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The parasite invades the central nervous system and causes severe encephalitis that is fatal if left untreated. We have previously identified ecotin-like inhibitors of serine peptidases, named ISPs, in trypanosomatid parasitic protozoa. Here, we investigated the role of ISP2 in bloodstream form<jats:italic>T<\/jats:italic>.<jats:italic>b<\/jats:italic>.<jats:italic>rhodesiense<\/jats:italic>. We generated gene-deficient mutants lacking ISP2 (\u0394<jats:italic>isp2<\/jats:italic>), which displayed a growth profile<jats:italic>in vitro<\/jats:italic>similar to that of wild-type (WT) parasites. C57BL\/6 mice infected with \u0394<jats:italic>isp2<\/jats:italic>displayed lower blood parasitemia, a delayed hind leg pathological phenotype and survived longer. The immune response was examined at two time-points that corresponded with two peaks of parasitemia. At 4 days, the spleens of \u0394<jats:italic>isp2<\/jats:italic>-infected mice had a greater percentage of NOS2<jats:sup>+<\/jats:sup>myeloid cells, IFN-\u03b3<jats:sup>+<\/jats:sup>-NK cells and increased TNF-\u03b1 compared to those infected with WT and parasites re-expressing ISP2 (\u0394<jats:italic>isp2<\/jats:italic>:<jats:italic>ISP2<\/jats:italic>). By 13 days the increased NOS2<jats:sup>+<\/jats:sup>population was sustained in \u0394<jats:italic>isp2<\/jats:italic>-infected mice, along with increased percentages of monocyte-derived dendritic cells, as well as CD19<jats:sup>+<\/jats:sup>B lymphocytes, and CD8<jats:sup>+<\/jats:sup>and CD4<jats:sup>+<\/jats:sup>T lymphocytes. Taken together, these findings indicate that ISP2 contributes to<jats:italic>T<\/jats:italic>.<jats:italic>b<\/jats:italic>.<jats:italic>rhodesiense<\/jats:italic>virulence in mice and attenuates the inflammatory response during early infection.<\/jats:p>","DOI":"10.1371\/journal.pntd.0009526","type":"journal-article","created":{"date-parts":[[2021,6,21]],"date-time":"2021-06-21T17:34:10Z","timestamp":1624296850000},"page":"e0009526","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Role of the inhibitor of serine peptidase 2 (ISP2) of Trypanosoma brucei rhodesiense in parasite virulence and modulation of the inflammatory responses of the host"],"prefix":"10.1371","volume":"15","author":[{"given":"David Jessula","family":"Levy","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3406-4689","authenticated-orcid":true,"given":"Amy","family":"Goundry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raquel S. S.","family":"Laires","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana F. R.","family":"Costa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3572-5426","authenticated-orcid":true,"given":"Carlos Mendes","family":"Novo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9558-6427","authenticated-orcid":true,"given":"Dennis J.","family":"Grab","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy C.","family":"Mottram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4631-2694","authenticated-orcid":true,"given":"Ana Paula C. 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