| 1. |
- Saeidi, Alireza, et al.
(författare)
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T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses
- 2018
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 9
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Forskningsöversikt (refereegranskat)abstract
- T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.
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| 2. |
- Selvavinayagam, Sivaprakasam T., et al.
(författare)
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Evolution of the Omicron B.1.1.529 Sars-Cov-2 and its Variants in Tamil Nadu, India – a State-Wide Prospective Longitudinal Genomic Surveillance
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: The emergence of the omicron SARS-CoV-2 variant beholding many mutations, especially in the spike (S) protein severely threatens global health. With an aim to understand the mutational pattern of the variant and its genetic interrelationship in the Indian population, here we prospectively followed the viral evolution and transmission between December 2021 and March 2023 in Tamil Nadu.Methods: A total of 11526 nasopharyngeal and oropharyngeal swabs (6431 males, 5095 females including 603 children) collected from across the 38 districts of Tamil Nadu were subjected to WGS. Of the 10663 samples (92.5%) positive for omicron variants, 1688 were sequenced at the State Public Health Laboratory. We longitudinally studied the evolutionary dynamics of the different omicron variants, starting from the first detected case (B.1.1.529) to the recently reported recombinant XBB variants by sequencing the S gene and by performing phylo-geographic and molecular modeling analyses.Findings: Administration of a booster dose was associated with reduced risk of hospitalization and death. BA.1 sub-variants and BA.2.75 were associated with increased risk of severe disease, whereas BA.1 and BA.2 were associated with increased risk of death. High quality WGS data from 150 samples revealed six major omicron clusters and several other sub-clusters. Seven variants in the same BA lineages with different divergences in the S protein were noticed. Of the 5009 mutations detected, the highest was seen in the receptor-binding domain (RBD) followed by the N-terminal domain (NTD) in varying proportions among the different omicron lineages. Importantly, the mutations were observed in the sub-domain (SD1/2) furin cleavage site, fusion peptide (FP), and the heptapeptide repeat sequence (HR1) regions. Notably, unique mutations Y473I, P479F, C480F, V483T, E484C, G485T, P491G, L492K, S494M, Y495C, and G496Q were detected in BA.2.43 whereas A475Q and T478S occurred in the RBD domain of the BA.2.43 variant. The XBB variant showed 41 different mutations between the HR1 and HR2 domains of the S2 subunit. Molecular modeling using BA.2 lineage as a template for seven divergent proteins showed that BA.2.12.1, BA.4 and BA.5 exhibited strong binding affinity towards ACE2.Interpretation: The high frequency of mutations in the RBD highlights the wider distribution of vaccine escape-variants that would impact the structural and functional attributes of the omicron variant in the population. Further, our work provides key insights on the evolutionary pattern leading to the identification of seven divergent variants of omicron in Tamil Nadu, India.
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| 3. |
- Selvavinayagam, Sivaprakasam T., et al.
(författare)
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Factors Associated With the Decay of Anti-SARS-CoV-2 S1 IgG Antibodies Among Recipients of an Adenoviral Vector-Based AZD1222 and a Whole-Virion Inactivated BBV152 Vaccine
- 2022
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Ingår i: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe magnitude of protection conferred following recovery from COVID-19 or by vaccine administration, and the duration of protective immunity developed, remains ambiguous. MethodsWe investigated the factors associated with anti-SARS-CoV-2 S1 IgG decay in 519 individuals who recovered from COVID-19 illness or received COVID-19 vaccination with two commercial vaccines, viz., an adenoviral vector-based (AZD1222) and a whole-virion-based inactivated (BBV152) vaccine in Chennai, India from March to December 2021. Blood samples collected during regular follow-up post-infection/-vaccination were examined for anti-SARS-CoV-2 S1 IgG by a commercial automated chemiluminescent immunoassay (CLIA). ResultsAge and underlying comorbidities were the two variables that were independently associated with the development of a breakthrough infection. Individuals who were >60 years of age with underlying comorbid conditions (viz., hypertension, diabetes mellitus and cardiovascular disease) had a ~15 times and ~10 times greater odds for developing a breakthrough infection and hospitalization, respectively. The time elapsed since the first booster dose was associated with attrition in anti-SARS-CoV-2 IgG, where each month passed was associated with an ebb in the anti-SARS-CoV-2 IgG antibody levels by a coefficient of -6 units. ConclusionsOur findings advocate that the elderly with underlying comorbidities be administered with appropriate number of booster doses with AZD1222 and BBV152 against COVID-19.
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| 4. |
- Selvavinayagam, Sivaprakasam T., et al.
(författare)
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Low SARS-CoV-2 viral load among vaccinated individuals infected with Delta B.1.617.2 and Omicron BA.1.1.529 but not with Omicron BA.1.1 and BA.2 variants
- 2022
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Ingår i: Frontiers In Public Health. - : Frontiers Media SA. - 2296-2565. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The rapid spread of SARS-CoV-2 variants in the global population is indicative of the development of selective advantages in emerging virus strains. Here, we performed a case-control investigation of the clinical and demographic characteristics, clinical history, and virological markers to predict disease progression in hospitalized adults for COVID-19 between December 2021 and January 2022 in Chennai, India. COVID-19 diagnosis was made by a commercial TaqPath COVID-19 RT-PCR, and WGS was performed with the Ion Torrent Next Generation Sequencing System. High-quality (<5% of N) complete sequences of 73 Omicron B.1.1.529 variants were randomly selected for phylogenetic analysis. SARS-CoV-2 viral load, number of comorbidities, and severe disease presentation were independently associated with a shorter time-to-death. Strikingly, this was observed among individuals infected with Omicron BA.2 but not among those with the BA.1.1.529, BA.1.1, or the Delta B.1.617.2 variants. Phylogenetic analysis revealed severe cases predominantly clustering under the BA.2 lineage. Sequence analyses showed 30 mutation sites in BA.1.1.529 and 33 in BA.1.1. The mutations unique to BA.2 were T19I, L24S, P25del, P26del, A27S, V213G, T376A, D405N and R408S. Low SARS-CoV-2 viral load among vaccinated individuals infected with Delta B.1.617.2 and the Omicron BA.1.1.529 variant but not with Omicron BA.1.1 or BA.2 suggests that the newer strains are largely immune escape variants. The number of vaccine doses received was independently associated with increased odds of developing asymptomatic disease or recovery. We propose that the novel mutations reported herein could likely bear a significant impact on the clinical characteristics, disease progression, and epidemiological aspects of COVID-19. Surging rates of mutations and the emergence of eclectic variants of SARS-CoV-2 appear to impact disease dynamics.
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| 5. |
- Selvavinayagam, Sivaprakasam T., et al.
(författare)
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Platelet-Large Cell Ratio and Erythrocyte Sedimentation Rate are Surrogate Predictors of Latent Tuberculosis Infection
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Aims: Prompt detection and treatment of latent tuberculosis infection (LTBI) holds the key to global TB elimination. The lack of an established test for predicting LTBI poses a substantial challenge in disease management. Here, we identified the biochemical and hematological markers of LTBI, and correlated their usefulness to discriminate LTBI from healthy controls. Main Methods: We conducted a cross-sectional investigation and correlated the various biochemical and hematological markers for detecting LTBI among household contacts (HHCs) of TB infection. Our study included 90 individuals – 30 healthy controls, 30 interferon-gamma release assay (IGRA) positive HHCs, and 30 IGRA-negative HHCs. Biomarkers were measured using designated auto analyzers. Key Findings: ESR, MPV, D-dimer, P-LCR, and PDW were significantly higher among LTBI subjects. ESR, PDW, and P-LCR were markedly associated with LTBI. Multivariate analysis showed that either ESR or P-LCR greater than their respective predetermined cut-off values showed higher odds of developing LTBI. Our study demonstrated that ESR and P-LCR are good surrogate markers for diagnosing LTBI. Also, significantly low ferritin in females and MCHC in males belonging to the HHC/IGRA-ve were observed. Significance: The ESR and P-LCR could aid in predicting LTBI among HHCs. Further, the low serum ferritin is associated with TB resisters.
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| 6. |
- Tan, Hong-Yien, et al.
(författare)
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Mucosal-Associated Invariant T Cells: Diplomatic Front-Runners in the Fight against Hepatitis B Virus Infection
- 2021
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Ingår i: Critical Reviews in Immunology. - : BEGELL HOUSE INC. - 1040-8401 .- 2162-6472. ; 41:5, s. 1-17
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal-associated invariant T (MAIT) cells are a unique subset of innate-like T cells that bridge between innate and adaptive immunity. MALT cells act like a biliary firewall protecting the epithelial lining of the liver against pathogenic intruders. MAIT1 and MAIT17 subsets respond rapidly to pathogenic presence both in the liver as well as in the peripheral circulation. In addition to chronic hepatitis B virus (HBV) infection, MAIT cells also appear to serve as potential therapeutic targets in several other chronic ailments. Evidence indicates that MAIT cells have tissue repair functions also paving way for fibrotic changes during chronic HBV infection. Observations also suggest that HBV-hepatitis delta virus (HDV) co-infection disease progression is closely associated with loss of MAIT cells. Furthermore, reduction in the number of hepatic MAIT cells in patients with cirrhotic non-alcoholic fatty liver disease and HBV-associated primary liver cancer has also been reported. Given their concrete role against HBV disease progression, and has also become evident that the tumor microenvironment can cause functional impairment of MAIT cells. Here, we reviewed the protective and the pathological role of MAIT cells in chronic HBV infection and certain other related medical conditions based on the understanding that an optimal functioning of the MAIT cell arsenal is key to a "host-friendly" immune defense against HBV disease progression.
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| 7. |
- Vignesh, Ramachandran, et al.
(författare)
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Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome-An Extempore Game of Misfiring with Defense Arsenals
- 2023
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Ingår i: Pathogens. - : MDPI. - 2076-0817. ; 12:2
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Forskningsöversikt (refereegranskat)abstract
- The lethal combination involving TB and HIV, known as "syndemic" diseases, synergistically act upon one another to magnify the disease burden. Individuals on anti-retroviral therapy (ART) are at risk of developing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). The underlying inflammatory complication includes the rapid restoration of immune responses following ART, eventually leading to exaggerated inflammatory responses to MTB antigens. TB-IRIS continues to be a cause of morbidity and mortality among HIV/TB coinfected patients initiating ART, and although a significant quantum of knowledge has been acquired on the pathogenesis of IRIS, the underlying pathomechanisms and identification of a sensitive and specific diagnostic marker still remain a grey area of investigation. Here, we reviewed the latest research developments into IRIS immunopathogenesis, and outlined the modalities to prevent and manage strategies for better clinical and diagnostic outcomes for IRIS.
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| 8. |
- Vimali, Jaisheela, et al.
(författare)
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Chronic viral infection compromises the quality of circulating mucosal-invariant T cells and follicular T helper cells via expression of both activating and inhibitory receptors
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Chronic viral infection results in impaired immune responses rendering viral persistence. Here, we investigated the role of immune activation and compared the quality of T-cell responses in chronic HBV, HCV, and HIV infections. Cytokines were measured using a commercial Bio-plex Pro Human Cytokine Grp I Panel 17-plex kit (BioRad, Hercules, CA, USA). Inflammation was assessed by measuring an array of plasma cytokines, and peripheral CD4+ T cells including circulating Tfh cells, CD8+ T cells, and TCR iVα7.2+ MAIT cells in chronic HBV, HCV, and HIV-infected patients and healthy controls. The cells were characterized based markers pertaining to immune activation (CD69, ICOS, and CD27) proliferation (Ki67), cytokine production (TNF-α, IFN-γ) and exhaustion (PD-1). The cytokine levels and T cell phenotypes together with cell markers were correlated with surrogate markers of disease progression. The activation marker CD69 was significantly increased in CD4+ hi T cells, while CD8+ MAIT cells expressing IFN-γ were significantly increased in chronic HBV, HCV and HIV infections. Six cell phenotypes, viz., TNF-α+CD4+ lo T cells, CD69+CD8+ T cells, CD69+CD4+ MAIT cells, PD-1+CD4+ hi T cells, PD-1+CD8+ T cells, Ki67+CD4+ MAIT cells were independently associated with decelerating the plasma viral load (PVL). TNF-α levels showed a positive correlation with increase in cytokine levels and decrease in PVL. Chronic viral infection negatively impacts the quality of peripheral MAIT cells and TFH cells via expression of both activating and inhibitory receptors.
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| 9. |
- Vimali, Jaisheela, et al.
(författare)
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HIV-HPgV Co-Infected Individuals Display Functional MAIT and Follicular T Cells Irrespective of PD-1 Expression
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Human Pegivirus (HPgV) appears to alter the clinical outcome of HIV disease by modulating T-cell homeostasis, chemokine/cytokine production, as well as by reducing T-cell activation, and proliferation to limit HIV replication. Here, we evaluated if HPgV had any ‘favorable’ impact on the quantity and quality of T cells in HIV-infected individuals. T-cell subsets such as CD4lo, CD4hi, and CD8+ T cells, CD4+ MAIT cells, CD8+ MAIT cells, follicular helper T cells (Tfh), and follicular cytotoxic T cells (Tfc) were characterized based on the expression of markers associated with immune activation (CD69, ICOS), proliferation (ki67), cytokine production (TNF-α, IFN-γ), and exhaustion (PD-1). HIV+HPgV+ individuals had lower plasma liver transaminase SGOT and GGT (biliary) than those who were HPgV-. HIV/HPgV co-infection was significantly associated with increased absolute CD4+ T-cell counts. HIV+HPgV+ and HIV+HPgV- individuals had highly activated T-cell subsets with high expression of CD69 and ICOS on bulk CD4+ and CD8+ T cells, CD4+ MAIT cells, CD8+ MAIT cells and CXCR5+CD4+ T cells and CXCR5+CD8+ T cells as compared to healthy controls. Irrespective of activation markers these cells also expressed higher levels of PD-1 on CD4+ T and CD8+ T cells and their counterparts. However, exploring their functionality based on the mitogen stimulation demonstrated higher levels of cytokine production by CD4+ MAIT and CD8+ MAIT cells as compared to healthy controls. Decrease in absolute CD4+ T cell counts correlated positively with intracellular IFN-γ levels by CD4lo T cells, whereas increase of the same correlated inversely with TNF-α in the CD4lo T cells of HIV+HPgV+ individuals. Together, we found that HIV/HPgV co-infected individuals display functional CD4+ and CD8+ MAIT, Tfh and Tfc cells irrespective of PD-1 expression.
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| 10. |
- Vimali, Jaisheela, et al.
(författare)
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Plasma interleukin-7 correlation with human immunodeficiency virus RNA and CD4+T cell counts, and interleukin-5 with circulating hepatitis B virus DNA may have implications in viral control
- 2022
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Ingår i: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Chronic viral infections represent a leading cause of global morbidity and mortality. Chronic HBV, HCV, and HIV infections result in cytokine perturbations that may hold key implications in understanding the complex disease mechanisms driving virus persistence and/or resolution. Here, we determined the levels of various plasma cytokines using a commercial Bio-Plex Luminex cytokine array in chronic HBV (n = 30), HCV (n = 15), and HIV (n = 40) infections and correlated with corresponding plasma viral loads (PVLs) and liver parameters. We observed differential perturbations in cytokine profiles among the study groups. The cytokines levels positively correlated with PVL and liver transaminases. The monocyte-derived cytokines viz., MIP-1 beta, IL-8, and TNF-alpha, and Th2 cytokines like IL-4, IL-5, and IL-13 showed a better correlation with liver enzymes as compared to their corresponding PVLs. Our investigation also identified two cytokines viz., IL-5 and IL-7 that inversely correlated with HBV DNA and HIV PVLs, respectively. Regression analysis adjusted for age showed that every increase of IL-5 by one unit was associated with a reduction in HBV PVL by log(10) 0.4, whereas, every elevation by a unit of IL-7 was associated with decreased HIV PVL by log(10) 2.5. We also found that IL-7 levels correlated positively with absolute CD4+ T cell counts in HIV-infected patients. We concluded that plasma IL-5 and IL-7 may likely have a key role on viral control in HBV and HIV infections, respectively. A noteworthy increase in cytokines appears to bear protective and pathological significance, and indeed is reflective of the hosts versatile immune armory against viral persistence.
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