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Cellular basis for SARS-CoV-2 infection

Research institutions, pharmaceutical companies and governmental organizations are working to identify and develop drugs and vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19. The development of new therapies relies on the understanding of host−virus interactions and the biology of infection. In Cell, Daniloski, Jordan et al. report a genome-wide CRISPR–Cas9-mediated loss-of-function screen to identify host factors required for SARS-CoV-2 viral infection.

Their screen used human alveolar basal epithelial carcinoma cells (A549ACE2) that ectopically express angiotensin converting-enzyme 2 (ACE2) — the host receptor to which viral envelope proteins bind and that is required for infection — and targeted 19,050 genes. As expected, the genes whose loss conferred resistance to SARS-CoV-2 included genes involved in viral entry and replication. Among the 50 most represented genes (top-ranking) were genes encoding proteins that function in complexes and/or in distinct pathways, prominently involved in endocytotic trafficking (for example the Retromer and Commander complexes).

Credit: V. Summersby/Springer Nature Limited

To further validate their screen, the authors used other methods to perturb the function of top-ranking genes in A549ACE2 cells: CRISPR knockout, siRNA knockdown, and small-molecule inhibitors that include some that are FDA approved or in phase II or phase III clinical trials for other diseases. Interestingly, some of the most effective inhibitors had an additive effect, increasing protection from SARS-CoV-2 infection when used in combination.

The authors also evaluated ACE2 cell surface expression following knockout of their top-ranking genes and found that ACE2 was substantially reduced in RAB7A-knockout cells. RAB7A encodes a small GTPase that regulates membrane trafficking and vesicular transport, and its knockout led to the accumulation of ACE2 in the cytoplasm and in vesicles similar to endo-lysosomes; however, the mechanisms by which RAB7A loss disrupts viral infection, which might involve multiple pathways, remain to be determined.

When looking at gene expression profiles (using single-cell transcriptomics) of cells in which the top-ranking genes were knocked out, the authors found that the CRISPR–Cas9-driven loss of six independent genes induced a similar transcriptional signature, which was associated with increased cholesterol synthesis. Indeed, cholesterol levels were higher in cells lacking each of these six genes. These findings are in agreement with another study reporting that cholesterol upregulation by pharmacological treatment might be a mechanism for viral inhibition.

Other studies are reporting loss-of-function screens to identify host factors required for SARS-CoV-2 infection — these studies, combined with protein−protein interaction network analyses and other large-scale screens, should provide useful resources for the development of therapeutic strategies against COVID-19.


Original article

  1. Daniloski, Z., Jordan, T. X. et al. Identification of required host factors for SARS-CoV-2 infection in human cells. Cell (2020)

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Correspondence to Kim Baumann.

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Baumann, K. Cellular basis for SARS-CoV-2 infection. Nat Rev Mol Cell Biol 22, 2 (2021).

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