Emergence of SARS-CoV-2 Omicron Variant JN.1 in Tamil Nadu, India - Clinical Characteristics and Novel Mutations.

In December 2023, we observed a notable shift in the COVID-19 landscape, when the JN.1 emerged as a predominant SARS-CoV-2 variant with a 95% incidence. We characterized the clinical profile, and genetic changes in JN.1, an emerging SARS-CoV-2 variant of interest. Whole genome sequencing was performed on SARS-CoV-2 positive samples, followed by sequence analysis. Mutations within the spike protein sequences were analyzed and compared with the previous lineages and sublineages of SARS-CoV-2, to identify the potential impact of these unique mutations on protein structure and possible functionality. Several unique and dynamic mutations were identified herein. Our data provides key insights into the emergence of newer variants of SARS-CoV-2 in our region and highlights the need for robust and sustained genomic surveillance of SARS-CoV-2.

Occult hepatitis B virus infection and current perspectives on global WHO 2030 eradication.

The current World Health Organization (WHO) Hepatitis Elimination Strategy suffers from lack of a target for diagnosing or expunging occult HBV infection. A sizable segment of the global population has an undetected HBV infection, particularly the high-risk populations and those residing in countries like India with intermediate endemicity. There is growing proof that people with hidden HBV infection can infect others, and that these infections are linked to serious chronic hepatic complications, especially hepatocellular carcinoma. Given the current diagnostic infrastructure in low-resource settings, the WHO 2030 objective of obliterating hepatitis B appears to be undeniably challenging to accomplish. Given the molecular basis of occult HBV infection strongly linked to intrahepatic persistence, patients may inexplicably harbour HBV genomes for a prolonged duration without displaying any pronounced clinical or biochemical signs of liver disease, and present histological signs of moderate degree necro-inflammation, diffuse fibrosis, and hence the international strategy to eradicate viral hepatitis warrants inclusion of occult HBV infection.

Chronic Viral Infection Compromises the Quality of Circulating Mucosal-Associated Invariant T Cells and Follicular T Helper Cells via Expression of Inhibitory Receptors.

BACKGROUND: Chronic viral infection results in impaired immune responses rendering viral persistence. Here, we compared the quality of T-cell responses among chronic hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV)-infected individuals by examining the levels of expression of selected immune activation and exhaustion molecules on circulating MAIT cells and Tfh cells. METHODS: 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 phenotypic alterations in 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 on 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. RESULTS: The activation marker CD69 was significantly increased in CD4+hi T cells, while CD8+ MAIT cells producing 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, and 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. CONCLUSION: Chronic viral infection negatively impacts the quality of peripheral MAIT cells and Tfh cells via differential expression of both activating and inhibitory receptors.

Genomic surveillance of omicron B.1.1.529 SARS-CoV-2 and its variants between December 2021 and March 2023 in Tamil Nadu, India-A state-wide prospective longitudinal study.

A state-wide prospective longitudinal investigation of the genomic surveillance of the omicron B.1.1.529 SARS-CoV-2 variant and its sublineages in Tamil Nadu, India, was conducted between December 2021 and March 2023. The study aimed to elucidate their mutational patterns and their genetic interrelationship in the Indian population. The study identified several unique mutations at different time-points, which likely could attribute to the changing disease characteristics, transmission, and pathogenicity attributes of omicron variants. The study found that the omicron variant is highly competent in its mutating potentials, and that it continues to evolve in the general population, likely escaping from natural as well as vaccine-induced immune responses. Our findings suggest that continuous surveillance of viral variants at the global scenario is warranted to undertake intervention measures against potentially precarious SARS-CoV-2 variants and their evolution.

Clinical characteristics and novel mutations of omicron subvariant XBB in Tamil Nadu, India - a cohort study.

Background: Despite the continued vaccination efforts, there had been a surge in breakthrough infections, and the emergence of the B.1.1.529 omicron variant of SARS-CoV-2 in India. There is a paucity of information globally on the role of newer XBB variants in community transmission. Here, we investigated the mutational patterns among hospitalised patients infected with the XBB omicron sub-variant, and checked if there was any association between the rise in the number of COVID-19 cases and the observed novel mutations in Tamil Nadu, India. Methods: Nasopharyngeal and oropharyngeal swabs, collected from symptomatic and asymptomatic COVID-19 patients were subjected to real-time PCR followed by Next Generation Sequencing (NGS) to rule out the ambiguity of mutations in viruses isolated from the patients (n = 98). Using the phylogenetic association, the mutational patterns were used to corroborate clinico-demographic characteristics and disease severity among the patients. Findings: Overall, we identified 43 mutations in the S gene across 98 sequences, of which two were novel mutations (A27S and T747I) that have not been reported previously with XBB sub-variants in the available literature. Additionally, the XBB sequences from our cohort had more mutations than omicron B.1.1.529. The phylogenetic analysis comprising six major branches clearly showed convergent evolution of XBB. Our data suggests that age, and underlying conditions (e.g., diabetes, hypertension, and cardiovascular disease) or secondary complications confers increased susceptibility to infection rather than vaccination status or prior exposure. Many vaccinated individuals showed evidence of a breakthrough infection, with XBB.3 being the predominant variant identified in the study population. Interpretation: Our study indicates that the XBB variant is highly evasive from available vaccines and may be more transmissible, and potentially could emerge as the 'next' predominant variant, which likely could overwhelm the existing variants of SARS-CoV-2 omicron variants. Funding: National Health Mission (India), SIDASARC, VINNMER (Sweden), ORIP/NIH (USA).

Plasma CXCL8 and MCP-1 as surrogate plasma biomarkers of latent tuberculosis infection among household contacts-A cross-sectional study.

Early detection of latent tuberculosis infection (LTBI) is critical to TB elimination in the current WHO vision of End Tuberculosis Strategy. The study investigates whether detecting plasma cytokines could aid in diagnosing LTBI across household contacts (HHCs) positive for IGRA, HHCs negative for IGRA, and healthy controls. The plasma cytokines were measured using a commercial Bio-Plex Pro Human Cytokine 17-plex assay. Increased plasma CXCL8 and decreased MCP-1, TNF-α, and IFN-γ were associated with LTBI. Regression analysis showed that a combination of CXCL8 and MCP-1 increased the risk of LTBI among HHCs to 14-fold. Our study suggests that CXCL-8 and MCP-1 could serve as the surrogate biomarkers of LTBI, particularly in resource-limited settings. Further laboratory investigations are warranted before extrapolating CXCL8 and MCP-1 for their usefulness as surrogate biomarkers of LTBI in resource-limited settings.

Plasma CXCL8 and MCP-1 as biomarkers of latent tuberculosis infection.

Background: Early detection of latent tuberculosis infection (LTBI) is critical to TB elimination in the current WHO vision of End Tuberculosis Strategy. Methods: We investigated whether detecting plasma cytokines could aid in diagnosing LTBI across household contacts (HHCs) positive for IGRA, HHCs negative for IGRA, and healthy controls. We also measured the plasma cytokines using a commercial Bio-Plex Pro Human Cytokine 17-plex assay. Results: Increased plasma CXCL8 and decreased MCP-1, TNF-α, and IFN-γ were associated with LTBI. Regression analysis showed that a combination of CXCL8 and MCP-1 increased the risk of LTBI among HHCs to 14-fold. Conclusions: We postulated that CXCL8 and MCP-1 could be the surrogate biomarkers of LTBI, especially in resource-limited settings.

The Implementation of HIV Self-Testing in Resource-Limited Settings Where the HIV Disease Burden is High.

In resource-limited settings, there is growing evidence that HIV testing is lacking among high-risk key populations such as men having sex with men, injection drug users, and transgenders largely due to stigma, discrimination, and lack of confidentiality. Findings from recent studies among high-risk key populations and the general population from various regions including resource-limited settings support the need for wider accessibility of HIV self-testing (HIV-ST) to reach those who may not otherwise have access to testing. Therefore, HIV-ST has untapped potential as a strategy to improve access to HIV testing and to increase testing frequency among key high-risk populations and their partners. Though HIV-ST has emerged as a safe, acceptable, and effective way to reach people, there are several roadblocks to implementing the HIV-ST policy, and fast-track policy implementation needs to be necessitated with newer or modified strategic plans.

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.

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.

Impact of COVID-19 Vaccination on Pregnant Women.

In light of the COVID-19 pandemic, researchers across the world hastened to develop vaccines that would aid in bolstering herd immunity. Utilizing mRNA coding and viral vector technology, the currently approved vaccines were required to undergo extensive testing to confirm their safety for mass usage in the general population. However, clinical trials failed to test the safety and efficacy of the COVID-19 vaccines in groups with weakened immune systems, especially pregnant women. Lack of information on the effects of vaccinations in pregnancy and the safety of fetuses are among the topmost reasons preventing pregnant women from receiving immunization. Thus, the lack of data examining the effects of COVID-19 vaccinations on pregnant women must be addressed. This review focused on the safety and efficacy of the approved COVID-19 vaccinations in pregnancy and their impact on both maternal and fetal immune responses. For that, we took the approach of combined systematic review/meta-analysis and compiled the available data from the original literature from PubMed, Web of Science, EMBASE and Medline databases. All articles analyzed presented no adverse effects of vaccination in pregnancy, with varying conclusions on the degree of effectiveness. The majority of the findings described robust immune responses in vaccinated pregnant women, successful transplacental antibody transfer, and implications for neonatal immunity. Hence, findings from the cumulative data available can be helpful in achieving COVID-19 herd immunization, including pregnant women.

Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome-An Extempore Game of Misfiring with Defense Arsenals.

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.

Host cell responses against the pseudomonal biofilm: A continued tale of host-pathogen interactions.

In biofilm formation, pathogens within the bacterial community coordinate a cell-cell communication system called quorum sensing (QS). This is achieved through various signalling pathways that regulate bacterial virulence and host immune response. Here, we reviewed the host responses, key clinical implications, and novel therapeutic approaches against the biofilms of P. aeruginosa. Given the high degree of intrinsic antibiotic resistance and biofilm formation by the pathogen, the ensuing treatment complications could result in high morbidity and mortality rates worldwide. Notwithstanding the availability of intervention strategies, there remains a paucity of effective therapeutic options to control biofilmogenesis. This review discusses the basic understanding of QS-associated virulence factors and several key therapeutic interventions to foil the biofilm menace of P. aeruginosa.

Surrogate Biomarkers of Disease Progression in Human Pegivirus Seropositive Human Immunodeficiency Virus-Infected Individuals.

Scientific observations indicate that an actively prevailing systemic condition could alleviate the pathology of another disease. Human pegivirus (HPgV), a highly ubiquitous flavivirus is believed to be associated with slow human immunodeficiency virus (HIV) disease progression, and has seldom been linked to hepatic pathology. In this study, we investigated whether HPgV seropositivity had any impact on surrogate markers of HIV disease progression in a cohort of HIV-infected HPgV seropositive (n = 28) and seronegative (n = 12) individuals who were prospectively evaluated for absolute CD4+ T cell counts, plasma viral load (PVL), liver enzymes, and plasma cytokine levels. The HIV PVL was relatively lower in HPgV seropositive than in HPgV seronegative HIV-infected subjects. Clinical markers of hepatic injury were significantly low among HPgV seropositive HIV-infected participants. HPgV seropositive individuals showed significantly higher levels of interleukin-7 (IL-7), and although not significant, the levels of IL-6 were lower among HPgV seropositive subjects. Spearman correlation analysis showed that the absolute CD4+T cell count was inversely correlated with HIV PVL. Exposure to HPgV appears to have a positive prognostic impact on the levels of surrogate biomarkers of HIV disease progression.

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.

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-1ß, IL-8, and TNF-α, 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 log10 0.4, whereas, every elevation by a unit of IL-7 was associated with decreased HIV PVL by log10 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 host's versatile immune armory against viral persistence.

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.

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.

T cell perturbations persist for at least 6 months following hospitalization for COVID-19.

COVID-19 is being extensively studied, and much remains unknown regarding the long-term consequences of the disease on immune cells. The different arms of the immune system are interlinked, with humoral responses and the production of high-affinity antibodies being largely dependent on T cell immunity. Here, we longitudinally explored the effect COVID-19 has on T cell populations and the virus-specific T cells, as well as neutralizing antibody responses, for 6-7 months following hospitalization. The CD8+ TEMRA and exhausted CD57+ CD8+ T cells were markedly affected with elevated levels that lasted long into convalescence. Further, markers associated with T cell activation were upregulated at inclusion, and in the case of CD69+ CD4+ T cells this lasted all through the study duration. The levels of T cells expressing negative immune checkpoint molecules were increased in COVID-19 patients and sustained for a prolonged duration following recovery. Within 2-3 weeks after symptom onset, all COVID-19 patients developed anti-nucleocapsid IgG and spike-neutralizing IgG as well as SARS-CoV-2-specific T cell responses. In addition, we found alterations in follicular T helper (TFH) cell populations, such as enhanced TFH-TH2 following recovery from COVID-19. Our study revealed significant and long-term alterations in T cell populations and key events associated with COVID-19 pathogenesis.

HIV-1 induction of tolerogenic dendritic cells is mediated by cellular interaction with suppressive T cells.

HIV-1 infection gives rise to a multi-layered immune impairment in most infected individuals. The chronic presence of HIV-1 during the priming and activation of T cells by dendritic cells (DCs) promotes the expansion of suppressive T cells in a contact-dependent manner. The mechanism behind the T cell side of this HIV-induced impairment is well studied, whereas little is known about the reverse effects exerted on the DCs. Herein we assessed the phenotype and transcriptome profile of mature DCs that have been in contact with suppressive T cells. The HIV exposed DCs from cocultures between DCs and T cells resulted in a more tolerogenic phenotype with increased expression of e.g., PDL1, Gal-9, HVEM, and B7H3, mediated by interaction with T cells. Transcriptomic analysis of the DCs separated from the DC-T cell coculture revealed a type I IFN response profile as well as an activation of pathways involved in T cell exhaustion. Taken together, our data indicate that the prolonged and strong type I IFN signaling in DCs, induced by the presence of HIV during DC-T cell cross talk, could play an important role in the induction of tolerogenic DCs and suppressed immune responses seen in HIV-1 infected individuals.