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In this study, we determined the impact of PI3K\u03b4 in immunity to Trypanosoma congolense, an African trypanosome that can manipulate and evade Ab responses critical for protection. Upon infection with T. congolense, PI3K\u03b4D910A mice lacking PI3K\u03b4 activity paradoxically show a transient enhancement in early control of parasitemia, associated with impaired production of regulatory IL-10 by B cells in the peritoneum. C57BL\/6 wild-type (WT) mice treated with the PI3K\u03b4 inhibitor (PI3K\u03b4i) Idelalisib showed a similar transient decrease in parasitemia associated with reduced IL-10. Strikingly, however, we find that PI3K\u03b4D910A mice were ultimately unable to control this infection, resulting in uncontrolled parasitemia and death within 2 wk. Assessment of humoral responses revealed delayed B cell activation, impaired germinal center responses, and compromised Ab responses to differing degrees in PI3K\u03b4D910A and PI3K\u03b4i-treated mice. To test the role of Abs, we administered serum from WT mice to PI3K\u03b4D910A mice and found that lethality was prevented by postinfection serum. Interestingly, serum from naive WT mice provided partial protection to PI3K\u03b4D910A mutants, indicating an additional role for natural Abs. Together our findings suggest that although PI3K\u03b4 drives immune regulatory responses that antagonize early control of parasite growth in the peritoneum, it is also required for generation of Abs that are critical for protection from systemic trypanosome infection. The essential role of PI3K\u03b4 for host survival of African trypanosome infection contrasts with findings for other pathogens such as Leishmania, underlining the critical importance of PI3K\u03b4-dependent humoral immunity in this disease.<\/jats:p>","DOI":"10.4049\/jimmunol.2100311","type":"journal-article","created":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T18:00:23Z","timestamp":1628704823000},"page":"1401-1410","source":"Crossref","is-referenced-by-count":2,"title":["Critical Roles of Phosphoinositide 3-Kinase \u03b4 in the Humoral Immune Response to <i>Trypanosoma congolense<\/i> Infection"],"prefix":"10.1093","volume":"207","author":[{"given":"Folayemi","family":"Olayinka-Adefemi","sequence":"first","affiliation":[{"name":"Department of Immunology, Max Rady College of Medicine, University of Manitoba , Winnipeg, Manitoba ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5592-7095","authenticated-orcid":false,"given":"Chukwunonso","family":"Onyilagha","sequence":"additional","affiliation":[{"name":"National Centre for Foreign Animal Disease, Canadian Food Inspection Agency , Winnipeg, Manitoba ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9205-8119","authenticated-orcid":false,"given":"Nipun","family":"Jayachandran","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania , Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8287-8981","authenticated-orcid":false,"given":"Sen","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Rady College of Medicine, University of Manitoba , Winnipeg, Manitoba ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Rady College of Medicine, University of Manitoba , Winnipeg, Manitoba ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2759-0664","authenticated-orcid":false,"given":"Jude","family":"Uzonna","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Rady College of Medicine, University of Manitoba , Winnipeg, Manitoba ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1175-5498","authenticated-orcid":false,"given":"Aaron J","family":"Marshall","sequence":"additional","affiliation":[{"name":"Department of Immunology, Max Rady College of Medicine, University of Manitoba , Winnipeg, Manitoba ,","place":["Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,9,1]]},"reference":[{"key":"2025022610320970200_r1","doi-asserted-by":"crossref","first-page":"e0005454","DOI":"10.1371\/journal.pntd.0005454","article-title":"Human African trypanosomiasis control: Achievements and challenges","volume":"11","author":"Aksoy","year":"2017","journal-title":"PLoS Negl. 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