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This parasite invades and multiplies in virtually all nucleated cells, using a variety of host cell receptors for infection.\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    has a gene that encodes an ecotin\u2010like inhibitor of serine peptidases, ISP2. We generated\n                    <jats:italic>ISP2<\/jats:italic>\n                    \u2010null mutants (\u0394\n                    <jats:italic>isp<\/jats:italic>\n                    2) in\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    Dm28c using CRISPR\/Cas9. Epimastigotes of \u0394\n                    <jats:italic>isp<\/jats:italic>\n                    2 grew normally in\u00a0vitro but were more susceptible to lysis by human serum compared to parental and\n                    <jats:italic>ISP2<\/jats:italic>\n                    add\u2010back lines. Tissue culture trypomastigotes of \u0394\n                    <jats:italic>isp<\/jats:italic>\n                    2 were more infective to human muscle cells in\u00a0vitro, which was reverted by the serine peptidase inhibitors aprotinin and camostat, suggesting that host cell epitheliasin\/TMPRSS2 is the target of ISP2. Pretreatment of host cells with an antagonist to the protease\u2010activated receptor 2 (PAR2) or an inhibitor of Toll\u2010like receptor 4 (TLR4) selectively counteracted the increased cell invasion by \u0394\n                    <jats:italic>isp<\/jats:italic>\n                    2, but did not affect invasion by parental and add\u2010back lines. The same was observed following targeted gene silencing of PAR2, TLR4 or TMPRSS2 in host cells by siRNA. Furthermore, \u0394\n                    <jats:italic>isp<\/jats:italic>\n                    2 caused increased tissue edema in a BALB\/c mouse footpad infection model after 3\u2009h differently to that observed following infection with parental and add\u2010back lines. We propose that ISP2 contributes to protect\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    from the anti\u2010microbial effects of human serum and to prevent triggering of PAR2 and TLR4 in host cells, resulting in the modulation of host cell invasion and contributing to decrease inflammation during acute infection.\n                  <\/jats:p>","DOI":"10.1096\/fj.202302091rr","type":"journal-article","created":{"date-parts":[[2024,3,25]],"date-time":"2024-03-25T12:25:28Z","timestamp":1711369528000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The ecotin\u2010like peptidase inhibitor of\n                    <i>Trypanosoma cruzi<\/i>\n                    prevents\n                    <scp>TMPRSS2\u2010PAR2\u2010TLR4<\/scp>\n                    crosstalk downmodulating infection and inflammation"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9266-6281","authenticated-orcid":false,"given":"Tatiana F. 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