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

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 T H2 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. image Asymptomatic Plasmodium falciparum malaria infection supports protective humoral responses, but it also features an immunosuppressive transcriptional signature with upregulation of pathways involved in the inhibition of T‐cell function. Asymptomatic malaria is thought to be beneficial for maintaining clinical immunity and remains untreated. Despite supporting protective humoral immune responses, asymptomatic malaria infections feature an immunosuppressive blood transcriptional signature with upregulation of pathways involved in the control of T‐cell function. These results suggest that asymptomatic malaria is not innocuous and might not support immune processes to fully control parasitemia or efficiently respond to malaria vaccines.