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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-\u03b1 and TNF-\u03b1 to control\n                    <jats:italic>L. infantum<\/jats:italic>\n                    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\n                    <jats:sup>hi<\/jats:sup>\n                    myeloid cells to the spleen, providing a potential mechanism for their reduced parasite burden. Finally, our data suggest that unlike\n                    <jats:italic>L. donovani<\/jats:italic>\n                    ,\n                    <jats:italic>L. infantum<\/jats:italic>\n                    cannot hijack cellular host serine peptidases and TLR signalling for survival, yet it remains dependent on these host enzymes to establish systemic spleen infection.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-10555-8","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T16:27:20Z","timestamp":1782750440000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cathepsin G and neutrophil elastase control Leishmania infantum parasitism through TLRs-dependent induction of IFN-\u03b1 and TNF-\u03b1"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3406-4689","authenticated-orcid":false,"given":"Amy","family":"Goundry","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aislan C.","family":"Vivarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalia S.","family":"Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulisses G.","family":"Lopes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5574-3766","authenticated-orcid":false,"given":"Jeremy C.","family":"Mottram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4631-2694","authenticated-orcid":false,"given":"Ana Paula C. 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