SARS-CoV-2 Variant Delta Potently Suppresses Innate Immune Response and Evades Interferon-Activated Antiviral Responses in Human Colon Epithelial Cells.

The Delta variant of SARS-CoV-2 has caused more severe infections than its previous variants. We studied the host innate immune response to Delta, Alpha, and two earlier variants to map the evolution of the recent ones. Our biochemical and transcriptomic studies in human colon epithelial cell line Caco2 reveal that Alpha and Delta have progressively evolved over the ancestral variants by silencing the innate immune response, thereby limiting cytokine and chemokine production. Though Alpha silenced the retinoic acid-inducible gene (RIG)-I-like receptor (RLR) pathway just like Delta did, it failed to persistently silence the innate immune response, unlike Delta. Both Alpha and Delta have evolved to resist interferon (IFN) treatment, while they are still susceptible to RLR activation, further highlighting the importance of RLR-mediated, IFN-independent mechanisms in restricting SARS-CoV-2. Our studies reveal that SARS-CoV-2 Delta has integrated multiple mechanisms to silence the host innate immune response and evade the IFN response. We speculate that Delta's silent replication and sustained suppression of the host innate immune response, thereby resulting in delayed or reduced intervention by the adaptive immune response, could have potentially contributed to the severe symptoms and poor recovery index associated with it. It is likely that this altered association with the host would play an important role in the coevolution of SARS-CoV-2 with humans. IMPORTANCE Viruses generally learn to coexist with the host during the process of evolution. It is expected that SARS-CoV-2 would also evolve to coexist in humans by trading off its virulence for longer persistence, causing milder disease. Clinically, the fatality associated with COVID-19 has been declining due to vaccination and preinfections, but the Delta variant caused the most severe disease and fatality across several parts of the world. Our study identified an evolving trend of SARS-CoV-2 variants where the variants that emerged during early parts of the pandemic caused a more robust innate immune response, while the later emerging variant Delta showed features of suppression of the response. The features that Delta has acquired could have strongly influenced the distinct pathophysiology associated with its infection. How these changed associations with the host influence the long-term evolution of the virus and the disease outcome should be closely studied to understand the process of viral evolution.

Spatio-temporal dynamics of intra-host variability in SARS-CoV-2 genomes.

During the course of the COVID-19 pandemic, large-scale genome sequencing of SARS-CoV-2 has been useful in tracking its spread and in identifying variants of concern (VOC). Viral and host factors could contribute to variability within a host that can be captured in next-generation sequencing reads as intra-host single nucleotide variations (iSNVs). Analysing 1347 samples collected till June 2020, we recorded 16 410 iSNV sites throughout the SARS-CoV-2 genome. We found ∼42% of the iSNV sites to be reported as SNVs by 30 September 2020 in consensus sequences submitted to GISAID, which increased to ∼80% by 30th June 2021. Following this, analysis of another set of 1774 samples sequenced in India between November 2020 and May 2021 revealed that majority of the Delta (B.1.617.2) and Kappa (B.1.617.1) lineage-defining variations appeared as iSNVs before getting fixed in the population. Besides, mutations in RdRp as well as RNA-editing by APOBEC and ADAR deaminases seem to contribute to the differential prevalence of iSNVs in hosts. We also observe hyper-variability at functionally critical residues in Spike protein that could alter the antigenicity and may contribute to immune escape. Thus, tracking and functional annotation of iSNVs in ongoing genome surveillance programs could be important for early identification of potential variants of concern and actionable interventions.

Genomic characterization and epidemiology of an emerging SARS-CoV-2 variant in Delhi, India.

Delhi, the national capital of India, experienced multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreaks in 2020 and reached population seropositivity of >50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant, B.1.617.2 (Delta), replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and reduced sensitivity to immune responses generated against earlier variants (median estimates: 1.5-fold greater transmissibility and 20% reduction in sensitivity). Seropositivity of an employee and family cohort increased from 42% to 87.5% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after a previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi.

SARS-CoV-2 seroprevalence in the city of Hyderabad, India in early 2021.

Background: COVID-19 emerged as a global pandemic in 2020, spreading rapidly to most parts of the world. The proportion of infected individuals in a population can be reliably estimated via serosurveillance, making it a valuable tool for planning control measures. Our serosurvey study aimed to investigate SARS-CoV-2 seroprevalence in the urban population of Hyderabad at the end of the first wave of infections. Methods: This cross-sectional survey, conducted in January 2021 and including males and females aged 10 years and above, used multi-stage random sampling. 9363 samples were collected from 30 wards distributed over six zones of Hyderabad, and tested for antibodies against SARS-CoV-2 nucleocapsid antigen. Results: Overall seropositivity was 54.2%, ranging from 50% to 60% in most wards. Highest exposure appeared to be among those aged 30-39 and 50-59 years, with women showing greater seropositivity. Seropositivity increased with family size, with only marginal differences among people with varying levels of education. Seroprevalence was significantly lower among smokers. Only 11% of the survey subjects reported any COVID-19 symptoms, while 17% had appeared for COVID-19 testing. Conclusion: Over half the city's population was infected within a year of onset of the pandemic. However, ∼ 46% of people remained susceptible, contributing to subsequent waves of infection.

A Distinct Phylogenetic Cluster of Indian Severe Acute Respiratory Syndrome Coronavirus 2 Isolates.

BACKGROUND: From an isolated epidemic, coronavirus disease 2019 has now emerged as a global pandemic. The availability of genomes in the public domain after the epidemic provides a unique opportunity to understand the evolution and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus across the globe. METHODS: We performed whole-genome sequencing of 303 Indian isolates, and we analyzed them in the context of publicly available data from India. RESULTS: We describe a distinct phylogenetic cluster (Clade I/A3i) of SARS-CoV-2 genomes from India, which encompasses 22% of all genomes deposited in the public domain from India. Globally, approximately 2% of genomes, which to date could not be mapped to any distinct known cluster, fall within this clade. CONCLUSIONS: The cluster is characterized by a core set of 4 genetic variants and has a nucleotide substitution rate of 1.1 × 10-3 variants per site per year, which is lower than the prevalent A2a cluster. Epidemiological assessments suggest that the common ancestor emerged at the end of January 2020 and possibly resulted in an outbreak followed by countrywide spread. To the best of our knowledge, this is the first comprehensive study characterizing this cluster of SARS-CoV-2 in India.