Comparative RNA-Seq Analysis Reveals Macrophage Polarization and T Cell Exhaustion Signatures in Visceral Leishmaniasis

The Syrian golden hamster (Mesocricetus auratus) is a universally accepted model for visceral leishmaniasis (VL) due to its ability to mimic human disease pathology. Mus musculus (BALB/c) is preferred for evaluating pharmaceutical and immunological responses. This study focuses on the precise role of gene signatures in L. donovani-infected M. auratus and M. musculus, using transcriptomic analysis. Principal component analysis (PCA) revealed distinct clustering among the four groups (uninfected vs. infected spleen samples from M. auratus and M. musculus). After differential expression analysis, 2054 genes in M. auratus and 1108 in M. musculus were found to be differentially expressed, with 153 genes common to both species. Except for 31 genes, most of the commonly dysregulated genes show a similar expression pattern. Although Th1-mediated immune signaling was observed in both cases, the overexpression of LAG3 in both infected groups underscores the important role of T cell exhaustion. Immunological responses against parasite infection in M. auratus appear to be more aggressive, while M. musculus seems more intense. Interestingly, only the M. musculus-infected group shows overexpression of IL-10. Without a definitive role for IL-10, the overexpression of Tgm2, Clec7a, and Adora2b in both species may drive disease outcome. These findings elucidate the immunological mechanisms driving the pathogenesis of VL in rodent models.