Publications by authors named "Subash Babu"

198 Publications

Antibody responses to the BBV152 vaccine in individuals previously infected with SARS-CoV-2: A pilot study.

Indian J Med Res 2021 Sep 16. Epub 2021 Sep 16.

Indian Council of Medical Research, New Delhi, India, India.

Background & Objectives: Vaccination against SARS-CoV-2 is a recommendation from the World Health Organization as the foremost preference in the current situation to control the COVID-19 pandemic. BBV152 is one of the approved vaccines against SARS-CoV-2 in India. In this study, we determined SARS-CoV-2-specific antibody levels at day 0 (baseline, before vaccination), day 28 ± 2 post-first dose (month 1) and day 56 ± 2 days post-first dose (month 2) of BBV152 whole-virion-inactivated SARS-CoV-2 recipients, and compared the antibody responses of individuals with confirmed pre-vaccination SARS-CoV-2 infection to those individuals without prior evidence of infection.

Methods: Blood samples were collected from 114 healthcare professionals and frontline workers who received BBV152 vaccine from February to May 2021. Prior infection with SARS-CoV-2 was determined at baseline. Serum samples were used to estimate SARS-CoV-2 nucleoprotein-specific IgG [IgG (N)], spike protein-specific IgG [IgG (S)] and neutralizing antibodies (NAb).

Results: Participants with previous SARS-CoV-2 infection after a single vaccine dose elicited IgG (N) and IgG (S) antibody levels along with NAb binding inhibition responses levels were similar to infection-naïve vaccinated participants who had taken two doses of vaccine.

Interpretation & Conclusions: Our preliminary data suggested that a single dose of BBV152-induced humoral immunity in previously infected individuals was equivalent to two doses of the vaccine in infection-naïve individuals. However, these findings need to be confirmed with large sized cohort studies.
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http://dx.doi.org/10.4103/ijmr.IJMR_2066_21DOI Listing
September 2021

Ex-vivo immunophenotyping and high dimensionality UMAP analysis of leucocyte subsets in tuberculous lymphadenitis.

Tuberculosis (Edinb) 2021 Jul 31;130:102117. Epub 2021 Jul 31.

National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai, India; Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Tuberculous lymphadenitis (TBL) is defined by reduced proinflammatory cytokines and elevated CD4, CD8 T cells and decreased CD8 cytotoxic markers. However, ex-vivo phenotyping of diverse leucocytes in TBL has not been done. We show activated and atypical B cells, myeloid dendritic cells (mDCs), classical, non-classical and intermediate monocytes, T regulatory (T regs) cells, CD4 T cell effector memory RA (TEMRA), CD4 effector and CD8 central memory phenotypes were significantly increased in TBL compared to LTB individuals. In contrast, classical memory and plasma B cells, plasmacytoid DCs (pDCs), CD8 TEMRA, CD4 naïve and central memory cells were significantly decreased in TBL compared to LTB individuals. Some of the leucocyte frequencies (atypical memory B cells, pDCs, myeloid-derived suppressor cells, CD4 effector and CD8 central memory was increased; activated memory and plasma B cell, mDCs, classical, non-classical, intermediate monocytes, T regs, CD4 TEMRA, CD4, CD8 naïve and effector memory cells and CD8 central memory cells were decreased) were significantly modulated after anti-TB treatment among TBL individuals. UMAP analysis show that leucocyte subsets or islands expressing specific markers were significantly different in TBL baseline and post-treatment individuals. Overall, we suggest altered frequencies of diverse leucocytes influences the disease pathology and protective immunity in TBL individuals.
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http://dx.doi.org/10.1016/j.tube.2021.102117DOI Listing
July 2021

Helminth Coinfection Is Associated With Enhanced Plasma Levels of Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Tuberculous Lymphadenitis.

Front Cell Infect Microbiol 2021 19;11:680665. Epub 2021 Jul 19.

National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai, India.

Matrix metalloproteinases (MMPs) are crucial for tissue remodeling and repair and are expressed in diverse infections, whereas tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of MMPs. However, the interaction of MMPs and TIMPs in tuberculous lymphadenitis (TBL), an extra-pulmonary form of tuberculosis (EPTB) and helminth (Hel+) coinfection is not known. Therefore, this present study investigates the levels of circulating MMPs (1, 2, 3, 7, 8, 9, 12, 13) and TIMPs (1, 2, 3, 4) in TBL individuals with helminth ( [Ss], hereafter Hel+) coinfection and without helminth coinfection (hereafter, Hel-). In addition, we have also carried out the regression analysis and calculated the MMP/TIMP ratios between the two study groups. We describe that the circulating levels of MMPs (except MMP-8 and MMP-12) were elevated in TBL-Hel+ coinfected individuals compared to TBL-Hel- individuals. Similarly, the systemic levels of TIMPs (1, 2, 3, 4) were increased in TBL-Hel+ compared to TBL-Hel- groups indicating that it is a feature of helminth coinfection . Finally, our multivariate analysis data also revealed that the changes in MMPs and TIMPs were independent of age, sex, and culture status between TBL-Hel+ and TBL-Hel- individuals. We show that the MMP-2 ratio with all TIMPs were significantly associated with TBL-helminth coinfection. Thus, our results describe how helminth infection has a profound effect on the pathogenesis of TBL and that both MMPs and TIMPs could dampen the immunity against the TBL-Hel+ coinfected individuals.
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http://dx.doi.org/10.3389/fcimb.2021.680665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326810PMC
August 2021

Effect of BCG vaccination on proinflammatory responses in elderly individuals.

Sci Adv 2021 08 4;7(32). Epub 2021 Aug 4.

ICMR-National Institute for Research in Tuberculosis- International Center for Excellence in Research, Chennai, India.

We investigated the influence of Bacillus Calmette-Guérin (BCG) vaccination on the unstimulated plasma levels of a wide panel of cytokines, chemokines, acute-phase proteins (APPs), matrix metalloproteinases (MMPs), and growth factors in a group of healthy elderly individuals (age, 60 to 80 years) at baseline (before vaccination) and 1 month after vaccination as part of our clinical study to examine the effect of BCG on COVID-19. Our results demonstrated that BCG vaccination resulted in diminished plasma levels of types 1, 2, and 17 and other proinflammatory cytokines and type 1 interferons. BCG vaccination also resulted in decreased plasma levels of CC, CXC chemokines, APPs, MMPs, and growth factors. Plasma levels of the aforementioned parameters were significantly lower in vaccinated individuals when compared to unvaccinated control individuals. Thus, our study demonstrates the immunomodulatory properties of BCG vaccination and suggests its potential utility in nonspecific vaccination of COVID-19 by down-modulating pathogenic inflammatory responses.
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http://dx.doi.org/10.1126/sciadv.abg7181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336950PMC
August 2021

Latent tuberculosis co-infection is associated with heightened levels of humoral, cytokine and acute phase responses in seropositive SARS-CoV-2 infection.

J Infect 2021 09 28;83(3):339-346. Epub 2021 Jul 28.

International Center for Excellence in Research, ICMR-National Institute for Research in Tuberculosis, Chennai, India.

Objectives: Latent Tuberculosis infection (LTBI) is postulated to modulate immune responses and alter disease severity in SARS-CoV-2 co-infection. However, no data exist on the effect of LTBI on the immune responses in SARS-CoV-2 co-infected individuals.

Methods: We examined the SARS-CoV-2 specific antibody responses, plasma cytokines, chemokines, acute phase proteins and growth factor levels in LTBI positive and negative individuals with SARS-CoV-2 infection.

Results: Our results demonstrated that individuals with LTBI (LTBI+) and seropositive for SARS-CoV-2 infection were associated with elevated SARS-CoV-2 specific IgM, IgG and IgA antibodies, as well as enhanced neutralization activity compared to those negative for LTBI (LTBI-) individuals. Our results also demonstrate that LTBI+ individuals exhibited significantly higher plasma levels of IFNγ, IL-2, TNFα, IL-1α, IL-1β, IL-6, IL-12, IL-15, IL-17, IL-3, GM-CSF, IL-10, IL-25, IL-33, CCL3 and CXCL10 compared to LTBI- individuals. Finally, our results show that LTBI+ individuals exhibit significantly higher levels of C-reactive protein, alpha-2 macroglobulin, VEGF and TGFα compared to LTBI- individuals.

Conclusions: Thus, our data clearly demonstrates that LTBI+ individuals seropositive for SARS-CoV-2 infection exhibit heightened levels of humoral, cytokine and acute phase responses compared to LTBI- individuals. Thus, LTBI is associated with modulation of antibody and cytokine responses as well as systemic inflammation in individuals seropositive for SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.jinf.2021.07.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316716PMC
September 2021

Systemic Inflammation and Microbial Translocation Are Characteristic Features of SARS-CoV-2-Related Multisystem Inflammatory Syndrome in Children.

Open Forum Infect Dis 2021 Jul 6;8(7):ofab279. Epub 2021 Jul 6.

National Institutes of Health-National Institute for Research in Tuberculosis - International Center for Excellence in Research, Chennai, India.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare manifestation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children that can result in increased morbidity and mortality. The inflammatory underpinnings of MIS-C have not been examined in detail.

Methods: We examined the plasma levels of acute phase proteins and microbial translocation markers in children with MIS-C, children with acute coronavirus disease 2019 (COVID-19) infection, SARS-CoV-2-seropositive children, and controls.

Results: MIS-C children exhibited significantly higher levels of C-reactive protein (CRP), alpha2 macroglobulin (α2M), serum amyloid P (SAP), lipopolysaccharide (LPS), sCD14, and LPS binding protein (LBP) and significantly lower levels of haptoglobin (Hp) in comparison with seropositive, control, and/or COVID-19 children. In addition, COVID-19 children exhibited significantly higher levels of most of the above markers in comparison with seropositive and control children. Principal component analysis using a set of these markers could clearly discriminate MIS-C and COVID-19 from seropositive and control children. MIS-C children requiring pediatric intensive care unit admission and COVID-19 children with severe disease had higher levels of CRP, SAP, and/or sCD14 at admission.

Conclusions: Our study describes the role of systemic inflammation and microbial translocation markers in children with MIS-C and COVID-19 and therefore helps in advancing our understanding of the pathogenesis of different presentations of SARS-CoV-2 infection in children.
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http://dx.doi.org/10.1093/ofid/ofab279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312521PMC
July 2021

BCG vaccination induces enhanced frequencies of dendritic cells and altered plasma levels of type I and type III interferons in elderly individuals.

Int J Infect Dis 2021 Jul 22;110:98-104. Epub 2021 Jul 22.

ICMR-National Institute for Research in Tuberculosis-International Center for Excellence in Research, Chennai, India. Electronic address:

Objective: BCG can improve the response to vaccines directed against viral infections, and also, BCG vaccination reduces all-cause mortality, most likely by protecting against unrelated infections. However, the effect of BCG vaccination on dendritic cell (DC) subsets is not well characterized.

Methods: We investigated the impact of BCG vaccination on the frequencies of DC subsets and type I and III interferons (IFNs) using whole blood and plasma samples in a group of elderly individuals (age 60-80 years) at one-month post-vaccination as part of our clinical study to examine the effect of BCG on COVID-19.

Results: Our results demonstrate that BCG vaccination induced enhanced frequencies of plasmacytoid DC (pDC) and myeloid DC (mDC). BCG vaccination also induced diminished plasma levels of type I IFNs, IFNα and IFNβ but increased levels of type III IFNs, IL-28A and IL-29.

Conclusions: Thus, BCG vaccination was associated with enhanced DC subsets and IL-28A/IL-29 in elderly individuals, suggesting its ability to induce non-specific innate immune responses.
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http://dx.doi.org/10.1016/j.ijid.2021.07.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295056PMC
July 2021

Impact of HIV status on systemic inflammation during pregnancy.

AIDS 2021 Jul 8. Epub 2021 Jul 8.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, USA Department of Medicine, Weill Cornell Medical College, New York, USA Department of Biostatistics, Columbia University Mailman School of Public Health, New York, USA Department of Obstetrics and Gynecology, Byramjee Jeejeebhoy Government Medical College, Pune, India Byramjee-Jeejeebhoy Government Medical college-Johns Hopkins University Clinical Research Site, Pune, India Instituto Goncalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil Multinational Organization Network Sponsoring Translational and Epidemiological Research, (MONSTER) Initiative, Salvador, Brazil Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Brazil Curso de Medicina, Faculdade de Tecnologia e Ciências, Salvador, Brazil Universidade Salvador (UNIFACS), Laureate Universities, Salvador, Brazil Escola Bahiana de Medicina e Saúde Pública (EBMSP), Salvador, Brazil National Institutes of Health, National Institute for Research in Tuberculosis, International Center for Excellence in Research, Chennai, India Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA.

Objective: There are limited studies on the association of HIV infection with systemic inflammation during pregnancy.

Design: A cohort study (N = 220) of pregnant women with HIV (N = 70) (all on antiretroviral therapy) and without HIV (N = 150) were enrolled from an antenatal clinic in Pune, India.

Methods: The following systemic inflammatory markers were measured in plasma samples using immunoassays: soluble CD163 (sCD163), soluble CD14 (sCD14), intestinal fatty acid-binding protein (I-FABP), C-reactive protein (CRP), alpha 1-acid glycoprotein (AGP), interferon-β (IFNβ), interferon-γ (IFNγ), interleukin (IL)-1β, IL-6, IL-13, IL-17A and tumor necrosis factor α (TNFα). Generalized estimating equation (GEE) and linear regression models were used to assess the association of HIV status with each inflammatory marker during pregnancy and by trimester, respectively.

Results: Pregnant women with HIV had higher levels of markers for gut barrier dysfunction (I-FABP), monocyte activation (sCD14) and markers of systemic inflammation (IL-6 and TNFα), but surprisingly lower levels of AGP, an acute phase protein, compared to pregnant women without HIV, with some trimester-specific differences.

Conclusions: Our data show that women with HIV had higher levels of markers of gut barrier dysfunction, monocyte activation and systemic inflammation. These markers, some of which are associated with preterm birth, might help explain the increase in adverse birth outcomes in women with HIV and could suggest targets for potential interventions.
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http://dx.doi.org/10.1097/QAD.0000000000003016DOI Listing
July 2021

Reduced neutrophil granular proteins and post-treatment modulation in tuberculous lymphadenitis.

PLoS One 2021 21;16(6):e0253534. Epub 2021 Jun 21.

National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai, India.

Background: Neutrophils are important for host innate immune defense and mediate inflammatory responses. Pulmonary tuberculosis (PTB) is associated with increased neutrophil granular protein (NGP) levels in the circulation. However, the systemic levels of neutrophil granular proteins were not examined in tuberculous lymphadenitis (TBL) disease.

Methods: We measured the systemic levels of NGP (myeloperoxidase [MPO], elastase and proteinase 3 [PRTN3]) in TBL and compared them to latent tuberculosis (LTB) and healthy control (HC) individuals. We also measured the pre-treatment (Pre-T) and post-treatment (Post-T) systemic levels of neutrophil granular proteins in TBL individuals upon anti-tuberculosis treatment (ATT) completion. In addition, we studied the correlation and discriminatory ability of NGPs using receiver operating characteristic (ROC) analysis.

Results: Our data suggests that systemic levels of NGPs (MPO, PRTN3, elastase) were significantly reduced in TBL individuals compared to LTB and HC individuals. Similarly, after ATT, the plasma levels of MPO and elastase but not PRTN3 were significantly elevated compared to pre-treatment levels. NGPs (except PRTN3) were positively correlated with absolute neutrophil count of TBL, LTB and HC individuals. Further, NGPs were able to significantly discriminate TBL from LTB and HC individuals.

Conclusion: Hence, we conclude reduced neutrophil granular protein levels might be associated with disease pathogenesis in TBL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253534PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216526PMC
June 2021

Effect of anti-tuberculosis treatment on the systemic levels of tissue inhibitors of metalloproteinases in tuberculosis - Diabetes co-morbidity.

J Clin Tuberc Other Mycobact Dis 2021 May 22;23:100237. Epub 2021 Apr 22.

National Institutes of Health - NIRT - International Center for Excellence in Research, Chennai, India.

Objectives: To study the association of Tissue inhibitors of matrix metalloproteinases (TIMP) levels with tuberculosis-diabetes comorbidity (TB-DM) comorbidity at baseline and in response to anti-TB treatment (ATT).

Methods: We examined the levels of TIMP-1, -2, -3 and -4 in pulmonary tuberculosis alone (TB) or TB-DM at baseline and after ATT.

Results: TIMP-1, -3 and -4 were significantly increased in TB-DM compared to TB at baseline and after ATT. ATT resulted in a significant reduction in TIMP-2 and -3 levels and a significant increase in TIMP-1 in both TB and TB-DM. TIMP-1, -3 and -4 were also significantly increased in TB-DM individuals with bilateral, cavitary disease and also exhibited a positive relationship with bacterial burden in TB-DM and HbA1c in all TB individuals. Within the TB-DM group, those known to be diabetic before incident TB (KDM) exhibited higher levels of TIMP-1, -2, -3 and -4 at baseline and TIMP-2 at post-treatment compared to those newly diagnosed with DM (NDM). KDM individuals on metformin treatment exhibited lower levels of TIMP-1, -2 and -4 at baseline and of TIMP-4 at post-treatment.

Conclusions: TIMP levels were elevated in TB-DM, associated with disease severity and bacterial burden, correlated with HbA1c levels and modulated by duration of DM and metformin treatment.
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http://dx.doi.org/10.1016/j.jctube.2021.100237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100611PMC
May 2021

Discovery and Validation of a Three-Cytokine Plasma Signature as a Biomarker for Diagnosis of Pediatric Tuberculosis.

Front Immunol 2021 16;12:653898. Epub 2021 Apr 16.

National Institutes of Health, National Institute for Research in Tuberculosis, International Center for Excellence in Research, Chennai, India.

Pediatric TB poses challenge in diagnosis due to the paucibacillary nature of the disease. We conducted a prospective diagnostic study to identify immune biomarkers of pediatric TB and controls (discovery cohort) and obtained a separate "validation" cohort of confirmed cases of pediatric TB and controls. Multiplex ELISA was performed to examine the plasma levels of cytokines. Discovery and validation cohorts revealed that baseline plasma levels of IFNγ, TNFα, IL-2, and IL-17A were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics (ROC) curve analysis revealed that IFNγ, IL-2, TNFα, and IL-17A (in the discovery cohort) and TNFα and IL-17A (in the validation cohort) could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 90%. In the discovery cohort, cytokines levels were significantly diminished following anti-tuberculosis treatment. In both the cohorts, combiROC models offered 100% sensitivity and 98% to 100% specificity for a three-cytokine signature of TNFα, IL-2, and IL-17A, which can distinguish confirmed or unconfirmed TB children from unlikely TB. Thus, a baseline cytokine signature of TNFα, IL-2, and IL-17A could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis.
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http://dx.doi.org/10.3389/fimmu.2021.653898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085486PMC
April 2021

Diminished circulating levels of angiogenic factors and RAGE ligands in helminth-diabetes comorbidity and reversal following anthelmintic treatment.

J Infect Dis 2021 Apr 2. Epub 2021 Apr 2.

National Institute of Health-NIRT-International Center for Excellence in Research, Chennai, India and Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Background: Various epidemiological and experimental studies propose that helminths could play a preventive role against the progression of Type 2 diabetes mellitus (T2DM). T2DM induces microvascular and large vessel complications mediated by elevated levels of angiogenic factors and soluble RAGE ligands. However, the interactions between helminths and host angiogenic factors and RAGE ligands are unexplored.

Methods: To assess the relationship between a soil-transmitted helminth, Strongyloides stercoralis (Ss) and T2DM, we measured plasma levels of VEGF-A, C, D, Angio-1 and Angio-2 and their receptors VEGF-R1, R2 and R3 as well as sRAGE and their ligands AGE, S100A12 and HMBG-1 in individuals with T2DM with Ss+ or without Ss infection (Ss-). In Ss+ individuals, we also measured the levels of aforementioned factors 6 months following anthelmintic therapy.

Results: Ss+ individuals exhibited significantly decreased levels of VEGF-A, C, D, Angio-1 and Angio-2 and their soluble receptors VEGF-R1, R2 and R3, that increased following anthelmintic therapy. Likewise, Ss+ individuals exhibited significantly decreased levels of AGE and their ligands sRAGE, S100A12 and HMBG-1 which reversed following anthelmintic therapy.

Conclusion: Our data suggest that Ss infection could play a beneficial role by limiting or delaying the T2DM related vascular complications.
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http://dx.doi.org/10.1093/infdis/jiab170DOI Listing
April 2021

Plasma biomarker profiling of PIMS-TS, COVID-19 and SARS-CoV2 seropositive children - a cross-sectional observational study from southern India.

EBioMedicine 2021 Apr 2;66:103317. Epub 2021 Apr 2.

National Institutes of Health-National Institute for Research in Tuberculosis - International Center for Excellence in Research, Chennai, India; LPD, NIAID, NIH, Bethesda, MD, United States.

Background: SARS-CoV-2 infection in children can present with varied clinical phenotypes and understanding the pathogenesis is essential, to inform about the clinical trajectory and management.

Methods: We performed a multiplex immune assay analysis and compared the plasma biomarkers of Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS), acute COVID-19 infection (COVID-19), SARS-CoV-2 seropositive and control children admitted to a tertiary care children's hospital in Chennai, India. Pro-inflammatory cytokines, chemokines and growth factors were correlated with SARS-CoV-2 clinical phenotypes.

Findings: PIMS-TS children had significantly elevated levels of cytokines, IFNγ, IL-2, TNFα, IL-1α, IFNα, IFNβ, IL-6, IL-15, IL-17A, GM-CSF, IL-10, IL-33 and IL-Ra; elevated chemokines, CCL2, CCL19, CCL20 and CXCL10 and elevated VEGF, Granzyme B and PDL-1 in comparison to COVID-19, seropositive and controls. COVID-19 children had elevated levels of IFNγ, IL-2, TNFα, IL-1α, IFNα, IFNβ, IL-6, IL-17A, IL-10, CCL2, CCL5, CCL11, CXCL10 and VEGF in comparison to seropositive and/or controls. Similarly, seropositive children had elevated levels of IFNγ, IL-2, IL-1α, IFNβ, IL-17A, IL-10, CCL5 and CXCL10 in comparison to control children. Plasma biomarkers in PIMS-TS and COVID-19 children showed a positive correlation with CRP and a negative correlation with the lymphocyte count and sodium levels.

Interpretation: We describe a comprehensive plasma biomarker profile of children with different clinical spectrum of SARS-CoV-2 infection from a low- and middle-income country (LMIC) and observed that PIMS-TS is a distinct and unique immunopathogenic paediatric illness related to SARS-CoV-2 presenting with cytokine storm different from acute COVID-19 infection and other hyperinflammatory conditions.
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http://dx.doi.org/10.1016/j.ebiom.2021.103317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016617PMC
April 2021

Systemic Inflammation in Pregnant Women With Latent Tuberculosis Infection.

Front Immunol 2020 27;11:587617. Epub 2021 Jan 27.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, United States.

Background: Recent studies in adults have characterized differences in systemic inflammation between adults with and without latent tuberculosis infection (LTBI+ . LTBI-). Potential differences in systemic inflammation by LTBI status has not been assess in pregnant women.

Methods: We conducted a cohort study of 155 LTBI+ and 65 LTBI- pregnant women, stratified by HIV status, attending an antenatal clinic in Pune, India. LTBI status was assessed by interferon gamma release assay. Plasma was used to measure systemic inflammation markers using immunoassays: IFN, CRP, AGP, I-FABP, IFN, IL-1, soluble CD14 (sCD14), sCD163, TNF, IL-6, IL-17a and IL-13. Linear regression models were fit to test the association of LTBI status with each inflammation marker. We also conducted an exploratory analysis using logistic regression to test the association of inflammatory markers with TB progression.

Results: Study population was a median age of 23 (Interquartile range: 21-27), 28% undernourished (mid-upper arm circumference (MUAC) <23 cm), 12% were vegetarian, 10% with gestational diabetes and 32% with HIV. In multivariable models, LTBI+ women had significantly lower levels of third trimester AGP, IL1β, sCD163, IL-6 and IL-17a. Interestingly, in exploratory analysis, LTBI+ TB progressors had significantly higher levels of IL1, IL-6 and IL-13 in multivariable models compared to LTBI+ non-progressors.

Conclusions: Our data shows a distinct systemic immune profile in LTBI+ pregnant women compared to LTBI- women. Data from our exploratory analysis suggest that LTBI+ TB progressors do not have this immune profile, suggesting negative association of this profile with TB progression. If other studies confirm these differences by LTBI status and show a causal relationship with TB progression, this immune profile could identify subsets of LTBI+ pregnant women at high risk for TB progression and who can be targeted for preventative therapy.
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http://dx.doi.org/10.3389/fimmu.2020.587617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873478PMC
July 2021

Altered plasma levels of βC and γC chain cytokines and post-treatment modulation in tuberculous lymphadenitis.

Cytokine 2021 02 17;138:155405. Epub 2020 Dec 17.

National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai, India; Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Background: Alterations in β common (βC) and γ common (γC) chain cytokines have been described in pulmonary tuberculosis. However, their role in tuberculous lymphadenitis (TBL) disease has not been assessed.

Methods: Thus, in the present study, we have examined the systemic levels of βC and γC chain cytokines in TBL, latent tuberculosis (LTB) and healthy control (HC) individuals. We have examined the discriminatory potential of both family of cytokines using ROC analysis. Finally, we measured the pre and post-treatment responses of these cytokines after anti-tuberculosis treatment.

Results: TBL individuals exhibit significantly increased (IL-3) and diminished systemic levels of (IL-5, GM-CSF) βC cytokines compared to LTB and HC individuals. TBL individuals also exhibit significantly diminished (IL-2, IL-7) and elevated (IL-4, IL-9) levels of γC cytokines compared to LTB and/or HC. ROC analysis shows a clear discriminatory capacity of both βC (IL-5) and γC (IL-2) chain cytokines to distinguish TBL from LTB and HCs. The systemic levels of βC chain cytokines were not significantly altered, but in contrast γC (IL-2 and IL-7) cytokines were significantly modulated after treatment. Finally, no significant correlation was observed for βC and γC chain cytokines with their respective lymphocyte count of TBL individuals.

Conclusions: Hence, we conclude that altered plasma levels of βC and γC cytokines are the characteristics of immune alteration in TBL disease and certain cytokines were modulated after treatment.
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http://dx.doi.org/10.1016/j.cyto.2020.155405DOI Listing
February 2021

Association of Vegetable and Animal Flesh Intake with Inflammation in Pregnant Women from India.

Nutrients 2020 Dec 8;12(12). Epub 2020 Dec 8.

Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA.

In pregnant women, studies are lacking on the relationship of vegetable and animal flesh (poultry, red meat and seafood) intake with inflammation, especially in low- and middle-income countries. We conducted a cohort study of pregnant women receiving antenatal care at BJ Medical College in Pune, India. The dietary intake of pregnant women was queried in the third trimester using a validated food frequency questionnaire. Twelve inflammatory markers were measured in plasma samples using immunoassays. Only 12% of the study population were vegetarians, although animal flesh intake levels were lower compared to Western populations. In multivariable models, higher intakes of total vegetables were associated with lower levels of the T-helper (Th) 17 cytokine interleukin (IL)-17a ( = 0.03) and the monocyte/macrophage activation marker soluble CD163 (sCD163) ( = 0.02). Additionally, higher intakes of poultry were negatively associated with intestinal fatty-acid binding protein (I-FABP) levels ( = 0.01), a marker of intestinal barrier dysfunction and Th2 cytokine IL-13 ( = 0.03), and higher seafood was associated with lower IL-13 ( = 0.005). Our data from pregnant women in India suggest that a higher quality diet emphasizing vegetables and with some animal flesh is associated with lower inflammation. Future studies should confirm these findings and test if modulating vegetables and animal flesh intake could impact specific aspects of immunity and perinatal health.
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http://dx.doi.org/10.3390/nu12123767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762525PMC
December 2020

Association of Plasma Matrix Metalloproteinase and Tissue Inhibitors of Matrix Metalloproteinase Levels With Adverse Treatment Outcomes Among Patients With Pulmonary Tuberculosis.

JAMA Netw Open 2020 12 1;3(12):e2027754. Epub 2020 Dec 1.

National Institutes of Health-National Institute for Research in Tuberculosis-International Center for Excellence in Research, Chennai, India.

Importance: Identifying biomarkers of treatment response is an urgent need in the treatment of tuberculosis (TB). Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) are potential diagnostic biomarkers in pulmonary TB (PTB).

Objective: To assess whether baseline plasma levels of MMPs and TIMPs are also prognostic biomarkers for adverse treatment outcomes in patients with PTB.

Design, Setting, And Participants: Two different cohorts (test and validation) of individuals with PTB were recruited from 2 different sets of primary care centers in Chennai, India, and were followed up for treatment outcomes. Participants were individuals with newly diagnosed TB that was sputum smear and culture positive and drug sensitive. A total of 68 cases and 133 controls were in the test cohort and 20 cases and 40 controls were in the validation cohort. A nested case-control study was performed by matching case patients to control participants in a 1:2 ratio for age, sex, and body mass index. Data for the test cohort was taken from a study performed from 2014 to 2019, and data for the validation cohort, from a study performed from 2008 to 2012. The data analysis was performed from November 2019 to May 2020.

Interventions: Individuals with PTB were treated with antituberculosis chemotherapy for 6 months and followed up for 1 year after completion of treatment.

Main Outcomes And Measures: Individuals with PTB with adverse outcomes (treatment failure, all-cause mortality, or recurrent TB) were defined as cases and those with favorable outcomes (recurrence-free cure) were defined as controls. Plasma levels of MMPs and TIMPs were measured before treatment as potential biomarkers.

Results: In all, 68 cases and 133 matched controls were enrolled in the study (170 [85%] males and 31 [15%] females; median age, 45 years [range, 23-73 years]) in the test cohort and 20 cases with 40 matched controls (51 [85%] males and 9 [15%] females; median age, 45 years [range, 19-61 years]) in the validation cohort. Baseline plasma levels of 5 MMPs and 2 TIMPs in the test cohort and 5 MMPs and all 4 TIMPS in the validation cohort were significantly higher in cases vs controls. In the test cohort, the geometric means (GMs), cases vs controls, were as follows: for MMP-1, 3680 vs 2484 pg/mL (P = .008); for MMP-2, 6523 vs 4762 pg/mL (P < .001); for MMP-7, 3346 vs 2100 pg/mL (P < .001); for MMP-8, 1915 vs 1066 pg/mL (P < .001); for MMP-9, 2774 vs 2336 pg/mL (P = .009); for TIMP-1, 4491 vs 2910 pg/mL (P < .001); and for TIMP-2, 3082 vs 2115 pg/mL (P < .001). In the validation cohort, the GMs, cases vs controls were as follows: for MMP-1, 3680 vs 2484 pg/mL (P < .001); for MMP-2, 6523 vs 4762 pg/mL (P < .001); for MMP-7, 3346 vs 2100 pg/mL (P < .001); for MMP-9, 1915 vs 1066 pg/mL (P < .001); for MMP-13, 2774 vs 2336 pg/mL (P < .001); for TIMP-1, 4491 vs 2910 pg/mL (P = .003); for TIMP-2, 3082 vs 2115 pg/mL (P = .003); for TIMP-3, 2066 vs 1020 pg/mL (P < .001); and for TIMP-4, 2130 vs 694 pg/mL (P < .001). Plasma levels of MMPs and TIMPs were associated with increased risk of adverse outcomes according to both univariate and multivariable analysis in the test cohort (eg, univariate analysis: odds ratio [OR] for MMP-8, 2.04; 95% CI, 1.33-3.14; P = .001; multivariable analysis: OR for MMP-8, 2.16; 95% CI, 1.34-3.47; P = .001). Combined receiver operating characteristic analysis revealed significant area under the curve (AUC), with high sensitivity and specificity in both cohorts (eg, for a combination of MMP-2, MMP-7, and TIMP-1 in the test cohort: sensitivity, 84%; specificity, 83%; and AUC, 0.886; for a combination of MMP-2, MMP-7, TIMP-1, and TIMP-2 in the validation cohort: sensitivity, 85%; specificity, 95%; and AUC, 0.944).

Conclusions And Relevance: Baseline plasma MMP and TIMP levels may be correlates of risk and prognostic biomarkers for treatment failure, relapse, and death in individuals with PTB and merit further evaluation as predictive biomarkers for stratification of patients to shortened or intensified treatment regimens.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.27754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709089PMC
December 2020

The recent trend in mycobacterial strain diversity among extra pulmonary lymph node tuberculosis and their association with drug resistance and the host immunological response in South India.

BMC Infect Dis 2020 Nov 26;20(1):894. Epub 2020 Nov 26.

Department of Immunology, National Institute for Research in Tuberculosis, Chetpet, Chennai, 600 031, India.

Background: Tuberculosis (TB) though primarily affects the lungs it may also affect the other parts of the body and referred as extra pulmonary (EPTB). This study is focused on understanding the genetic diversity and molecular epidemiology of Mycobacterium tuberculosis (M.tb) among tuberculous lymphadenitis (TBL), a form of EPTB patients identified in Chennai, Tamil Nadu.

Methods: The genetic diversity was identified by performing spoligotyping on the M.tb clinical isolates that were recovered from lymph node samples. A total of 71 M.tb isolates were recovered from extra pulmonary lymph node samples and subjected to Drug susceptibility testing and spoligotyping was carried out. In addition, immunological characterization from blood of same individuals from whom M.tb was isolated was carried out between the two major lineages groups East African Indian 3 (EAI3) and non-EAI3 strains by ELISA. The results of spoligotyping patterns were compared with the world Spoligotyping Database of Institute Pasteur de Guadeloupe (SpolDB4).

Results: We found 41 spoligotype patterns and their associated lineages. Out of 41 spoligotype pattern, only 22 patterns are available in the spoldB4 database with Spoligotype international Type (SIT) number and remaining patterns were orphan strains without SIT number. The most predominant spoligotype lineage that was found in lymph node sample in this region of India was EAI (36), followed by central Asian strain (CAS) (6), T1 (5), Beijing (3), Latin American & Mediterranean (LAM) (2), U (1), X2 (1) and orphan (22). In addition to EAI, CAS and Beijing, our study identified the presence of orphan and unique spoligotyping patterns in Chennai region. We observed six drug resistant isolates. Out of six drug resistant isolates, four were resistant to isoniazid drug and associated with EAI family. Moreover, we observed increased levels of type 2 and type 17 cytokine profiles between EAI3 and non-EAI family, infected individuals.

Conclusions: The study confirms that EAI lineage to be the most predominant lineages in EPTB patients with lymphadenitis and were found to have increased type 1 and type 17 proinflammatory cytokine profiles.
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http://dx.doi.org/10.1186/s12879-020-05597-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690019PMC
November 2020

Impact of malnutrition on systemic immune and metabolic profiles in type 2 diabetes.

BMC Endocr Disord 2020 Nov 12;20(1):168. Epub 2020 Nov 12.

National Institute of Health-NIRT-International Center for Excellence in Research, Chetpet, Chennai, 600031, India.

Background: While obesity and overweight status are firmly established risk factors for Type 2 diabetes mellitus (T2DM), a substantial proportion of diabetic individuals, especially in Africa and Asia, are often underweight or normal weight. However, very little is known about the immunological and metabolic profiles of these individuals.

Methods: This study aimed to assess the relationship between malnutrition and Type 2 diabetes mellitus (T2DM). We examined a variety of analytes associated with the immunological and metabolic profiles of T2DM individuals with low (< 18.5 kg/m2) or normal (18.5-24.9 kg/m2) body mass index (BMI). To this end, we measured plasma levels of HbA1c, glucose, insulin, glucagon, adipocytokines and Type 1, Type 2, Type 17, pro-inflammatory and regulatory cytokines in T2DM individuals with low BMI (LBMI) or normal BMI (NBMI) with small sample size n = 44 in each group.

Results: LBMI individuals exhibited significantly higher levels of HbA1c, random blood glucose, insulin and glucagon compared to NBMI individuals. Similarly, LBMI individuals exhibited significantly higher levels of adiponectin and adipsin and significantly lower levels of leptin in comparison to NBMI individuals. LBMI individuals also exhibited significantly lower levels of the Type 1, Type 2, Type 17, pro-inflammatory and regulatory cytokines in comparison to NBMI individuals. Finally, while the metabolic parameters exhibited a significant negative correlation with BMI, the immunological parameters exhibited a significant positive correlation with BMI.

Conclusions: Malnutrition is associated with a significant modulation of glycemic, hormonal and cytokine parameters in T2DM. Hence, the biochemical and immunological profiles of T2DM is significantly influenced by BMI.
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http://dx.doi.org/10.1186/s12902-020-00649-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659078PMC
November 2020

Diminished Frequencies of Cytotoxic Marker Expressing T- and NK Cells at the Site of Infection.

Front Immunol 2020 25;11:585293. Epub 2020 Sep 25.

International Center for Excellence in Research, National Institutes of Health, National Institute for Research in Tuberculosis, Chennai, India.

Tuberculous lymphadenitis (TBL) individuals exhibit reduced frequencies of CD8 T cells expressing cytotoxic markers in peripheral blood. However, the frequencies of cytotoxic marker expressing CD4, CD8 T cells, and NK cells at the site of infection is not known. Therefore, we measured the baseline and mycobacterial antigen specific frequencies of cytotoxic markers expressing CD4, CD8 T cells, and NK cells in the LN ( = 18) and whole blood ( = 10) of TBL individuals. TBL LN is associated with lower frequencies of CD4 T cells expressing cytotoxic markers (Granzyme B, CD107a) compared to peripheral blood at baseline and in response to PPD, ESAT-6, and CFP-10 antigen stimulation. Similarly, lower frequencies of CD8 T cells expressing cytotoxic markers (Perforin, Granzyme B, and CD107a) were also present in the TBL LN at baseline and following (except perforin) antigen stimulation. Finally, at baseline and after antigen (PPD, ESAT-6, and CFP-10) stimulation, frequencies of NK cells expressing cytotoxic markers were also significantly lower in TBL LN compared to whole blood. Hence, TBL is characterized by diminished frequencies of cytotoxic marker expressing CD4, CD8 T cells, and NK cells at the site of infection, which might reflect the lack of protective immune responses at the site of infection.
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http://dx.doi.org/10.3389/fimmu.2020.585293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546427PMC
June 2021

Impact of Helminth Infection on Metabolic and Immune Homeostasis in Non-diabetic Obesity.

Front Immunol 2020 16;11:2195. Epub 2020 Sep 16.

National Institute of Health-National Institute for Research in Tuberculosis (NIRT)-International Center for Excellence in Research, Chennai, India.

Several epidemiological and immunological studies indicate a reciprocal association between obesity/metabolic syndrome and helminth infections. Numerous studies demonstrated that obesity is concomitant with chronic low-grade inflammation, which is marked by vital changes in cellular composition and function of adipose tissue. However, the effect of helminth infection on the homeostatic milieu in obesity is not well-understood. To determine the relationship between infection and obesity, we examined an array of parameters linked with obesity both before and at 6 months following anthelmintic treatment. To this end, we measured serum levels of pancreatic hormones, incretins, adipokines and Type-1, Type-2, Type-17, and other proinflammatory cytokines in those with non-diabetic obesity with (INF) or without infection (UN). In INF individuals, we evaluated the levels of these parameters at 6 months following anthelmintic treatment. INF individuals revealed significantly lower levels of insulin, glucagon, C-peptide, and GLP-1 and significantly elevated levels of GIP compared to UN individuals. INF individuals also showed significantly lower levels of Type-1, Type-17 and other pro-inflammatory cytokines and significantly increased levels of Type-2 and regulatory cytokines in comparison to UN individuals. Most of these changes were significantly reversed following anthelmintic treatment. infection is associated with a significant alteration of pancreatic hormones, incretins, adipokines, and cytokines in obese individuals and its partial reversal following anthelmintic treatment. Our data offer a possible biological mechanism for the protective effect of infection on obesity.
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http://dx.doi.org/10.3389/fimmu.2020.02195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524873PMC
April 2021

Helminth Mediated Attenuation of Systemic Inflammation and Microbial Translocation in Helminth-Diabetes Comorbidity.

Front Cell Infect Microbiol 2020 31;10:431. Epub 2020 Aug 31.

National Institute of Health-NIRT-International Center for Excellence in Research, Chennai, India.

Type 2 diabetes mellitus (T2DM) is characterized by heightened systemic inflammation and microbial translocation. Whether concomitant helminth infections can modulate this systemic response is unclear. We examined the presence of markers of systemic inflammation (levels of acute phase proteins) and of microbial translocation [levels of lipopolysaccharide (LPS) and its associated products] in T2DM individuals with ( ) or without ( ) () infection. We also analyzed these parameters at 6 months following anthelmintic treatment in individuals. individuals exhibited significantly diminished levels of alpha-2 macroglobulin, C-reactive protein, haptoglobin and serum amyloid protein A1 compared to individuals and these levels increased significantly following therapy. Similarly, individuals exhibited significantly diminished levels of LPS, sCD14, intestinal fatty acid binding protein, LPS binding protein and endotoxin IgG antibody and most of these levels increased significantly following therapy. Thus, helminth infection is associated with attenuation of systemic inflammation and microbial translocation in T2DM and its reversal following anthelmintic therapy.
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http://dx.doi.org/10.3389/fcimb.2020.00431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488178PMC
June 2021

Prevalence of SARS-CoV-2 infection in India: Findings from the national serosurvey, May-June 2020.

Indian J Med Res 2020 Jul & Aug;152(1 & 2):48-60

State TB Training & Demonstration Centre, Ranchi, Jharkhand, India.

Background & Objectives: Population-based seroepidemiological studies measure the extent of SARS-CoV-2 infection in a country. We report the findings of the first round of a national serosurvey, conducted to estimate the seroprevalence of SARS-CoV-2 infection among adult population of India.

Methods: From May 11 to June 4, 2020, a randomly sampled, community-based survey was conducted in 700 villages/wards, selected from the 70 districts of the 21 States of India, categorized into four strata based on the incidence of reported COVID-19 cases. Four hundred adults per district were enrolled from 10 clusters with one adult per household. Serum samples were tested for IgG antibodies using COVID Kavach ELISA kit. All positive serum samples were re-tested using Euroimmun SARS-CoV-2 ELISA. Adjusting for survey design and serial test performance, weighted seroprevalence, number of infections, infection to case ratio (ICR) and infection fatality ratio (IFR) were calculated. Logistic regression was used to determine the factors associated with IgG positivity.

Results: Total of 30,283 households were visited and 28,000 individuals were enrolled. Population-weighted seroprevalence after adjusting for test performance was 0.73 per cent [95% confidence interval (CI): 0.34-1.13]. Males, living in urban slums and occupation with high risk of exposure to potentially infected persons were associated with seropositivity. A cumulative 6,468,388 adult infections (95% CI: 3,829,029-11,199,423) were estimated in India by the early May. The overall ICR was between 81.6 (95% CI: 48.3-141.4) and 130.1 (95% CI: 77.0-225.2) with May 11 and May 3, 2020 as plausible reference points for reported cases. The IFR in the surveyed districts from high stratum, where death reporting was more robust, was 11.72 (95% CI: 7.21-19.19) to 15.04 (9.26-24.62) per 10,000 adults, using May 24 and June 1, 2020 as plausible reference points for reported deaths.

Interpretation & Conclusions: Seroprevalence of SARS-CoV-2 was low among the adult population in India around the beginning of May 2020. Further national and local serosurveys are recommended to better inform the public health strategy for containment and mitigation of the epidemic in various parts of the country.
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http://dx.doi.org/10.4103/ijmr.IJMR_3290_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853249PMC
September 2020

Plasma chemokines are baseline predictors of unfavorable treatment outcomes in pulmonary tuberculosis.

Clin Infect Dis 2020 Aug 7. Epub 2020 Aug 7.

National Institutes of Health-NIRT- International Center for Excellence in Research, Chennai, India.

Background: Plasma chemokines are biomarkers of greater disease severity, higher bacterial burden and delayed sputum culture conversion in pulmonary tuberculosis (PTB). Whether plasma chemokines could also serve as biomarkers of unfavorable treatment outcomes in PTB is not known.

Methods: A cohort of newly diagnosed, sputum smear and culture positive adult individuals with drug-sensitive PTB were recruited under the Effect of diabetes on Tuberculosis Severity study in Chennai, India. Plasma chemokine levels measured before treatment initiation were compared between 68 cases with unfavorable outcomes (treatment failure, death or recurrence) and 136 control individuals who had recurrence-free cure. A second validation cohort comprising of newly diagnosed, culture positive adults with drug-sensitive TB was used to measure plasma chemokine levels in 20 cases and 40 controls.

Findings: Six chemokines (CCL2, CCL3, CCL4, CXCL8, CXCL10 and CX3CL1) were associated with increased risk, while CXCL1 was associated with decreased risk of unfavorable outcomes in unadjusted and adjusted analyses in the test cohort. Similarly, CCL3, CXCL8 and CXCL10 were associated with increased risk of unfavorable treatment outcomes in the validation cohort. Receiver operating characteristic analysis revealed combinations of CCL3, CXCL8 and CXCL10 exhibited very high sensitivity and specificity in differentiating cases versus controls.

Conclusions: Our study reveals a plasma chemokine signature that can be used as a novel biomarker for predicting adverse treatment outcomes in PTB.
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http://dx.doi.org/10.1093/cid/ciaa1104DOI Listing
August 2020

Potential Metabolite Nymphayol Isolated from Water Lily () Flower Inhibits MCF-7 Human Breast Cancer Cell Growth via Upregulation of Cdkn2a, pRb2, p53 and Downregulation of PCNA mRNA Expressions.

Metabolites 2020 Jul 8;10(7). Epub 2020 Jul 8.

Cancer Molecular Biology Research Lab, Department of Food Science and Nutrition, College of Food Science and Agriculture, King Saud University, Riyadh 11451, Saudi Arabia.

Controlled production of cyclin dependent kinases (CDK) and stabilization of tumor suppressor genes are the most important factors involved in preventing carcinogenesis. The present study aimed to explore the cyclin dependent apoptotic effect of nymphayol on breast cancer MCF-7 cells. In our previous study, we isolated the crystal from a chloroform extract of flower petals and it was confirmed as nymphayol (17-(hexan-2-yl)-10,13-dimethylhexadecahydro-1-cyclopenta[]phenanthren-3-ol) using x-ray diffraction (XRD), Fourier transform infrared (FTIR), and mass spectroscopy (MS) methods. The cytotoxic effect of nymphayol on MCF-7 cells were analyzed using the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The cellular and nuclear damage was determined using propidium iodide (PI) and acridine orange/ethidium bromide (AO/ErBr) staining. Tumor suppressor and apoptosis related mRNA transcript levels were determined using real-time polymerase chain reaction (RT-PCR). Nymphayol potentially inhibits MCF-7 cell viability up to 78%, and the IC value was observed as 2.8 µM in 24 h and 1.4 µM in 48 h. Treatment with nymphayol significantly increased reactive oxygen species (ROS) level and the tunnel assay confirmed DNA damage. We found characteristically 76% apoptotic cells and 9% necrotic cells in PI and AO/ErBr staining after 48 h treatment with 2.8 µM of nymphayol. Gene expression analysis confirmed significantly ( ≤ 0.001) increased mRNA levels of cyclin dependent kinase inhibitor 2A (Cdkn2a), retinoblastoma protein 2 (pRb2), p53, nuclear factor erythroid 2-factor 2 (Nrf2), caspase-3, and decreased B-cell lymphoma 2 (Bcl-2), murine double minute 2 (mdm2), and proliferating cell nuclear antigen (PCNA) expression after 48 h. Nymphayol effectively inhibited breast cancer cell viability, and is associated with early expression of Cdkn2a, pRb2, and activation of p53 and caspases.
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http://dx.doi.org/10.3390/metabo10070280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408605PMC
July 2020

Aging increases the systemic molecular degree of inflammatory perturbation in patients with tuberculosis.

Sci Rep 2020 07 9;10(1):11358. Epub 2020 Jul 9.

Fundação Oswaldo Cruz, Instituto Gonçalo Moniz, Salvador, 40296-710, Brazil.

Tuberculosis (TB) is a chronic infection that can affect individuals of all ages. The description of determinants of immunopathogenesis in TB is of tremendous interest due to the perspective of finding a reliable host-directed therapy to reduce disease burden. The association between specific biomarker profiles related to inflammation and the diverse clinical disease presentations in TB has been extensively studied in adults. However, relatively scarce data on profiling the inflammatory responses in pediatric TB are available. Here, we employed the molecular degree of perturbation (MDP) score adapted to plasma biomarkers in two distinct databanks from studies that examined either adults or children presenting with pulmonary or extrapulmonary disease. We used multidimensional statistical analyses to characterize the impact of age on the overall changes in the systemic inflammation profiles in subpopulation of TB patients. Our findings indicate that TB results in significant increases in molecular perturbation, with the highest values being detected in adult patients. Furthermore, there were unique differences in the biomarker perturbation patterns and the overall degree of inflammation according to disease site and age. Importantly, the molecular degree of perturbation was not influenced by sex. Our results revealed that aging is an important determinant of the differences in quality and magnitude of systemic inflammatory perturbation in distinct clinical forms of TB.
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http://dx.doi.org/10.1038/s41598-020-68255-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347549PMC
July 2020

Altered systemic levels of acute phase proteins in tuberculous lymphadenitis and modulation after treatment.

PLoS One 2020 29;15(5):e0233426. Epub 2020 May 29.

National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai, India.

Background: Pulmonary tuberculosis (PTB) is characterized by elevated levels of acute phase proteins (APPs), but their association with tuberculous lymphadenitis (TBL) is poorly studied.

Methods: We examined the systemic levels of APPs (alpha-2-macroglobulin [⍺-2MG], serum amyloid A [SAA], C-reactive protein [CRP] and haptoglobin [Hp]) in TBL, PTB, latent tuberculosis (LTB) and healthy controls (HC) at baseline and in TBL after the completion of anti-tuberculosis treatment (ATT). We have also examined the association of these proteins with lymph node (LN) size, culture grade and multiple versus single LN involvement.

Results: TBL individuals exhibited increased systemic levels of ⍺-2MG, SAA, CRP and Hp in comparison to HCs and increased CRP levels in comparison to LTB individuals. TBL individuals also exhibited decreased systemic levels of Hp compared to PTB individuals. APPs were not significantly associated with LN size, LN involvement and culture grade, indicating a lack of association with disease severity. Following ATT, post-treatment levels of ⍺-2MG, CRP and Hp were significantly diminished compared to pre-treatment levels.

Conclusion: TBL disease is characterized by altered levels of APPs at baseline and modulated following treatment, indicating the presence of systemic inflammation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233426PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259661PMC
August 2020

Low body mass index has minimal impact on plasma levels of cytokines and chemokines in tuberculous lymphadenitis.

J Clin Tuberc Other Mycobact Dis 2020 Aug 5;20:100163. Epub 2020 May 5.

National Institutes of Health-NIRT-International Center for Excellence in Research, Chennai, India.

Malnutrition, due to low body mass index (LBMI), is considered to be one of the key risk factors for tuberculosis (TB) development. The link between pro and anti-inflammatory cytokines and BMI has been studied in active pulmonary TB. However, the association of BMI with cytokines and chemokines in TB lymphadenitis (TBL) has not been examined. Hence, we wanted to examine the plasma levels of different cytokines and chemokines in TBL individuals with LBMI, normal BMI (NBMI) and high BMI (HBMI). LBMI with TBL disease is associated with enhanced systemic levels of type 1 (tumor necrosis factor alpha [TNFα], interleukin-2 [IL-2]) and type 2 (IL-4, IL-13) cytokines in comparison with NBMI and/or HBMI. However, other pro-inflammatory (IFNγ, IL-1β, IL-17A, IL-6, IL-7, IL-12, G-CSF, and GM-CSF) and anti-inflammatory (IL-5 and IL-10) cytokines were not significantly different among the TBL individuals with different BMI status. Likewise, no significant differences were observed in the CC (CCL-1, CCL-2/MCP-1, CCL3/MIP1α, CCL4/MIP-1β, CCL11/eotaxin) and CXC (CXCL-1/GRO-⍺, CXCL2/GRO-β, CXCL9/MIG, CXCL10/IP-10, CXCL11/ITAC 1) chemokine profile among the TBL individuals with different BMI. Hence, our data implies that TBL individuals with LBMI are characterized by minimal effects on plasma cytokines and chemokines in TBL.
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http://dx.doi.org/10.1016/j.jctube.2020.100163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218292PMC
August 2020
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