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also known as sleeping sickness, and penetrates the central nervous system, leading to meningoencephalitis. The Cathepsin L-like cysteine peptidase of T. b. rhodesiense has been implicated in parasite penetration of the blood\u2013brain barrier and its activity is modulated by the chagasin-family endogenous inhibitor of cysteine peptidases (ICP). To investigate the role of ICP in T. b. rhodesiense bloodstream form, ICP-null (\u0394icp) mutants were generated, and lines re-expressing ICP (\u0394icp:ICP). Lysates of \u0394icp displayed increased E-64-sensitive cysteine peptidase activity and the mutant parasites traversed human brain microvascular endothelial cell (HBMEC) monolayers in vitro more efficiently. \u0394icp induced E-selectin in HBMECs, leading to the adherence of higher numbers of human neutrophils. In C57BL\/6 mice, no \u0394icp parasites could be detected in the blood after 6 days, while mice infected with wild-type (WT) or \u0394icp:ICP displayed high parasitemia, peaking at day 12. In mice infected with \u0394icp, there was increased recruitment of monocytes to the site of inoculation and higher levels of IFN-\u03b3 in the spleen. At day 14, mice infected with \u0394icp exhibited higher preservation of the CD4+, CD8+, and CD19+ populations in the spleen, accompanied by sustained high IFN-\u03b3, while NK1.1+ populations receded nearly to the levels of uninfected controls. We propose that ICP helps to downregulate inflammatory responses that contribute to the control of infection.<\/jats:p>","DOI":"10.3390\/ijms24010656","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T04:07:09Z","timestamp":1672632429000},"page":"656","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Trypanosoma brucei rhodesiense Inhibitor of Cysteine Peptidase (ICP) Is Required for Virulence in Mice and to Attenuate the Inflammatory Response"],"prefix":"10.3390","volume":"24","author":[{"given":"Tatiana F. R.","family":"Costa","sequence":"first","affiliation":[{"name":"Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3406-4689","authenticated-orcid":false,"given":"Amy","family":"Goundry","sequence":"additional","affiliation":[{"name":"Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Morrot","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Imunoparasitologia, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-900, Brazil"},{"name":"Centro de Pesquisa em Tuberculose, Funda\u00e7\u00e3o Oswaldo Cruz (FIOCRUZ), Manguinhos 21040-900, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis J.","family":"Grab","sequence":"additional","affiliation":[{"name":"Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5574-3766","authenticated-orcid":false,"given":"Jeremy C.","family":"Mottram","sequence":"additional","affiliation":[{"name":"York Biomedical Research Institute and Department of Biology, University of York, York YO10 5DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Paula C. A.","family":"Lima","sequence":"additional","affiliation":[{"name":"Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3389\/fimmu.2019.00039","article-title":"Clinical and neuropathogenetic aspects of human African trypanosomiasis","volume":"10","author":"Kennedy","year":"2019","journal-title":"Front. 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