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<p><i>Leishmania infantum</i> and <i>Leishmania donovani</i> are protozoan parasites that cause visceral leishmaniasis, a potentially fatal disease targeting the liver, spleen and bone marrow. To survive, these parasites manipulate host macrophage microbicidal responses and metabolic pathways. Here, we demonstrate that the host serine proteases neutrophil elastase (NE) and cathepsin G (CG), acting in concert with Toll-like receptors TLR2, TLR3, and TLR4, induce the inflammatory cytokines IFN-α and TNF-α to control <i>L. infantum</i> infection in macrophages. Conversely, in vivo experiments revealed that while NE and CG are necessary for inflammatory responses, including IL-12, nitric oxide, and CCL2 production, they unexpectedly promote splenic parasitism. CG-deficient mice failed to recruit Ly6C<sup>hi</sup> myeloid cells to the spleen, providing a potential mechanism for their reduced parasite burden. Finally, our data suggest that unlike <i>L. donovani</i>, <i>L. infantum</i> cannot hijack cellular host serine peptidases and TLR signalling for survival, yet it remains dependent on these host enzymes to establish systemic spleen infection.</p>

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Cathepsin G and neutrophil elastase control Leishmania infantum parasitism through TLRs-dependent induction of IFN-α and TNF-α

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Amy Goundry,
  • Aislan C. Vivarini,
  • Nathalia S. Rodrigues,
  • Ulisses G. Lopes,
  • Jeremy C. Mottram,
  • Ana Paula C. A. Lima

摘要

Leishmania infantum and Leishmania donovani are protozoan parasites that cause visceral leishmaniasis, a potentially fatal disease targeting the liver, spleen and bone marrow. To survive, these parasites manipulate host macrophage microbicidal responses and metabolic pathways. Here, we demonstrate that the host serine proteases neutrophil elastase (NE) and cathepsin G (CG), acting in concert with Toll-like receptors TLR2, TLR3, and TLR4, induce the inflammatory cytokines IFN-α and TNF-α to control L. infantum infection in macrophages. Conversely, in vivo experiments revealed that while NE and CG are necessary for inflammatory responses, including IL-12, nitric oxide, and CCL2 production, they unexpectedly promote splenic parasitism. CG-deficient mice failed to recruit Ly6Chi myeloid cells to the spleen, providing a potential mechanism for their reduced parasite burden. Finally, our data suggest that unlike L. donovani, L. infantum cannot hijack cellular host serine peptidases and TLR signalling for survival, yet it remains dependent on these host enzymes to establish systemic spleen infection.