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Topics in Antiviral Medicine ; 31(2):95, 2023.
Artigo em Inglês | EMBASE | ID: covidwho-2319250

RESUMO

Background: Omicron lineages, including BA.1 and BA.2, emerged following mass COVID-19 vaccination campaigns, displaced previous SARS-CoV-2 variants of concern worldwide, and gave rise to sublineages that continue to spread among humans. Previous research has shown that Omicron lineages exhibit a decreased propensity for lower respiratory tract (lung) infection compared to ancestral SARS-CoV-2, which may explain the decreased pathogenicity associated with Omicron infections. Nonetheless, Omicron lineages exhibit an unprecedented transmissibility in humans, which until now has been solely attributed to escape from vaccine-induced neutralizing antibodies. Method(s): We comprehensively analyzed BA1 and BA2 infection in primary human nasal epithelial cells cultured at the air-liquid interface, which recapitulates the physiological architecture of the nasal epithelium in vivo. Meanwhile we also took advantage of the VSV-based pseudovirus decorated with different Spike variants. Result(s): In primary human nasal epithelial cells cultured at the air-liquid interface, which recapitulates the physiological architecture of the nasal epithelium in vivo, BA.1 and BA.2 exhibited enhanced infectivity relative to ancestral SARS-CoV-2. Using VSV-based pseudovirus decorated with different Spike variants, we found that increased infectivity conferred by Omicron Spike is due to superior attachment and entry into nasal epithelial cells. In contrast to ancestral SARS-CoV-2, invasion of nasal epithelia by Omicron occurred via the cell surface and endosomal routes of entry and was accompanied by elevated induction of type-I interferons, indicative of a robust innate immune response. Furthermore, BA.1 was less sensitive to inhibition by the antiviral state elicited by type-I and type-III interferons, and this was recapitulated by pseudovirus bearing BA.1 and BA.2 Spike proteins. Conclusion(s): Our results suggest that the constellation of Spike mutations unique to Omicron allow for increased adherence to nasal epithelia, flexible usage of virus entry pathways, and interferon resistance. These findings inform our understanding of how Omicron evolved elevated transmissibility between humans despite a decreased propensity to infect the lower respiratory tract. Additionally, the interferon insensitivity of the Omicron Spike-mediated entry process may explain why Omicron lineages lost the capacity to antagonize interferon pathways compared to ancestral SARS-CoV-2.

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