<i>Plasmodium</i> 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 <i>Plasmodium</i> 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 <i>P.y</i>17XL-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 <i>Plasmodium</i>-induced circRNA expression as a novel mechanism by which the parasite modulates host immune signaling, advancing the understanding of <i>Plasmodium-</i>host cell interactions. In addition, 42 circRNAs were found in normal BALB/c mice, and 25 circRNAs were discovered in <i>P.y</i>17XL-infected BALB/c mice, excluding 1238 circRNAs shared by normal and <i>P.y</i>17XL-infected BALB/c mice. <i>Plasmodium</i> 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, <i>Plasmodium</i> possibly regulates the reverse splicing of pre-mRNA or m6A modification of RNA, inducing the production of novel circRNAs in the host.