Abstract
The spike aspartic acid-614 to glycine (D614G) substitution is prevalent in global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains, but its effects on viral pathogenesis and transmissibility remain unclear. We engineered a SARS-CoV-2 variant containing this substitution. The variant exhibits more efficient infection, replication, and competitive fitness in primary human airway epithelial cells but maintains similar morphology and in vitro neutralization properties, compared with the ancestral wild-type virus. Infection of human angiotensin-converting enzyme 2 (ACE2) transgenic mice and Syrian hamsters with both viruses resulted in similar viral titers in respiratory tissues and pulmonary disease. However, the D614G variant transmits significantly faster and displayed increased competitive fitness than the wild-type virus in hamsters. These data show that the D614G substitution enhances SARS-CoV-2 infectivity, competitive fitness, and transmission in primary human cells and animal models.
Highlights
SARS-CoV-2 S pseudotyped viruses encoding the D614G substitution were reported to exhibit increased infectivity in continuous cell lines and increased sensitivity to neutralization (4, 5)
To address these questions, we generated an isogenic SARS-CoV-2 variant containing only the D614G substitution in the S glycoprotein, along with a second variant that contained the nanoLuciferease gene in place of accessory gene 7a (Fig. 1A), using a D614-form SARS-CoV-2 strain WA1 as the backbone (8)
To evaluate the replication of SARS-CoV-2 D614G variant in the human respiratory tract, we compared the multi-step growth kinetics (MOI = 0.1) of the WT and D614G viruses in ex vivo primary human nasal epithelial (HNE) cells from five donors, large airway epithelial (LAE) cells from
Summary
SARS-CoV-2 S pseudotyped viruses encoding the D614G substitution were reported to exhibit increased infectivity in continuous cell lines and increased sensitivity to neutralization (4, 5). The D614G substitution has yet to be evaluated in the authentic SARS-CoV-2 infection models, and its functions in viral replication, pathogenesis and transmissibility remain unclear.
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