Exposure to host inflammation in vivo induces rapid transcriptomic change and impaired maturation in malaria parasites.

Abstract

Abstract We previously reported slowing of the Plasmodium life-cycle in acutely-infected wild-type but not immune-deficient mice, suggesting a role for host responses in mediating this effect. Here, we hypothesized that parasites sense and rapidly adapt to host inflammation in vivo. We tested this in mice using a combination of immunological, metabolomic and parasite single-cell RNA-sequencing (scRNA-seq) approaches. Firstly, systemic treatment with LPS, but not CpG or Poly I:C, impaired in vivo maturation of parasites, the magnitude of which correlated with plasma TNF/IFNγ levels. This supported our idea that a systemic inflammatory response alone could impair malaria parasite maturation. Metabolomic analysis of plasma indicated host inflammation was associated with substantial changes to the external environment in which parasites circulated. Subsequent in vitro culture confirmed this plasma directly impaired maturation, and moreover, suggested the presence of inhibitory factor(s) within it. scRNAseq conducted on asynchronous parasites exposed to host-inflammation in vivo, suggested a global down-regulation of transcription, specifically in mid-stage of the blood-cycle – also confirmed by flow-cytometric analysis. In addition, we noted specific down-regulation of protein translation associated genes. Thus, malaria parasites in the mid-stages of their blood-stage cycle actively sense systemic host inflammation, and respond by slowing down gene transcription and protein translation, resulting in slowed maturation. Our work suggests systemic inflammatory responses may control malaria parasites not via their clearance, nor directly killing, but by slowing down the rate of parasite maturation and replication.