Insights into the genomic features and lifestyle of B1 subcluster mycobacteriophages.

Bacteriophages infecting Mycobacterium smegmatis mc2155 are numerous and, hence, are classified into clusters based on nucleotide sequence similarity. Analyzing phages belonging to clusters/subclusters can help gain deeper insights into their biological features and potential therapeutic applications. In this study, for genomic characterization of B1 subcluster mycobacteriophages, a framework of online tools was developed, which enabled functional annotation of about 55% of the previously deemed hypothetical proteins in B1 phages. We also studied the phenotype, lysogeny status, and antimycobacterial activity of 10 B1 phages against biofilm and an antibiotic-resistant M. smegmatis strain (4XR1). All 10 phages belonged to the Siphoviridae family, appeared temperate based on their spontaneous release from the putative lysogens and showed antibiofilm activity. The highest inhibitory and disruptive effects on biofilm were 64% and 46%, respectively. This systematic characterization using a combination of genomic and experimental tools is a promising approach to furthering our understanding of viral dark matter.

Systematic review and meta-analysis of human Toll-like receptors genetic polymorphisms for susceptibility to tuberculosis infection.

Epidemiological data from the world health organization (WHO) show that Globally an estimated 10 million (range, 8.9-11.0 million) people around the world were infected with TB in 2019. M.tuberculosis (M.tb) is the major cause of tuberculosis. Infection with M.tb has varied host immune responses because of the host genetic factor and its response to the infection. Genetic polymorphism in TLRs imparts susceptibility or resistance to the host against several diseases. In the present study, a systematic review and meta-analysis were performed to describe the relationship among various TLRs and SNPs involved in M.tb infection and their association with susceptibility to pulmonary tuberculosis in various populations of the world. PubMed and Scihub databases from 2008 to 2019 were searched and 58 articles were shortlisted for the present study to explore the association between TLRs gene polymorphisms and susceptibility to tuberculosis infection. The combined analysis showed that the polymorphisms TLR1 (rs5743618), TLR1 (rs4833095), TLR2 (-196 to -174) del, TLR2 (rs3804099), TLR4 (rs4986790), TLR4 (rs4986791), TLR4 (rs7873784), TLR6 (rs5743810), TLR8 (rs3764880), TLR9 (rs5743836), TLR9 (rs352139) were significantly associated with TB disease in certain ethnic population. In our meta-analysis study, we have also found variations between studies in some polymorphism, for example. The TLR1 (rs 5743618), TLR2 (rs5743708), TLR4 Asp299Gly, TLR4 Thr399Ile, TLR4 (rs7873784), TLR6 (rs5743810), TLR9 (rs5743836) was associated with the protection against TB. Meta-analysis was performed between polymorphisms and pulmonary tuberculosis to define increase or decrease in susceptibility to tuberculosis in various populations, which indicated that a relationship exists between SNPs/host genetic factors and susceptibility or resistance in patients suffering from pulmonary tuberculosis our finding concludes that this gene polymorphism may be associated with susceptibility to TB. The present study adds value to the various researches and studies going on various populations of the world in better understanding the role of TLR polymorphism in TB.

Identification and differential expression of serotransferrin and apolipoprotein A-I in the plasma of HIV-1 patients treated with first-line antiretroviral therapy.

BACKGROUND: Plasma proteins are known to interfere the drug metabolism during therapy. As limited information is available regarding the role of plasma proteins in HIV drug resistance during ART in HIV/AIDS patients, the present study aimed to identify and characterize the differentially expressed plasma proteins in the drug resistant and drug respondent groups of HIV-1 infected patients with > 6 years of first line ART. METHODS: Four-drug resistant (treatment failure) and four-drug respondent (treatment responder) patients were selected for plasma proteomic analysis based on viral load and drug resistance associated mutations from a cohort study designed on the first line ART patients who were enrolled in the antiretroviral therapy center, Sarojini Naidu Medical College, Agra, India from December 2009 to November 2016. After depleting high abundant proteins, plasma proteins were resolved using two-dimensional gel electrophoresis on IPG strips, pH range of 3-10. Spots were selected in the gel based on the density of staining which was common in the drug resistant and drug respondent groups separately. The fold change of each spot was calculated using image-J. Each protein spot was identified using the matrix assisted laser desorption/ionization-time of flight/time of flight (MALDI-TOF/TOF) after tryptic digestion. Peptide peaks were identified through flex analysis version 3.3, and a search against a protein data base using the internal Mascot. Gene ontology study was completed through STRING v.11 and Panther15.0. RESULTS: Out of eight spots from 2D gel samples analyzed by MALDITOF/TOF, two proteins were found to have significant score (> 56) after Flex analysis. These two proteins were identified to be apolipoprotein A1 and serotransferrin. The fold change expression of these two proteins were analyzed in drug resistant and drug respondent group. Apolipoprotein-A1 and serotransferrin were observed to be expressed 1.76 and 1.13-fold more respectively in drug respondent group compared to drug resistant group. The gene ontology analysis revealed the involvement of these two proteins in various important physiological processes. CONCLUSION: Apolipoprotein A-I and serotransferrin were found to be expressed more in drug respondent group compared to drug resistant group.

Autoantibodies in acquired myasthenia gravis: Clinical phenotype and immunological correlation.

BACKGROUND: Data on antibody profile in myasthenia gravis (MG) from India are limited. OBJECTIVES: To investigate antibody profile in patients with MG and their clinical correlates. PATIENTS AND METHODS: Patients of MG (n = 85, M:F::1.1:1, mean age: 39.29 ± 17.3 years, mean symptom duration: 72.94 ± 91.8 months) were evaluated for clinical features, MG foundation of America (MGFA) score, response to treatment, and outcome at last follow-up. Antibodies to acetylcholine receptor (AChR), muscle-specific kinase (MUSK), titin and ryanodine receptor (RYR) were analysed using ELISA. RESULTS: Based on the regional distribution of weakness, the cohort could be categorized as: generalized: 60, ocular: 16 and oculo-bulbar: 9. Sixty patients were followed up for a mean duration of 26.74 ± 13.8 months. Outcome at last follow-up was as follows: remission-22, no remission-33 and dead-5. AChR and MUSK antibodies were detected in 58 and 8 patients, respectively. Frequency of generalized MG, worse MGFA score during the disease course and thymomatous histology significantly correlated with presence of AChR-antibodies, though outcome at last follow-up was comparable between AChR-antibody positive and negative groups. Patients with MUSK antibodies had oculo-bulbar or generalized MG and frequent respiratory crisis, but majority improved or remitted with treatment. Titin antibodies were detected in 31.8% and RYR antibodies in 32.9%. Their presence did not correlate with age at onset of MG, severity or presence of thymoma. CONCLUSION: This report highlights the spectrum of antibodies in MG in an Indian cohort. AChR-antibody positivity correlated with clinical severity. Outcome was good in majority of MUSK antibody-positive MG. The role of other antibodies, complementary vs epiphenomenon, remains open.

Significance of immune response to Mycobacterium tuberculosis culture filtrate protein antigens in cerebrospinal fluid of tuberculous meningitis patients: A search for diagnostic marker.

Mycobacterium tuberculosis (H37Ra) culture filtrate proteins (CFP) are explored as a diagnostic marker for tuberculous meningitis (TBM). Cerebrospinal fluid (CSF) samples from patients were categorized as confirmed (n = 47), suspected (n = 20), and non-TBM (n = 25) cases. Immune response by Western blot revealed TBM CSF samples are having heterogeneous response to CFP. CFP ELISA was 92% sensitive and 38.30% specific. ODs of confirmed TBM and non-TBM cases were significantly different (P < 0.0001) and also the suspected TBM and non-TBM cases (P = 0.0001). No significant difference noticed in TBM and suspected TBM (P = 0.90). Thus, CFP can be a better biomarker for the diagnosis of TBM.

Comparative Evaluation of Multiplex PCR, RLEP PCR and LAMP PCR in Urine, Stool and Blood Samples for the Diagnosis of Pediatric Leprosy - A Cross-Sectional Study.

OBJECTIVE: To compare the diagnostic efficacy of multiplex polymerase chain reaction (PCR), Mycobacterium leprae-specific repetitive element (RLEP) PCR and loop-mediated isothermal amplification (LAMP) PCR in the diagnosis of pediatric leprosy as an alternative to slit-skin smear (SSS) examination. METHODS: A cross-sectional study was performed on 26 children aged 0-18 years with characteristic skin lesions of leprosy. SSS examination for acid fast bacilli (AFB) was performed for all children. Additionally, urine, stool and blood samples were tested by three PCR techniques - multiplex, RLEP and LAMP. The results of these tests were compared with each other and with results of SSS examination for acid fast bacilli (AFB) using appropriate statistical tests. RESULTS: Out of 26 patients studied, SSS examination was positive for AFB in 7 cases (26.9%). In blood samples, the positivity of multiplex PCR, RLEP PCR and LAMP PCR was 84.6%, 80.8%, and 80.8%, respectively. Multiplex PCR in blood samples was positive in 100% (n = 7) of SSS positive cases and 84.2% (16 out of 19) of the SSS negative cases (P < 0.001). The positivity of all PCR methods in urine and stool samples was significantly lesser than in blood. CONCLUSION: Multiplex PCR in blood sample is a superior diagnostic tool for pediatric leprosy compared to RLEP PCR and LAMP PCR as well as SSS examination.

Comparative evaluation of ELISA and dot-blot for the diagnosis of tuberculous meningitis.

Tuberculous meningitis is a central nervous system tuberculosis caused by M. tuberculosis. It causes high mortality if delayed in diagnosis and treatment. In this comparative study, Cerebrospinal fluid from TBM and non TBM patients were analyzed by ELISA and Dot-blot for anti-tuberculous antibodies. About 70% of the TBM samples showed positivity by Dot-blot and 72.5% by ELISA. Among the non TBM controls, 2.9% showed positivity by Dot-blot and 4.4% by ELISA. Both methods did not differ significantly as seen by Fisher's exact test (p = 0.50). Thus, Dot-blot could be an easy alternative to ELISA for quick diagnosis of TBM.

Mycobacteriophage D29 Lysin B exhibits promising anti-mycobacterial activity against drug-resistant Mycobacterium tuberculosis.

IMPORTANCE: To combat the rapidly emerging drug-resistant M. tuberculosis, it is now essential to look for alternative therapeutics. Mycobacteriophages can be considered as efficient therapeutics due to their natural ability to infect and kill mycobacteria including M. tuberculosis. Here, we have exploited the mycolyl-arabinogalactan esterase property of LysB encoded from mycobacteriophage D29. This study is novel in terms of targeting a multi-drug-resistant pathogenic strain of M. tuberculosis with LysB and also examining the combination of anti-TB drugs and LysB. All the experiments include external administration of LysB. Therefore, the remarkable lytic activity of LysB overcomes the difficulty to enter the complex cell envelope of mycobacteria. Targeting the intracellularly located M. tuberculosis by LysB and non-toxicity to macrophages take the process of the development of LysB as a drug one step ahead, and also, the interaction studies with rifampicin and isoniazid will help to form a new treatment regimen against tuberculosis.

SWATH-MS analysis of plasma proteins among Indian HIV-1 infected patients.

The identification and characterization of plasma proteins in drug resistant and drug sensitive in HIV-1 infected/AIDS patients were carried out using the SWATH-MS protocol. In total, 204 proteins were identified and quantified, 57 proteins were differentially expressed, out of which 25 proteins were down regulated and 32 proteins were up regulated in drug resistant patients. Six proteins such as complement C4-A, immunoglobulin heavy variable 1-2, carboxylic ester hydrolase, fibulin-1, immunoglobulin lambda constant7, secreted phosphoprotein 24 were differentially expressed in individuals with drug resistant HIV as compared to individuals with drug sensitive HIV. Gene ontology of 57 differentially expressed proteins was analysed and documented.

Pathogen-specific TLR2 protein activation programs macrophages to induce Wnt-beta-catenin signaling.

Innate immunity recognizes and resists various pathogens; however, the mechanisms regulating pathogen versus nonpathogen discrimination are still imprecisely understood. Here, we demonstrate that pathogen-specific activation of TLR2 upon infection with Mycobacterium bovis BCG, in comparison with other pathogenic microbes, including Salmonella typhimurium and Staphylococcus aureus, programs macrophages for robust up-regulation of signaling cohorts of Wnt-ß-catenin signaling. Signaling perturbations or genetic approaches suggest that infection-mediated stimulation of Wnt-ß-catenin is vital for activation of Notch1 signaling. Interestingly, inducible NOS (iNOS) activity is pivotal for TLR2-mediated activation of Wnt-ß-catenin signaling as iNOS(-/-) mice demonstrated compromised ability to trigger activation of Wnt-ß-catenin signaling as well as Notch1-mediated cellular responses. Intriguingly, TLR2-driven integration of iNOS/NO, Wnt-ß-catenin, and Notch1 signaling contributes to its capacity to regulate the battery of genes associated with T(Reg) cell lineage commitment. These findings reveal a role for differential stimulation of TLR2 in deciding the strength of Wnt-ß-catenin signaling, which together with signals from Notch1 contributes toward the modulation of a defined set of effector functions in macrophages and thus establishes a conceptual framework for the development of novel therapeutics.

Nitric oxide is involved in Mycobacterium bovis bacillus Calmette-Guérin-activated Jagged1 and Notch1 signaling.

Pathogenic mycobacteria have evolved unique strategies to survive within the hostile environment of macrophages. Modulation of key signaling cascades by NO, generated by the host during infection, assumes critical importance in overall cell-fate decisions. We show that NO is a critical factor in Mycobacterium bovis bacillus Calmette-Guérin-mediated Notch1 activation, as the generation of activated Notch1 or expression of Notch1 target genes matrix metalloproteinase-9 (MMP-9) or Hes1 was abrogated in macrophages derived from inducible NO synthase (iNOS) knockout (iNOS(-/-)), but not from wild-type, mice. Interestingly, expression of the Notch1 ligand Jagged1 was compromised in M. bovis bacillus Calmette-Guérin-stimulated iNOS(-/-) macrophages, and loss of Jagged1 expression or Notch1 signaling could be rescued by NO donors. Signaling perturbations or genetic approaches implicated that robust expression of MMP-9 or Hes1 required synergy and cross talk between TLR2 and canonical Notch1-PI3K cascade. Further, CSL/RBP-Jk contributed to TLR2-mediated expression of MMP-9 or Hes1. Correlative evidence shows that, in a murine model for CNS tuberculosis, this mechanism operates in vivo only in brains derived from WT but not from iNOS(-/-) mice. Importantly, we demonstrate the activation of Notch1 signaling in vivo in granulomatous lesions in the brains of Mycobacterium tuberculosis-infected human patients with tuberculous meningitis. Current investigation identifies NO as a pathological link that modulates direct cooperation of TLR2 with Notch1-PI3K signaling or Jagged1 to regulate specific components of TLR2 responses. These findings provide new insights into mechanisms by which Notch1, TLR2, and NO signals are integrated in a cross talk that modulates a defined set of effector functions in macrophages.

PE_PGRS antigens of Mycobacterium tuberculosis induce maturation and activation of human dendritic cells.

Mycobacterium tuberculosis, the causative agent of pulmonary tuberculosis, infects one-third of the world's population. Activation of host immune responses for containment of mycobacterial infections involves participation of innate immune cells, such as dendritic cells (DCs). DCs are sentinels of the immune system and are important for eliciting both primary and secondary immune responses to pathogens. In this context, to understand the molecular pathogenesis of tuberculosis and host response to mycobacteria and to conceive prospective vaccine candidates, it is important to understand how cell wall Ags of M. tuberculosis and, in particular, the proline-glutamic acid_polymorphic guanine-cytosine-rich sequence (PE_PGRS) family of proteins modulate DC maturation and function. In this study, we demonstrate that two cell wall-associated/secretory PE_PGRS proteins, PE_PGRS 17 (Rv0978c) and PE_PGRS 11 (Rv0754), recognize TLR2, induce maturation and activation of human DCs, and enhance the ability of DCs to stimulate CD4(+) T cells. We further found that PE_PGRS protein-mediated activation of DCs involves participation of ERK1/2, p38 MAPK, and NF-kappaB signaling pathways. Priming of human DCs with IFN-gamma further augmented PE_PGRS 17 or PE_PGRS 11 Ag-induced DC maturation and secretion of key proinflammatory cytokines. Our results suggest that by activating DCs, PE_PGRS proteins, important mycobacterial cell wall Ags, could potentially contribute in the initiation of innate immune responses during tuberculosis infection and hence regulate the clinical course of tuberculosis.

Significance of antibody detection in the diagnosis of cryptococcal meningitis.

Cryptococcus neoformans is the causative agent of Cryptococcosis, a chronic and life-threatening infection common in AIDS patients. Sonicated proteins of cryptococci were reported to contain antigenic properties. In the present study antigens are prepared from cryptococcal culture filtrate and by sonication. Secretory antigens are prepared by precipitation of culture filtrate using saturated ammonium sulfate followed by dialysis. Prepared antigens are tested for the presence of antibodies in the CSF samples of cryptococcal meningitis cases by ELISA. Comparison is made between India ink staining, latex antigen test, and the antibodies to the sonicated and secretory antigens. The results indicate that although antigen could be detected in the majority of samples, antibody could also be detected to the extent of 80-85%. It is interesting to note that some samples that were negative for India ink staining also showed high antibody responses. Hence, antibody detection could be a valuable marker in association with India ink staining for the early diagnosis of the cryptococcal infection. This test may also counter false positivity encountered in latex antigen test. Antibody detection assay would be a viable alternative, which has 83% sensitivity and 100% specificity. Thus the presently described test aids in immunodiagnosis of cryptococcal infection.

A putative short-chain dehydrogenase Rv0148 of Mycobacterium tuberculosis affects bacterial survival and virulence.

During infection, Mycobacterium tuberculosis combats the stress generated by the host cells through the action of short-chain dehydrogenases/reductases (SDRs). Rv0148 belongs to the oxidoreductase family with the SDRs domain, which regulates the homeostasis of M. tuberculosis. In our earlier studyusing knockout mutant strain (∆0148), we reported that Rv0148 is involved in intermediary metabolism, drug resistance and cell homeostasis of M. tuberculosis. In the current study, we explored the functional role of Rv0148 using gene knockout mutant in-vitro and in-vivo models of infection. We report the ∆0148 is attenuated for virulence of M. tuberculosis. During human monocyte (THP-1) cell line infection, M. tuberculosis Δ0148 displayed reduced intracellular survival compared to the wild type at successive time points. Similarly, in a guinea pig animal model of aerosol infection, Δ0148 displayed a growth attenuation at 5- and 10-week post-infection in the lungs and spleen compared to the wild-type M. tuberculosis and Rv0148-complemented Δ0148 strains. Our study suggest that Rv0148 has a distinct role in the intracellular virulence of M. tuberculosis.

Role of a Putative Alkylhydroperoxidase Rv2159c in the Oxidative Stress Response and Virulence of Mycobacterium tuberculosis.

Mycobacterium tuberculosis, which causes tuberculosis, is one of the leading infectious agents worldwide with a high rate of mortality. Following aerosol inhalation, M. tuberculosis primarily infects the alveolar macrophages, which results in a host immune response that gradually activates various antimicrobial mechanisms, including the production of reactive oxygen species (ROS), within the phagocytes to neutralize the bacteria. OxyR is the master regulator of oxidative stress response in several bacterial species. However, due to the absence of a functional oxyR locus in M. tuberculosis, the peroxidase stress is controlled by alkylhydroperoxidases. M. tuberculosis expresses alkylhydroperoxide reductase to counteract the toxic effects of ROS. In the current study, we report the functional characterization of an orthologue of alkylhydroperoxidase family member, Rv2159c, a conserved protein with putative peroxidase activity, during stress response and virulence of M. tuberculosis. We generated a gene knockout mutant of M. tuberculosis Rv2159c (MtbΔ2159) by specialized transduction. The MtbΔ2159 was sensitive to oxidative stress and exposure to toxic transition metals. In a human monocyte (THP-1) cell infection model, MtbΔ2159 showed reduced uptake and intracellular survival and increased expression of pro-inflammatory molecules, including IL-1ß, IP-10, and MIP-1α, compared to the wild type M. tuberculosis and Rv2159c-complemented MtbΔ2159 strains. Similarly, in a guinea pig model of pulmonary infection, MtbΔ2159 displayed growth attenuation in the lungs, compared to the wild type M. tuberculosis and Rv2159c-complemented MtbΔ2159 strains. Our study suggests that Rv2159c has a significant role in maintaining the cellular homeostasis during stress and virulence of M. tuberculosis.

Genomic signatures of protease and reverse transcriptase genes from HIV-1 subtype C isolated from first-line ART patients in India.

Genomic signatures of the protease and reverse transcriptase gene of HIV-1 from HIV infected North Indian patients who were under ART from 1 to ≤ 7 years were analyzed. The DNA from plasma samples of 9 patients and RNA from 57 patients were isolated and subjected to amplification for the protease and reverse transcriptase gene of HIV-1 subtype C. Then sequencing was carried out following the WHO dried blood spot protocol. The drug resistance mutation patterns were analyzed using the HIV Drug Resistance Database, Stanford University, USA. Lamivudine-associated drug-resistance mutations such as M184V/M184I, nevirapine-associated drug resistance mutations Y181C and H221Y, and efavirenz-associated drug resistance mutations M230I were observed in reverse transcriptase gene of archived DNA of two HIV-1 infected patients. No mutation was observed in the remaining 7 patients. Various computational tools and websites like viral epidemiological signature pattern analysis (VESPA), hyper mutation, SNAP version 2.1.1, and entropy were utilized for the analysis of the signature pattern of amino acids, hyper mutation, selection pressure, and Shannon entropy in the protease and reverse transcriptase gene sequences of the 9 archived DNA, 56 protease gene and 51 reverse transcriptase gene from the HIV-1 DNA amplified sequences of RNA. The HIV-1 Subtype-C (Gene bank accession number: AB023804) and first isolate HXB2 (Gene bank accession number: K03455.1) was taken as reference sequence. The signature amino acid sequences were identified in the protease and reverse transcriptase gene, no hyper mutation, highest entropy was marked in the amino acid positions and synonymous to non-synonymous nucleotide ratio was calculated in the protease and reverse transcriptase gene of 9 archived DNA sequences, 56 protease and 51 reverse transcriptase gene sequences of HIV-1 Subtype C isolates.

Src homology 3-interacting domain of Rv1917c of Mycobacterium tuberculosis induces selective maturation of human dendritic cells by regulating PI3K-MAPK-NF-kappaB signaling and drives Th2 immune responses.

Mycobacterium tuberculosis, an etiological agent of pulmonary tuberculosis, causes significant morbidity and mortality worldwide. Pathogenic mycobacteria survive in the host by subverting host innate immunity. Dendritic cells (DCs) are professional antigen-presenting cells that are vital for eliciting immune responses to infectious agents, including pathogenic mycobacteria. DCs orchestrate distinct Th responses based on the signals they receive. In this perspective, deciphering the interactions of the proline-glutamic acid/proline-proline-glutamic acid (PE/PPE) family of proteins of M. tuberculosis with DCs assumes significant pathophysiological attributes. In this study, we demonstrate that Rv1917c (PPE34), a representative member of the proline-proline-glutamic-major polymorphic tandem repeat family, interacts with TLR2 and triggers functional maturation of human DCs. Signaling perturbations implicated a critical role for integrated cross-talk among PI3K-MAPK and NF-κB signaling cascades in Rv1917c-induced maturation of DCs. However, this maturation of DCs was associated with a secretion of high amounts of anti-inflammatory cytokine IL-10, whereas Th1-polarizing cytokine IL-12 was not induced. Consistent with these results, Rv1917c-matured DCs favored secretion of IL-4, IL-5, and IL-10 from CD4(+) T cells and contributed to Th2-skewed cytokine balance ex vivo in healthy individuals and in patients with pulmonary tuberculosis. Interestingly, the Rv1917c-skewed Th2 immune response involved induced expression of cyclooxygenase-2 (COX-2) in DCs. Taken together, these results indicate that Rv1917c facilitates a shift in the ensuing immunity toward the Th2 phenotype and could aid in immune evasion by mycobacteria.

The multifunctional PE_PGRS11 protein from Mycobacterium tuberculosis plays a role in regulating resistance to oxidative stress.

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-κB 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.