Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria

Stephanie I. Studniberg, Lisa J. Ioannidis, Retno A.S. Utami, Leily Trianty, Yang Liao, Waruni Abeysekera, Connie S.N. Li-Wai-Suen, Halina M. Pietrzak, Julie Healer, Agatha M. Puspitasari, Dwi Apriyanti, Farah Coutrier, Jeanne R. Poespoprodjo, Enny Kenangalem, Benediktus Andries, Pak Prayoga, Novita Sariyanti, Gordon K. Smyth, Alan F. Cowman, Ric N. PriceRintis Noviyanti, Wei Shi, Alexandra L. Garnham, Diana S. Hansen

Research output: Contribution to journalArticlepeer-review

Abstract

Clinical immunity to P. falciparum malaria is non-sterilizing, with adults often experiencing asymptomatic infection. 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 P. falciparum infection. Defined populations of classical and atypical memory B cells and a TH2 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-cell function, and CTLA-4 as a predicted regulator in these processes. As proof of concept, we demonstrated a role for CTLA-4 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.

Original languageEnglish
Article numbere10824
JournalMolecular Systems Biology
Volume18
Issue number4
DOIs
Publication statusPublished - Apr 2022

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