Mycobacterial dormancy associated proteins: Role in the survival of bacteria under stress conditions
Year: 2016
Type: article
Abstract: Background: Mycobacterium tuberculosis, the cause of tuberculosis in humans, is present approximately in one third of the world's population, mostly in a dormant state. The proteins encoded by the dormancy survival regulon (DosR regulon) are mainly responsible for survival of the bacilli in a latent form. To maintain latency, mycobacteria orchestrate a balanced interplay of different cytokines secreted by immune cells during the granulomatous stage. The function of most of the DosR regulon proteins of M. tuberculosis is unknown. Rv3131 and Rv2004c are members of DoSR antigens category and conserved hypothetical proteins which are significantly up-regulated under different stress conditions. Rv3131 contains FMN binding nitroreductase domain and is predicted to be responsible for virulence, detoxification and adaptation of bacteria under hostile conditions. Rv2004c was reported to be localized on the surface of M.tb and its high active binding peptide sequence interacts with U937 macrophages and A549 epithelial cells. Methods & Materials: Rv3131 and Rv2004c genes were cloned and respective proteins were purified. Results: In this study, we have shown that the DosR regulon proteins, encoded by the genes Rv3131 and Rv2004c, can stimulate macrophages and peripheral blood mononuclear cells (PBMC) to secrete important cytokines that may be significant in granuloma formation and its maintenance. Computational modeling, docking and simulation study suggested that these proteins might interact with TLR2. This was further confirmed through the interaction of recombinant Rv3131 and 2004c with TLR2 expressed by HEK293 cells. In THP-1 cells treated with RV3131 and 2004c, Tlr2 mRNA levels were significantly increased. When in vitro differentiated THP-1 cells were treated with recombinant Rv3131 and Rv2004c, increased secretion of TNF- α, IL-1b and IL-8 was observed in a dose dependent manner. Similarly, human PBMCs when treated with recombinant Rv3131 and 2004c, showed upregulated secretion of pro-inflammatory cytokines IFN-ɼ, TNF-α, IL-1b and IL-8. FACS analyses on THP-1 cell surface following RV3131 and Rv2004c protein treatment demonstrated increased expression of TLR2. Further experiments are being carried out to decipher the functional role of these proteins. Conclusion: The cytokine profiles dissected herein point to a possible role of these proteins in maintenance of latency with the help of the pro-inflammatory responses.
Authors: V. Peddireddy, S.N. Doddam, N. Ahmed
Institution: University of Hyderabad
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,900
OpenAlex ID: W2334411596