Plasmodium Infection Modulates Host Inflammatory Response through circRNAs during the Intracellular Stage in Red Blood Cells.

The integration of RNA- and DNA-based assays enables the investigation of disease dynamics, specifically assessing the role of asymptomatic or subclinical infections in malaria transmission. Circular RNAs (circRNAs), a distinct category of noncoding RNAs, are implicated in numerous pathogenic mechanisms. As of now, research has yet to explore circRNAs' function in malaria infection. The findings revealed that Plasmodium infection upregulated 60 circRNAs and downregulated 71 in BALB/c mice. We selected 11 differentially expressed (DE) circRNAs according to function prediction of target miRNA-mRNA and coding protein, and these were further confirmed by validation experiments. IRESfinder, GO, and KEGG evaluations indicated that 7 DE circRNAs possess protein-coding potential and are enriched in the MAPK signaling cascade. In P.y17XL-infected BALB/c mouse models, the findings substantiated that the dynamic characteristics of DE circRNAs correlated with inflammation, and the MAPK and NF-κB signaling cascades were activated, also contributing to the inflammatory reaction during malaria infection. This study establishes Plasmodium-induced circRNA expression as a novel mechanism by which the parasite modulates host immune signaling, advancing the understanding of Plasmodium-host cell interactions. In addition, 42 circRNAs were found in normal BALB/c mice, and 25 circRNAs were discovered in P.y17XL-infected BALB/c mice, excluding 1238 circRNAs shared by normal and P.y17XL-infected BALB/c mice. Plasmodium infection changes the expression profile of circRNAs in the host, and these altered circRNAs are involved in the inflammatory response during malaria infection. In addition, Plasmodium possibly regulates the reverse splicing of pre-mRNA or m6A modification of RNA, inducing the production of novel circRNAs in the host.