Abstract
The emergence of SARS-CoV-2 variants of concern with progressively increased transmissibility between humans is a threat to global public health. The Omicron variant of SARS-CoV-2 also evades immunity from natural infection or vaccines1, but it is unclear whether its exceptional transmissibility is due to immune evasion or intrinsic virological properties. Here we compared the replication competence and cellular tropism of the wild-type virus and the D614G, Alpha(B.1.1.7), Beta(B.1.351), Delta(B.1.617.2) and Omicron(B.1.1.529) variants in ex vivo explant cultures of human bronchi and lungs. We also evaluated the dependence on TMPRSS2and cathepsins for infection. We show that Omicron replicates faster than all other SARS-CoV-2 variants studied in the bronchi but less efficiently in the lung parenchyma. All variants of concern have similar cellular tropism compared to the wild type. Omicron is more dependent on cathepsins than the other variants of concern tested, suggesting that the Omicron variant enters cells through a different route compared with the other variants. The lower replication competence of Omicron in the human lungs may explain the reduced severity of Omicron that is now being reported in epidemiological studies, although determinants of severity are multifactorial. These findings provide important biological correlates to previous epidemiological observations.
Highlights
This is a PDF file of a peer-reviewed paper that has been accepted for publication
The first virus variant emerged in February 2020 carrying the D614G amino acid substitution in the S protein and this quickly became the dominant virus variant globally
The B.1.351 lineage (Beta variant) first detected in South Africa in August 2020, contained 10 mutations in the S protein and mutations N501Y and K417N enhanced viral transmission while E484K contributed to immune evasion[7,8]
Summary
ShAuRmSa-nCobVro-2nOchmuiscaronndvluanrigaenxt rveivpolicatioVnIiEn W Received:13January2022 E Accepted: 27 January 2022 R Accelerated Article Preview online xx xx xxxx. W Tonia Tong Kam[1], Haogao Gu1, Ko-Yung Sit[3], Michael KY Hsin[3], Timmy WK Au3, Leo LM Poon[1,2], IE Malik Peiris[1,2], John M Nicholls[4], Michael CW Chan1,2† REV 1School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, P Hong Kong SAR, China; E 2Centre for Immunology and Infection (C2I), Hong Kong Science Park, Hong Kong SAR, China; ICL 3Division of Cardiothoracic Surgery, Department of Surgery, Queen Mary Hospital, Pokfulam, Hong. We initially compared the virus L replication kinetics of wild type SARS-CoV-2 (WT) with the D614G variant and VOCs from IC B.1.1.7 (Alpha) and B.1.351 (Beta) lineages in ex vivo explant cultures of human bronchus T and lung. We investigated the TMPRSS2 expression and showed significantly higher expression of TMPRSS2 in the bronchus than the lung by mRNA expression levels (Figure 4a)
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