Abstract
Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. Transcriptomic studies in humans have so far been limited to retrospective analysis of blood samples from clinical cases. In this prospective, proof-of-principle study, we compared whole-blood RNA-seq profiles at pre-and post-infection time points from Malian adults who were either asymptomatic (n = 5) or febrile (n = 3) during their first seasonal PCR-positive P. falciparum infection with those from malaria-naïve Dutch adults after a single controlled human malaria infection (n = 5). Our data show a graded activation of pathways downstream of pro-inflammatory cytokines, with the highest activation in malaria-naïve Dutch individuals and significantly reduced activation in malaria-experienced Malians. Newly febrile and asymptomatic infections in Malians were statistically indistinguishable except for genes activated by pro-inflammatory cytokines. The combined data provide a molecular basis for the development of a pyrogenic threshold as individuals acquire immunity to clinical malaria.
Highlights
Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled
We previously reported that recent malaria exposure can dampen subsequent P. falciparum-induced inflammation via a regulatory state mediated in part by the anti-inflammatory
The over-arching theme of these transcriptomic studies is that interferon- and toll-like-receptor-mediated inflammatory signaling and antigen presentation pathways predominate during blood-stage infections, with significant T-cell activation occurring in malaria-experienced individuals during acute malaria. These studies were limited to the analysis of individuals who were susceptible to clinical malaria and were not designed to prospectively identify molecular predictors and mechanisms of clinical immunity to P. falciparum
Summary
Identifying molecular predictors and mechanisms of malaria disease is important for understanding how Plasmodium falciparum malaria is controlled. A recent report demonstrated that tolerance to malaria disease in children with a history of heavy malaria exposure is associated with the loss and dysfunction of Vδ2+γδT cells, which normally produce pro-inflammatory cytokines in response to infection[8] These studies have provided valuable insight on how tolerance to malarial disease may be conferred, primarily by measuring host modulation of inflammation in vitro using parasite-stimulated peripheral blood mononuclear cells obtained from individuals with varying degrees of prior malaria exposure. The over-arching theme of these transcriptomic studies is that interferon- and toll-like-receptor-mediated inflammatory signaling and antigen presentation pathways predominate during blood-stage infections, with significant T-cell activation occurring in malaria-experienced individuals during acute malaria These studies were limited to the analysis of individuals who were susceptible to clinical malaria and were not designed to prospectively identify molecular predictors and mechanisms of clinical immunity to P. falciparum. We provide evidence for disease tolerance to malaria at the transcriptome level, demonstrating that malaria-experienced individuals dampen P. falciparum-induced interferon and inflammatory responses during acute infection despite having higher parasite densities than naïve individuals
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