, and genetic ablation of TSLP from dermal TRMs reduced the number of dermal TRMs, IL-5+ ILC2s, and eosinophils, and disease was ameliorated. Thus, by orchestrating localized type 2 circuitries with ILC2s and eosinophils, dermal TRMs contribute to their own maintenance as a replicative niche for L. major. Visceral leishmaniasis (VL) is a tropical disease caused by Leishmania species within the L. donovani complex (L. donovani/L. infantum). Macrophages in the liver, spleen, and bone-marrow are the principal target cells for infection. Kupffer cells (KCs) are liver resident macrophages that are seeded embryonically, self-maintained throughout adulthood by local proliferation, and remain non-migratory during homeostatic conditions. In some inflammatory settings or when deliberately targeted for depletion, they can be rapidly replaced by monocyte-derived cells. The consequences of replacing the tissue resident KCs (res-KCs) with monocyte derived KCs (mo-KCs) is unknown in the context of chronic liver infections. We employed the chronic infection model of VL in mice, and reveal an open niche established by KCs migration outside of the sinusoids to form granulomas, and their death by ferroptosis. Using differential expression of Clec4f and Tim4 to distinguish res-KCs and monocyte-mo-KCs, we show that VL results in gradual and partial replacement of Tim4+res-KCs by Tim4-mo-KCs to form heterogeneous, spatially coordinated granulomas composed of infected, iNOS+res-KCs, and recently differentiated, uninfected mo-KCs. Single-cell RNA sequencing identified heterogenous mo-KCs populations that were pro-inflammatory or more fully integrated as homeostatic cells. Absence of mo-KCs in infected CCR2-/- mice compromised hepatic resistance. We provide insights into KC dynamics and mechanism of replacement during VL, and its implications for parasite control that may be relevant in other chronic infections.