National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center

Chennai, India

National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center

Chennai, India
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Singh B.,Burnet Institute | Anbalagan S.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Selvaraj P.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center
Human Immunology | Year: 2016

Genetic variations in chemokine genes influence the chemoattractive properties of T cells which may be associated with outcome of infections. In present study, we have investigated the regulatory role played by In1.1T/C (rs2280789) polymorphism of CCL5 and -135G/A (rs56061981) polymorphism of CXCL10 gene on intracellular CCL5 and CXCL10 expression in T cells. Whole blood cell cultures were stimulated with culture filtrate antigen (CFA) and infected with live M. tuberculosis were used for intracellular CCL5 and CXCL10 expression using flow cytometry. Genotyping was performed using polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP). Significantly higher expression of CCL5 expressing CD3+ and CD3+ CD8+ T cells were observed in HCs with In1.1TT genotype compared to C allele carrier (TT + TC) under unstimulated and CFA induced cultures (p. <. 0.05). In -135G/A (rs56061981) polymorphism, PTB patients with GG genotype showed a significantly decreased expression of CD3+ CXCL10+ and CD3+ CD4+ CXCL10+ T cells compared to A allele carrier (GA + AA) under unstimulated, CFA induced and M. tuberculosis infected cultures (P. <. 0.05). The present study suggest that TT genotype of CCL5 In1.1T/C (rs2280789) polymorphism play an important role to increased CCL5 expression in T cell which may enhanced Th1 immunity and help in protection against tuberculosis. The study also suggests GG genotype of CXCL10 -135G/A (rs56061981) polymorphism decreased CXCL10 expression in T cells which may have defective recruitment of mononuclear cells at the site of infection as well granuloma formation and in turn contribute to progression of TB. © 2017.


Harishankar M.,National Institute for Research in Tuberculosis formerly Tuberculosis Research Center | Selvaraj P.,National Institute for Research in Tuberculosis formerly Tuberculosis Research Center
Clinical Therapeutics | Year: 2017

Purpose: We studied the effect of 1,25(OH)2D3 (vitamin D3) on intracellular chemokine-positive T-cell subsets in whole blood cultures of healthy controls and patients with pulmonary tuberculosis. Methods: Genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method. The regulatory role of the Cdx2 and 3[U+02B9]UTR TaqI gene variants on chemokine-positive T-cell subsets was studied from culture filtrate antigen stimulated with or without vitamin D3 treated whole blood cultures of 60 healthy controls and 50 patients with pulmonary tuberculosis. Findings: Vitamin D3 significantly suppressed monocyte chemoattractant protein 1, macrophage inhibitory protein (MIP)-1α, MIP-1β, regulated on activation, normal T-cell expressed and secreted (RANTES), and interferon-γ inducible protein 10 (IP-10)-positive T-cell subsets compared with culture filtrate antigen stimulated cells without vitamin D3 treatment. In the Cdx2 AA genotype, vitamin D3 decreased MIP-1α, MIP-1β, and RANTES-positive T cells compared with the GG genotype. Whereas in the TaqI tt genotype, decreased MIP-1β and RANTES and increased IP-10-positive T cells were observed compared with the TT genotype in vitamin D3 treated cells (p < 0.05). Implications: This study suggests that vitamin D3 may regulate the chemokine-positive T cells through the Cdx2 AA and TaqI tt genotypes. This could be helpful to regulate chemokine-mediated inflammatory response during active disease condition. Hence, vitamin D3 supplementation along with tuberculosis drugs may be useful for faster recovery from the disease. © 2017 Elsevier HS Journals, Inc.


Harishankar M.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Afsal K.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Banurekha V.V.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Meenakshi N.,Institute of Thoracic Medicine | Selvaraj P.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center
International Immunopharmacology | Year: 2014

1,25-Dihydroxy vitamin D3[1,25(OH)2D3] is a potent immunomodulator and regulates various immune responses to Mycobacterium tuberculosis (Mtb). The present study aimed to understand the effect of 1,25(OH)2D3on pro-inflammatory cytokine response to Mtb antigen. Peripheral blood mononuclear cells from 42 healthy controls (HCs) and 42 pulmonary tuberculosis (PTB) patients were cultured with culture filtrate antigen (CFA) of Mtb with and without 1,25(OH)2D3at 10- 7M concentration for 72 h. The levels of IL-1α, IL-1β, TNF-α, TNF-β, IL-17 and IL-23 were estimated in the culture supernatants by ELISA. 1,25(OH)2D3significantly suppressed all the CFA induced pro-inflammatory cytokines (p < 0.05) studied except IL-1β in both HCs and PTB patients. Among the PTB patients, the observed suppression was visible both in patients with and without cavitary tuberculosis. The present study results suggest that 1,25(OH)2D3downregulates the production of pro-inflammatory cytokines and may control the exacerbated inflammatory response that may protect the host from excessive tissue damage at the site of infection. © 2014 Elsevier B.V.


Seenivasan S.,Government of Tamilnadu | Vaitheeswaran N.,Government of Tamilnadu | Seetha V.,Government of Tamilnadu | Anbalagan S.,National Institute for Research in Tuberculosis formerly Tuberculosis Research Center | And 2 more authors.
Indian Pediatrics | Year: 2015

Objective: To analyze the outcomes of Prevention of Parent to Child Transmission (PPTCT) of HIV program in an urban Southern Indian setting. Design: Observational study. Setting: Anti-retroviral Therapy (ART) Centers/ Integrated Counseling and Testing Centers (ICTC) at four government Obstetrics Institutes in an urban area. Participants: 100 HIV-positive pregnant women and their infants delivered in the study centers. Methods: Triple drug ART to HIV-positive pregnant women was started for maternal indications only. Rest of the pregnant women were given single dose Nevirapine (200 mg) at the onset of labor. All infants were given single dose Nevirapine (2 mg/kg) prophylaxis, according to National AIDS Control Organization guidelines. Mothers were counseled regarding breastfeeding and artificial feeding, and the choice was left to them. Whole blood HIV 1 DNA PCR was done for all infants at 6 weeks of life. A second PCR was done at 6 months or 6 weeks after stopping breastfeeds. PCR-positive infants were started on ART, and were followed-up till18 months of life. Results: Four infants were PCR-positive for HIV. All of them were breastfed. They were born to mothers of HIV stage 1 or 2 who were not on ART as CD4 counts were >350 cells/mm3. Among the mothers in Stage 3 or 4 or CD4 count <200 cells/mm3 and on ART, none of the infants was HIV-positive. The cumulative HIV-free survival at 18 months was 94%. Conclusion: Parent-to-child transmission rate in HIV was low with the currently used strategies. Triple drug ART to mother reduces mother-to-child transmission despite advanced maternal stage or low CD4 counts. © 2015, Indian Academy of Pediatrics.


Sundaramurthi J.C.,National Institute for Research in Tuberculosis | Ramanathan V.D.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Hanna L.E.,National Institute for Research in Tuberculosis
AIDS Research and Human Retroviruses | Year: 2013

HLA-B*27:05 is one of the widely reported alleles associated with resistance to HIV, while HLA-A24, HLA-B7, HLA-B*07:02, HLA-B*35:01, HLA-B*53:01, and HLA-B40 are reported to be associated with susceptibility to HIV. Using a bioinformatics approach we attempted to predict potential HLA-B*27:05-specific HIV-1C epitopes that do not bind to susceptibility-associated HLA alleles based on our hypothesis that such epitopes have a greater probability of eliciting a protective immune response in the host. A consensus sequence was built for all proteins of Indian clade C virus. Epitopes specific to HLA-B*27:05 were predicted from the consensus sequence using two different bioinformatics methods to enhance the accuracy of the prediction. Epitopes that were also predicted to bind to any of the susceptibility-associated HLA alleles were excluded from the list. The short-listed epitopes were modeled using MODPROPEP to refine the prediction. Fourteen peptides were identified as epitopes by both sequence-based methods and were found to interact strongly with HLA-B*27:05 by molecular modeling studies. Five of the 14 epitopes were previously reported as immunogenic by other researchers, while the remaining nine are novel. The 14 epitopes have been repeatedly identified by three different methods indicating their potential as useful candidates for an effective HIV vaccine. © Copyright 2013, Mary Ann Liebert, Inc. 2013.


Harishankar M.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Selvaraj P.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center
Human Immunology | Year: 2016

Vitamin D receptor (VDR) gene variants have been shown to be regulating the immune response in tuberculosis. We studied the regulatory role of VDR promoter Cdx-2 and 3'UTR TaqI gene variants on chemokine levels from culture filtrate antigen (CFA) stimulated with or without 1,25(OH)2D3 treated peripheral blood mononuclear cells of 50 pulmonary tuberculosis patients (PTB) and 51 normal healthy controls (HCs). In CFA with 1,25(OH)2D3 treated cultures, the MIP-1α, MIP-1β, RANTES levels were significantly decreased in Cdx-2 AA genotype compared to GG genotype, while a significantly increased MIG level was observed in Cdx-2 AA genotype (p<0.05). In TaqI polymorphism, tt genotype significantly decreased MIP-1β and RANTES levels compared to TT genotype. Moreover, a significantly increased level of IP-10 and MIG was observed in TaqI tt genotype compared with TT genotype (p<0.05). The results suggests that the 1,25(OH)2D3 may alter the chemokine response through the VDR polymorphic variants during infection. © 2016.


Harishankar M.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Anbalagan S.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Selvaraj P.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center
International Immunopharmacology | Year: 2016

1,25-DihydroxyVitamin D3 [1,25(OH)2D3] the active form of Vitamin D3 acts as an immunomodulator in various immune cells. The present study is aimed to study the effect of 1,25(OH)2D3 on chemokine levels and regulatory T-cells in 51 healthy controls (HCs) and 50 pulmonary tuberculosis (PTB) patients. Peripheral blood mononuclear cells were cultured with culture filtrate antigen (CFA) of Mycobacterium tuberculosis in the presence or absence of 1,25(OH)2D3 at 10- 7 M concentration for 72 h and the percentage positive regulatory T-cell subsets were studied using flow cytometry. The chemokine levels were estimated in the culture supernatants by ELISA. 1,25(OH)2D3 significantly upregulated the frequency of regulatory T-cell subsets while suppressed the production of chemokine levels in CFA stimulated cultures of HCs and PTB patients (p < 0.05). Correlation analysis revealed a significant negative correlation between CD4 + Foxp3 + regulatory T-cells and MCP-1, MIP-1β and IP-10 in CFA stimulated with 1,25(OH)2D3 treated cells (p < 0.05). The results suggested that 1,25(OH)2D3 upregulated regulatory T-cells and act as anti-inflammatory by downregulating chemokine levels which could be beneficial to protect the host from inflammation and tissue damage during infection. © 2016 Published by Elsevier B.V.


Sundaramurthi J.C.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Swaminathan S.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Hanna L.E.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center
Immunogenetics | Year: 2012

Earlier studies have identified a large number of immunogenic epitopes in HIV-1. Efforts are required to prioritize these epitopes in order to identify the best candidates for formulating an effective multi-epitope vaccine for HIV. We modeled 155 known cytotoxic T lymphocyte epit-opes of HIV-1 subtype C on the 3D structure of HLA-A *0201, HLA-B *2705, and HLA-B *5101 using MOD-PROPEP, as these alleles are known to be associated with resistance to HIV/slow progression to AIDS. Thirty-six epitopes were identified to bind to all the three HLA alleles with better binding affinity than the control peptides com-plexed with each HLA allele but not to any of the HLA alleles reported to be associated with susceptibility to HIV infection/rapid progression to disease. As increase in stability of the epitope-HLA complex results in increased immu-nogenicity, the short-listed epitopes could be suitable candidates for vaccine development. Twenty of the 36 epit-opes were polyfunctional in nature adding to their immuno-logical relevance for vaccine design. Further, 9 of the 20 polyfunctional epitopes were found to bind to all three resistance-associated HLA alleles using an additional method, adding worth to their potential as candidates for a vaccine formulation for HIV-1C. © Springer-Verlag 2012.


Sundaramurthi J.C.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Brindha S.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Shobitha S.R.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Swathi A.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | And 2 more authors.
Infection, Genetics and Evolution | Year: 2012

Cell-mediated immunity is critical for the control of . Mycobacterium tuberculosis infection. We hypothesized that those proteins of . M. tuberculosis (MTB) that do not have homologs in humans as well as human gut flora, would mount a good antigenic response in man, and employed a bioinformatics approach to identify MTB antigens capable of inducing a robust cell-mediated immune response in humans. In the first step we identified 624 MTB proteins that had no homologs in humans. Comparison of this set of proteins with the proteome of 77 different microbes that comprise the human gut flora narrowed down the list to 180 proteins unique to MTB. Twenty nine of the 180 proteins are known to be associated with dormancy. Since dormancy associated proteins are known to harbor CTL epitopes, we selected four representative unique proteins and subjected them to epitope analysis using ProPred1. Nineteen novel promiscuous epitopes were identified in the four proteins. Population coverage for 7 of the 19 shortlisted epitopes including Rv3852 (58-KPAEAPVSL, 112-VPLIVAVTL, 118-VTLSLLALL and 123-LALLLIRQL), Rv2706c (66-RPLSGVSFL) Rv3466 (8- RIVEVFDAL and 38-RSLERLECL) was >74%. These novel promiscuous epitopes are conserved in other virulent MTB strains, and can therefore be further investigated for their immunological relevance and usefulness as vaccine candidates. © 2012 Elsevier B.V..


Singh B.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Chitra J.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center | Selvaraj P.,National Institute for Research in Tuberculosis Formerly Tuberculosis Research Center
International Journal of Immunogenetics | Year: 2014

Polymorphisms in chemokine genes are important to determine the host-pathogen interactions which influence the chemokine levels. This study was carried out to find whether various CC chemokine gene polymorphisms, located in the promoter, exon-2 and intron-1 regions are associated with susceptibility or resistance to pulmonary tuberculosis (PTB) in south Indian population. The polymorphisms in various CC chemokine genes, MCP-1 (CCL2) [-2518A/G, 903C/T], MIP-1α (CCL3) [-2021C/T, +740A/G] and MIP-1β (CCL4) [-5725A/C] were studied in 295 healthy controls (HCs) and 303 patients with PTB using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). The allele and genotype frequencies of CCL2, CCL3 and CCL4 were not different between HCs and patients with PTB. However, a significantly decreased frequency of CCL2 -2518GG genotype was observed in male patients with PTB [P value = 0.015, P corrected (Bonferroni correction) Pc = 0.045, odds ratio (OR) 0.43 95% CI (0.21-0.86)], and a significantly increased frequency of the same genotype was observed among female patients with PTB [P value = 0.049, Pc = 0.147, OR 2.28 95% CI (1.00-5.27)]. The results suggest that -2518GG genotype may be associated with protection in males and susceptibility to PTB in females. Moreover, we also observed differences in the haplotype frequencies of these chemokine genes between HCs and patients with PTB. However, these polymorphisms are not associated with disease independently, probably in combination with other genes, they may be associated with susceptibility or resistance to TB in south Indian population. © 2013 John Wiley & Sons Ltd.

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