The Spike D614G mutation increases SARS-CoV-2 infection of multiple human cell types

Author:

Daniloski Zharko12ORCID,Jordan Tristan X3ORCID,Ilmain Juliana K4ORCID,Guo Xinyi12,Bhabha Gira4ORCID,tenOever Benjamin R3ORCID,Sanjana Neville E12ORCID

Affiliation:

1. New York Genome Center, New York, United States

2. Department of Biology, New York University, New York, United States

3. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, United States

4. Department of Cell Biology and Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States

Abstract

A novel variant of the SARS-CoV-2 virus carrying a point mutation in the Spike protein (D614G) has recently emerged and rapidly surpassed others in prevalence. This mutation is in linkage disequilibrium with an ORF1b protein variant (P314L), making it difficult to discern the functional significance of the Spike D614G mutation from population genetics alone. Here, we perform site-directed mutagenesis on wild-type human-codon-optimized Spike to introduce the D614G variant. Using multiple human cell lines, including human lung epithelial cells, we found that the lentiviral particles pseudotyped with Spike D614G are more effective at transducing cells than ones pseudotyped with wild-type Spike. The increased transduction with Spike D614G ranged from 1.3- to 2.4-fold in Caco-2 and Calu-3 cells expressing endogenous ACE2 and from 1.5- to 7.7-fold in A549ACE2 and Huh7.5ACE2 overexpressing ACE2. Furthermore, trans-complementation of SARS-CoV-2 virus with Spike D614G showed an increased infectivity in human cells. Although there is minimal difference in ACE2 receptor binding between the D614 and G614 Spike variants, the G614 variant is more resistant to proteolytic cleavage, suggesting a possible mechanism for the increased transduction.

Funder

American Heart Association

National Institute of Allergy and Infectious Diseases

Pew Charitable Trusts

Searle Scholars Program

Defense Advanced Research Projects Agency

National Human Genome Research Institute

National Cancer Institute

Sidney Kimmel Foundation

Melanoma Research Alliance

Brain and Behavior Research Foundation

NIH

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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