The Multifunctional PE_PGRS11 Protein from Mycobacterium tuberculosis Plays a Role in Regulating Resistance to Oxidative Stress

Abstract

Mycobacterium tuberculosis utilizes unique strategies to survive amid the hostile environment of infected host cells. Infection-specific expression of a unique mycobacterial cell surface antigen that could modulate key signaling cascades can act as a key survival strategy in curtailing host effector responses like oxidative stress. We demonstrate here that hypothetical PE_PGRS11 ORF encodes a functional phosphoglycerate mutase. The transcriptional analysis revealed that PE_PGRS11 is a hypoxia-responsive gene, and enforced expression of PE_PGRS11 by recombinant adenovirus or Mycobacterium smegmatis imparted resistance to alveolar epithelial cells against oxidative stress. PE_PGRS11-induced resistance to oxidative stress necessitated the modulation of genetic signatures like induced expression of Bcl2 or COX-2. This modulation of specific antiapoptotic molecular signatures involved recognition of PE_PGRS11 by TLR2 and subsequent activation of the PI3K-ERK1/2-NF-B signaling axis. Furthermore, PE_PGRS11 markedly diminished H 2 O 2 -induced p38 MAPK activation. Interestingly, PE_PGRS11 protein was exposed at the mycobacterial cell surface and was involved in survival of mycobacteria under oxidative stress. Furthermore, PE_PGRS11 displayed differential B cell responses during tuberculosis infection. Taken together, our investigation identified PE_PGRS11 as an in vivo expressed immunodominant antigen that plays a crucial role in modulating cellular life span restrictions imposed during oxidative stress by triggering TLR2-dependent expression of COX-2 and Bcl2. These observations clearly provide a mechanistic basis for the rescue of pathogenic Mycobacterium-infected lung epithelial cells from oxidative stress.

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

“…TLR2 receptors, while acting as sensors for extracellular cues or the endocytic network, drive signaling events in response to recognition of pathogen-associated molecular patterns, including mycobacterial antigens like ESAT-6, PE_PGRS antigens; NOD1 and NOD2 operate as cytosolic sensors initiating signaling pathways upon recognition of diaminopimelic acid and muramyl dipeptide (MDP), components of bacterial peptidoglycan (15)(16)(17)(18)(19)(20). Although TLR2 or NOD receptor-induced signaling events culminate in activation and nuclear translocation of NF-B, transcriptome profiles in response to TLR2 or NOD receptors could markedly diverge.…”

PPE38 Modulates the Innate Immune Response and Is Required for Mycobacterium marinum Virulence

“…To further confirm the cell surface association of PPE38, whole cells of recombinant M. marinum strains expressing FLAG-tagged PPE38 or GFP were subjected to proteinase K and trypsin digestion as described previously (19,28). The PPE38 protein expressed in M. marinum cells was rapidly degraded by proteinase K and trypsin within 10 min of the reaction (Fig.…”

“…Recombinant M. marinum strains harboring the pMMppe38_FLAG and pRvppe38_FLAG constructs were grown and subjected to cell fractionation by using a method described previously (19). Briefly, the cells were lysed by sonication, and cell debris and unlysed cells were removed by centrifugation at 3,000 ϫ g for 5 min.…”

“…Proteinase K and trypsin sensitivity assays were performed as described previously (19). Briefly, cells of recombinant M. marinum harboring pMMppe38_FLAG and pRvppe38_FLAG were mixed with proteinase K or trypsin at a concentration of 100 g/ml and incubated at 37°C for the indicated times.…”

Sonic hedgehog-Dependent Induction of MicroRNA 31 and MicroRNA 150 Regulates Mycobacterium bovis BCG-Driven Toll-Like Receptor 2 Signaling

“…In this context, integration of key signaling centers modulating immunity to pathogenic mycobacterial infections remains unexplored. However, macrophages as sentinels are known to tailor differential immune responses to infections with pathogenic mycobacteria, including Mycobacterium tuberculosis, Mycobacterium bovis, etc., by utilizing dynamic interplay of signaling networks (14)(15)(16)(17)(18)(19). We propose SHH signaling to constitute one such signaling network.…”