Abstract
Mycobacteria propelled modulation of host responses is of considerable interest in the face of emerging drug resistance. Although it is known that Abl tyrosine kinases affect entry and persistence of mycobacteria, mechanisms that couple c-Abl to proximal signaling pathways during immunity are poorly understood. Loss-of-function of c-Abl through Imatinib, in a mouse model of tuberculosis or RNA interference, identified bone morphogenesis protein (BMP) signaling as its cellular target. We demonstrate that c-Abl promotes mycobacterial survival through epigenetic modification brought about by KAT5-TWIST1 at Bmp loci. c-Abl-BMP signaling deregulated iNOS, aggravating the inflammatory balance. Interestingly, BMP signaling was observed to have far-reaching effects on host immunity, as it attenuated TLR3 pathway by engaging miR27a. Significantly, these events were largely mediated via WhiB3 and DosR/S/T but not SecA signaling pathway of mycobacteria. Our findings suggest molecular mechanisms of host pathways hijacked by mycobacteria and expand our understanding of c-Abl inhibitors in potentiating innate immune responses.
Highlights
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), has garnered our attention as a leading cause of public health emergency due to its unprecedented toll on the world’s population
We found that Imatinib demonstrated a substantial inhibition of c-Abl at a concentration of 5 μM and significantly reduced c-Abl-bone morphogenesis protein (BMP) Facilitate Mycobacterial Immune Evasion c-Abl phosphorylation at 10 μM (Figure S1E in Supplementary Material), while PDGF (Figure S1F in Supplementary Material) and c-Kit (Figure S1G in Supplementary Material) phosphorylation was inhibited at higher concentrations of Imatinib
When KAT5YF (Tyr44 was mutated to a non-phosphorylatable phenylalanine) was overexpressed in macrophages, followed by Mtb infection, BMP signaling failed to be activated (Figure 3D), underscoring the importance of c-Abl phosphorylated KAT5 in driving BMP signaling during Mtb infection
Summary
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), has garnered our attention as a leading cause of public health emergency due to its unprecedented toll on the world’s population. Tyrosine kinase c-Abl, is activated in murine bone marrow derived macrophages infected with mycobacteria and was elucidated to mediate TNF-dependent apoptosis [6]. This kinase was shown to promote entry and enhance microbial survival through its inhibition of c-Abl-BMP Facilitate Mycobacterial Immune Evasion acidification of the Mtb-containing phagosome [7,8,9,10]. C-Abl is known to regulate a member of the TGF-β superfamily, the bone morphogenesis protein (BMP) pathway in osteoblasts [14, 15] In line with this literature, Andreu et al report an enrichment of signaling pathways associated with bone tissue in macrophages infected with Mtb [16]. We surmised the probable activation of BMP pathway during mycobacterial infection
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