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Historically, asymptomatic malaria has been viewed as beneficial and required to help maintain clinical immunity. Emerging views suggest that these infections are detrimental and constitute a parasite reservoir that perpetuates transmission. To define the impact of asymptomatic malaria, we pursued a systems approach integrating antibody responses, mass cytometry, and transcriptional profiling of individuals experiencing symptomatic and asymptomatic\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    infection. Defined populations of classical and atypical memory B cells and a T\n                    <jats:sub>H2<\/jats:sub>\n                    cell bias were associated with reduced risk of clinical malaria. Despite these protective responses, asymptomatic malaria featured an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T\u2010cell function, and CTLA\u20104 as a predicted regulator in these processes. As proof of concept, we demonstrated a role for CTLA\u20104 in the development of asymptomatic parasitemia in infection models. The results suggest that asymptomatic malaria is not innocuous and might not support the induction of immune processes to fully control parasitemia or efficiently respond to malaria vaccines.\n                  <\/jats:p>","DOI":"10.15252\/msb.202110824","type":"journal-article","created":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T07:31:40Z","timestamp":1651044700000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria"],"prefix":"10.1038","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9452-4977","authenticated-orcid":false,"given":"Stephanie I","family":"Studniberg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1287-7347","authenticated-orcid":false,"given":"Lisa 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