Abstract
Mycobacterium tuberculosis instigates interactions with host factors to promote its survival within the host inimical conditions. Among such factors, nuclear receptors (NRs) seem to be promising candidates owing to their role in bacterial pathogenesis. However, only few members of NR superfamily have been implicated in M. tuberculosis infection and there is a dearth of comprehensive knowledge about expression or function of the entire superfamily. In this study, we performed detailed expression analysis and identified key NRs getting differentially regulated in murine macrophages and dendritic cells (DC) upon infection with H37Rv. The murine macrophages and DCs infected with H37Rv entailed overlapping changes in the expression of certain NRs which reflect upon the possibility that both cells might utilize similar transcriptional programs upon M. tuberculosis infection. We identified Nr4a3 and Rora, which have not been implicated in M. tuberculosis pathogenesis, undergo similar changes in expression in macrophages and DCs upon H37Rv infection. Interestingly, a similar pattern in their expression was also observed in infected human monocyte derived macrophages and the findings corroborated well with PBMCs obtained from TB patients. This all-inclusive analysis provides the basis for a precise approach in identifying NRs that can be targeted therapeutically in intracellular bacterial infections.
Highlights
Macrophage polarization towards M2 phenotype, augments the bacterial survival[12,16]
We observed that nuclear receptors (NRs) such as vitamin D receptor (Vdr), liver X receptor alpha (Lxra), Pparg, Rarg, Nr4a’s, RAR-related orphan receptor alpha (Rora), androgen receptor (Ar), and thyroid hormone receptor beta (Thrb) were undergoing differential regulation in both macrophages and dendritic cells (DC) upon M. tuberculosis infection suggesting a plausible cross-talk between these NRs and M. tuberculosis
While Ar and Vdr remained constantly repressed during later time points of infection, the expression of Rarg and Thrb started to rescue at 48 h post infection
Summary
Macrophage polarization towards M2 phenotype, augments the bacterial survival[12,16]. Along with Lxr the binding sites of retinoic acid receptor (Rar) are enriched in H3K4me[1] regions (a marker for active or poised enhancers) in M. tuberculosis infected THP-1 cells[19] In accordance with these findings, studies performed on human DCs infected with M. tuberculosis revealed enrichment of Lxr and Rar binding sites[20]. A composite gene expression analysis of NRs performed in macrophages and DCs has suggested a regulatory role of NR superfamily in macrophages and DC functionality[8,30] These studies have examined the expression of these NRs only in the presence of a PAMP or an immunological modulator and we still need to unravel a composite list of all NRs being modulated by mycobacteria in its innate immune cell niches. Examining the potential of ligands for such NRs as an approach to anti-TB therapy could be promising
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