A single mutation in the SARS-CoV-2 Omicron variant reduces spike protein expression and weakens disease severity while conferring a replication advantage in the upper airway, according to research published in Nature Communications.
Omicron variants emerged in 2022 carrying more than 30 novel mutations in the spike protein alone. While most scientific studies focused on alterations in the receptor binding domain, a research team led by the University of Texas Medical Branch investigated three mutations in the C-terminus of S1 adjacent to the furin cleavage site: H655Y, N679K, and P681H.
Experiments with a combined triple mutant designated YKH showed increased spike processing. When tested in male golden Syrian hamsters, the YKH mutant caused attenuated disease while augmenting viral loads.
Tests on the individual N679K mutation showed that it reduced viral replication in Calu3 human respiratory cells and led to less severe disease in male golden Syrian hamsters. Mechanistically, N679K increased spike processing but reduced the total amount of spike protein present in purified virions. This reduction in spike protein was further exacerbated in infected Calu3 cell lysates, and exogenous expression experiments confirmed that N679K lowered overall spike levels within the epidemic strain.
Transmission competition assays demonstrated that although N679K acts as a loss-of-function mutation for spike expression, it provides a distinct replication advantage in the upper airway that may influence transmissibility.
Grants from the National Institute of Allergy and Infectious Diseases, the University of Texas System, and the Burroughs Wellcome Fund supported the work. Researchers Vineet D. Menachery and Michelle N. Vu have filed a provisional patent on a stabilized SARS-CoV-2 spike protein.
