Exploring the Potential of miRNA-92a-3p as Lead for Sequence-Based Therapies for Malaria

Purpose: An upsurge in antimalarial drug resistance is compounded by the constant emergence and dispersal of genetic diversity in the virulent malaria parasite, Plasmodium falciparum (Pf), conferring a survival advantage that poses a serious threat to malaria control efforts. The highly polymorphic nature of the multicopy multigene var family that encodes erythrocyte membrane protein (EMP) drives the phenotypes associated with complicated malaria. Despite significant antigenic variation, analyzing the overlapping patterns among parasite isolates from different regions is crucial for effective vaccine development. While microRNAs are emerging as crucial modulators in influencing the host-parasite interactions, host miR-92a-3p revealed possibility to disrupt PfEMP variants associated with clinical malaria. Methods: The present study was performed to understand the crucial involvement of miR-92a-3p as an inhibitor of PfEMP during clinical malaria. For the cross-sectional study, the sequences for the Pf Duffy binding-like (DBL) domain were amplified and analyzed from 20 infected patient samples through PCR, cloning, and Sanger sequencing to assess the sequence variability and explore for the availability of the miR-92a target site among uncomplicated and complicated malaria cases. Extending to the host genome, a case-control study was undertaken to assess the relative impact of miR-92a gene polymorphisms. Results: Despite notable sequence variability in the DBLα domain across parasite isolates, a conserved motif facilitating host miR-92a binding was consistently observed, indicating a potential target site for therapeutic intervention. The comparative miR-92a mutation analysis revealed two healthy controls and nine cases with single-nucleotide and multi-nucleotide variants, suggestive of genetic influences on miRNA-mediated regulation. Conclusion: The identification of conserved miR-92a binding motifs within the DBLα domain of PfEMP, despite the genetic variability among isolates, underscores the regulatory potential of this miRNA. The findings of the present study are also informative of mutational mechanisms affecting miRNA synthesis and thus reveal the prospects of implementing miR-92a as an antisense strategy to target candidate genes for specific therapeutic interventions.