Study of cell signalling pathways affected by pathogen entry comprises a fundamental aspect of understanding host-pathogen interactions. In this respect, the current study attempted to ascribe novel roles to Bone Morphogenesis Protein (BMP) signaling during infection. BMP pathway has been majorly studied in context of development where it plays an imperative role and its contribution to immunity has been poorly documented. Subsequent narrative talks about the perturbation of BMP signaling in context of specific signaling networks and its collaboration with other molecular players of host innate armamentarium.
There is a pressing need to develop effective chemotherapy against Mycobacterium tuberculosis, the causative agent of tuberculosis, which has garnered the world’s attention as a leading cause of public health emergency. The tyrosine kinase, c-Abl was previously reported to be activated in murine bone marrow derived macrophages infected with mycobacteria. Yet, the identities of host signaling players and mechanisms exploited by mycobacteria in association with c-Abl lacked identification. Here, we deciphered an intricate signaling mechanism linking tyrosine kinase c-Abl, chromatin modifier, lysine acetyl transferase KAT5 and transcription factor, TWIST1 acting at Bmp2 and Bmp4 promoters. This molecular circuitry was observed to affect mycobacterial survival. Emerging studies suggest repurposing of c-Abl inhibitor, Imatinib, as an adjunct to existing anti-tuberculosis therapy. Through the use of Imatinib in an established model of tuberculosis, we demonstrated the ability of c-Abl inhibitors in potentiating innate immune responses.
Distinctive instances report the cross regulation among Pattern Recognition Receptors (PRRs). Interestingly, TLR3 signaling cascade induced in response to its cognate ligand was dampened through c-Abl-BMP induced miR27a. TLR3 is known to activate immune surveillance upon viral infections; however, recent studies also suggest its role in tumour regression and induction of apoptosis. Our observation of mycobacteria elicited down regulation of TLR3 pathway corroborated with increased incidences of lung cancer among TB patients and mycobacterial evasion of a well characterized form of cell-death i.e. apoptosis. Further, we utilized a panel of such Mtb mutants associated with virulence and questioned their relevance in the activation of c-Abl-dependent BMP signaling. We found that nitric oxide, hypoxia and carbon monoxide-responsive mycobacterial WhiB3 and DosR, but not the sec-dependent protein secretion pathway, orchestrate mycobacteria driven c-Abl-BMP signaling.
Continuing with the theme of exploring roles for BMP signaling during infection, we identified an important role for the C-type Lectin Receptor (CLR), Dectin-2, in activating Candida albicans-driven BMP signaling. Mounting evidences suggest BMP antagonists promote repair and regeneration in cells of varied lineages. We observed a role for BMP signaling in aggravating MMP2 and MMP9, factors that result in chronic non-healing wounds. Wounds are now increasingly recognized as being colonized with fungi along with bacteria. We propose a role for C. albicans orchestrated BMP signaling in contributing to enriched repressive methylation at Egf, Pdgf and Tissue Inhibitors of Matrix Metalloproteases (Timp2/3/4) promoters. Repressive H3K27me3 at these loci impedes the reparative tissue homeostasis, resulting in C. albicans endorsed impaired wound healing. Altogether, we uncovered hitherto unknown roles of BMP signaling during mycobacterial and fungal infections, enabling a better understanding of lesser studied pathways in mediating pathogenesis.
| Identifer | oai:union.ndltd.org:IISc/oai:etd.iisc.ernet.in:2005/3695 |
| Date | January 2017 |
| Creators | Mahadik, Kasturi Suryakant |
| Contributors | Balaji, K N |
| Source Sets | India Institute of Science |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
| Relation | G28577 |
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