Differential expression of miRNAs dictates the susceptibility/resistance during malaria pathogenesis

Malaria continues to pose a significant global health challenge, with the severity of the disease being influenced by intricate host–parasite interactions. MicroRNAs (miRNAs), which function as post-transcriptional regulators, are pivotal in modulating host immune responses during infection. This study conducted a comparative analysis of miRNA expression profiles in splenocytes of mice infected with two closely related Plasmodium yoelii strains- Py17XL (lethal) and Py17XNL (non-lethal), utilizing small RNA sequencing on day 13 post-infection. A total of 171 and 220 miRNAs were differentially expressed in the Py17XL and Py17XNL groups, respectively, in comparison to uninfected controls. Among these, 79 miRNAs were found commonly dysregulated, while 53 and 86 miRNAs were unique to the lethal and non-lethal P. yoelii infection, respectively. Further, RT-qPCR validation corroborated the expression patterns of selected miRNAs. In Py 17XNL group, miR-875–3p, miR-30a-3p, miR-499–5p, and miR-212–3p were significantly upregulated, whereas miR-6992–5p, miR-704, miR-7676–3p, and miR-1933–3p were predominantly elevated in the Py17XL group. Pathway enrichment analysis indicated that these miRNAs target genes involved in immune-related signalling pathways, including MAPK, mTOR, FoxO, Th-17 cell differentiation and TGF-β signalling. These findings suggest distinct miRNA-mediated regulatory mechanisms underlying lethal and non-lethal malaria outcomes and offer potential molecular targets for therapeutic intervention and biomarker development.