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 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.

Distinct transcriptomic signatures define febrile malaria depending on initial infective states, asymptomatic or uninfected

“…The analysis of gene expression pro les from PBMCs in this study, showed that febrile infections were indeed characterized by the upregulation of immune pathways related to immune effector functions, production of in ammatory cytokines, and humoral responses. These results agree with previous studies that compared pre-infection and early febrile malaria infection and revealed a marked activation of pro-in ammatory responses pathways in febrile infections (22,23,38).…”

“…Furthermore, prior malaria exposure may interfere with vaccine e cacy as malaria exposed adults have been shown to elicit reduced immune responses, particularly antibodies, compared to infants and malaria naïve adults (19,20). Asymptomatic malaria infections have previously been explored using transcriptomic studies, which revealed reduced transcription of pro-in ammatory genes (21), inhibition of T-cell function (22) and enhanced P53 pathway expression by monocytes (23). Other studies have associated these infections with greater levels immunoregulatory cytokines (24,25).…”

Distinct transcriptomic signatures define febrile malaria depending on initial infective states, asymptomatic or uninfected

“…The analysis of gene expression profiles from PBMCs in this study, showed that febrile infections were indeed characterized by the upregulation of immune pathways related to immune effector functions, production of inflammatory cytokines, and humoral responses. These results agree with previous studies that compared pre-infection and early febrile malaria infection and revealed a marked activation of pro-inflammatory response pathways in febrile infections [ 22 , 23 , 57 ].…”

“…Therefore, immune tolerance to the parasite clones circulating during an asymptomatic infection potentially reduces the risk of subsequent febrile infections with the same clone [ 20 ]. Furthermore, prior malaria exposure may interfere with vaccine efficacy as malaria exposed adults have been shown to elicit reduced immune responses, particularly antibodies, compared to infants and malaria naïve adults [ 21 , 22 ].…”

Plasmodium falciparum infection coinciding with the malaria vaccine candidate BK-SE36 administration interferes with the immune responses in Burkinabe children

“…The malaria parasite is known to induce immunosuppression in the host during asexual/blood-stage development and this impairs the generation as well as the function of humoral and cell-mediated immunity ( 31 ). Molecular profiling has shown that asymptomatic P. falciparum malaria is characterized by an important immunoregulatory blood transcriptional signature with the upregulation of various pathways involved in the inhibition of CD4 + T-cell function ( 32 ). As such, asymptomatic malaria might not support the induction of immune processes to control parasitemia or respond efficiently to malaria vaccines.…”