# ApoA1-driven cholesterol efflux and macrophage polarization orchestrate T-cell differentiation towards controlling Leishmania donovani pathogenesis

## TL;DR

ApoA1 helps control Leishmania infection by managing cholesterol in immune cells and promoting protective immune responses.

## Contribution

This study reveals ApoA1's role in modulating macrophage and T-cell responses during Leishmania donovani infection.

## Key findings

- Low serum ApoA1 levels are observed in visceral leishmaniasis and post-kala-azar dermal leishmaniasis patients.
- ApoA1 promotes cholesterol efflux in macrophages, reducing Leishmania infectivity and ER stress.
- ApoA1 primes macrophages toward M1 polarization and supports Th1 T-cell differentiation.

## Abstract

Lipid metabolism plays a decisive role in host-pathogen interactions and immune regulation, with apolipoproteins (Apo) being central to this process. However, their role in leishmaniasis remains unexplored. Herein, we deliberate the immunoregulatory function of ApoA1 during Leishmania donovani infection using THP-1-derived macrophages alone and in combination with T lymphocytes derived from human PBMC. We found low serum ApoA1 levels in active VL and PKDL than in healthy controls. It was shown that direct interaction of ApoA1 with ABCA1 (ATP-binding cassette transporter A1) on macrophages promotes cholesterol efflux, reflected by increased HDL levels and reduced total cellular cholesterol. This phenomenon was associated with reduced Leishmania infectivity and its downstream signaling in macrophages, i.e., downregulation of PPAR-γ and the endoplasmic reticulum-stress marker CHOP. Additionally, ApoA1 in the presence of extracellular HDL slightly promoted macrophage polarization towards M1, as indicated by increased expression of IL-12 and iNOS2 or nitric oxide production, alongside reduced expression of M2 phenotype-associated markers, including IL-10 and arginase. In co-culture with PBMC-derived T-cells, ApoA1-primed macrophages facilitated Th1 polarization, as demonstrated by increased IFN-γ and STAT1, and indirectly by reduced expression of Th2-specific markers (GATA-3 and IL-4). Overall, these results implicate ApoA1 as a vital immunomodulatory factor and potential therapeutic target in leishmaniasis.

The online version contains supplementary material available at 10.1038/s41598-025-30130-1.