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Health & Medical

Replication of SARS-CoV-2 variants in different cell and organ models


The emergence of genetically diverse severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, with altered phenotypic properties, has occurred due to the continuous mutation of the original strain first reported in Wuhan, China, in 2019. In 2021, the World Health Organization categorized these variants as variants of concern (VOC) and variants of interest (VOI) based on transmissibility, severity, and capability to escape immune responses.

Study: Post-entry, spike-dependent replication advantage of B.1.1.7 and B.1.617.2 over B.1 SARS-CoV-2 in an ACE2-deficient human lung cell line. Image Credit: CKA/ ShutterstockStudy: Post-entry, spike-dependent replication advantage of B.1.1.7 and B.1.617.2 over B.1 SARS-CoV-2 in an ACE2-deficient human lung cell line. Image Credit: CKA/ Shutterstock

SARS-CoV-2 Alpha and Delta variants

The B.1.1.7 lineage is also known as the Alpha variant and is categorized as a VOC. It was first reported in the United Kingdom in September 2020. Scientists revealed that the Alpha variant has a significantly higher reproduction number and causes a more severe infection with a higher mortality rate than the original strain.

B.1.617.2 lineage is known as the Delta variant and falls under the category of VOC. This variant was first reported in India in October 2020. It has higher transmissibility, causes severe disease with an elevated rate of mortality. At present, the Delta variant is predominantly circulating the world.

Genomic studies revealed genetic hallmarks of B.1.1.7 consisting of a set of mutations that includes deletion of amino acids 69, 70, and 144 in the aminoterminal domain. It also contains an N501Y exchange in the receptor-binding domain (RBD) of the SARS-CoV-2’s Spike region. Other mutations that occur in the S1 domain of the Spike protein are P681H and T716 and D1118H in the S2 domain.

Scientists have pointed out that functional correlations for the enhanced transmission and pathogenicity of B.1.1.7 and B.1.617.2 are unavailable. Previous studies showed that B.1.1.7- and B.1.617.2-infected individuals shed viral RNA of increased levels and longer durations. These studies also showed that compared to B.617.2, B.1.1.7 is readily neutralized by antibodies. Also, compared to the Alpha stain, the Delta strain can evade the immune response elicited via vaccination or natural infection.

Scientists observed that in vitro and in vivo replication of B.1.1.7 differed depending on the model used. For example, certain epithelial cell cultures and hamster models revealed equal or inferior replication for B.1.1.7., while primate and ferret models exhibited marginally superior replication. Animal models have limited ability to reproduce adaptive processes that occur in a virus while establishing endemicity in humans.

A new study published on the bioRxiv* preprint server focuses on the identification of a human cell line that reflects the replicative phenotype of B.1.1.7 and B.1.617.2. In this study, the replication of B.1.1.7 viruses was analyzed in different cell and organ models and dwarf hamsters.

About the study

Previous studies showed that SARS-CoV-2 predominantly infects the epithelial cells, and B.1.1.7-infected patients shed viral RNA 10-fold more than the original strain. Considering this, researchers of the present study hypothesized that B.1.1.7 has a replication advantage in human epithelial cell cultures.

This study revealed that even though all immortalized, primary and organoid cultures considered in this study were highly permissive for SARS-CoV-2 infection, no specific B.1.1.7-specific growth were identified. This result is in line with previous research that reported a similar growth rate of B.1.1.7 and B.1. viruses in common culture cells and primary human airway epithelial (HAE) cells. Researchers did not identify infected cultures even after ten days, and no elevated virus production in human organoid models was observed.

The current study is also in line with earlier reports and confirmed the lack of significant differences in growth between B.1.1.7 and B.1 variants in experimentally infected dwarf hamsters. It reported that B.1.1.7 is extremely infectious, and its transmissibility can be recapitulated only in some animal models, but it cannot be demonstrated in most cell culture systems.

The authors performed a biochemical peptide cleavage assay and observed reduced proteolytic cleavage in spike plasmid transfected and SARS-CoV-2-infected cells to be consistent with reduced furin-mediated processing of B.1.1.7 spike. Although an increase in the B.1.1.7 replication has been observed in patients, the early phase of infection has been difficult to capture in clinical observations due to late sampling, making cell culture studies potentially more insightful. Researchers stated that cell cultures analyzed in this study might not reflect the differences in virus production in later stages of tissue infection due to the limiting effect of cytopathogenic effects in vitro.

The current study revealed a delayed onset of cytopathic effect, a slower ramp-up of virus production, and moderately decreased levels of IFNL expression in the case of B.1.1.7. These observations are consistent with a stealthy invasion of tissue with initially limited production of PAMPs and more efficient evasion of cell-intrinsic innate immunity. Although cell-intrinsic immunity may be involved during infection, the onset and degree of infection depend on several factors.

Researchers showed that NCI-H1299 cells produced higher replication and infectious virus production levels associated with both B.1.1.7 and B.1.617.2. This cell line is devoid of detectable ACE2 protein and remains susceptible to SARS-CoV-2 infection even in the presence of ACE2-neutralizing antibodies.

Future Studies

The authors stated that more research is required for the identification of a hypothetical alternative receptor of SARS-CoV-2. Also, research related to the cellular environment of NCI-H1299 cells is recommended to understand better replication of B.1.1.7 and B.1.617.2 SARS-CoV-2.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.



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