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Researchers in the United States and Japan have conducted a study suggesting that a common genetic variant influences susceptibility to infection with coronavirus 2 (SARS-CoV-2), the severe acute respiratory syndrome, the agent that causes disease by coronavirus 2019 (COVID-19).
The team found that allelic conversion in the common rs4702 variant affected SARS-CoV-2 infection in human neurons and alveolar cells. in vitro.
Kristen Brennand (Icahn School of Medicine at Mount Sinai, New York) and her colleagues say their study provides proof of principle that common human genetic variation can directly affect susceptibility to SARS-CoV-2 infection and thus therefore, contribute to the variability in welcoming responses between individuals.
“This work supports ongoing efforts to discover host genes associated with SARS-CoV-2 infection, both in vitro and in the clinic,” the researchers said. “Our hope is that such efforts can better predict clinical outcomes before symptoms appear and facilitate the discovery of drugs that could prevent or treat COVID-19 disease.”
A pre-printed version of the paper is available on the server. bioRxiv *, while the article undergoes peer review.
Interindividual Variability in Host Response to SARS-CoV-2
The host response to SARS-CoV-2 infection varies significantly between individuals, with outcomes ranging from asymptomatic infection to mild to moderate symptoms and severe or critical illness.
Additionally, although men, the elderly, and people with underlying health conditions are more likely to develop serious illness, SARS-CoV-2 can also cause serious complications in healthy people without any of these risk factors.
The different clinical outcomes post-infection do not appear to be due simply to variations in the adaptive immune response, as a growing body of evidence suggests that seroconversion may occur before symptoms have resolved.
Several human genetic variants have previously been identified that influence susceptibility or resistance to virus infection, including influenza, respiratory syncytial virus, norovirus, rotavirus, parvovirus, and human immunodeficiency virus.
“We presume that, in addition to the host’s viral load and antibody repertoire, host genetic variants also affect vulnerability to infection,” write Brennand and colleagues.
How does SARS-CoV-2 infect cells?
To infect target cells, SARS-CoV-2 uses a viral surface protein called a spike to bind to the host cell receptor, angiotensin-converting enzyme 2 (ACE2) and host cell transmembrane protease, serine 2 (TMPRSS2. ). SARS-CoV-2 fuses with the host cell membrane after TMPRSS2 has processed the spike protein to reveal the fusion peptide.
The virus has evolved a four amino acid insert that is believed to be cleaved by a host membrane bound proprotease convertase called furin to prime the spike protein for TMPRSS2 processing.
“In contrast to SARS-CoV-2, the SARS-CoV spike protein lacks this FURIN cleavage site, thus requiring cleavage to facilitate subsequent cellular entry,” Brennand and colleagues write. “This theoretical sequestration of host FURIN activity is a possible explanation for the increased infectivity of SARS-CoV-2.”
What did the current study involve?
To determine whether host variants that may influence SARS-CoV-2 host cell entry could contribute to inter-individual variability in COVID-19 symptoms, the researchers evaluated FURIN gene variants in cell-derived lungs. human-induced pluripotent stem (hiPSC). , intestinal and brain models.
Allelic conversion to FURIN rs4702 in alveolospheres and neurons affects SARS-CoV-2 infection. Representative immunofluorescence staining against SARS-CoV-2 nucleocapsid (N) protein (red), epithelial marker EPCAM (green) and DAPI (blue). The alveolospheres were generated from the C2 FURIN rs4702 AA and GG lines and were infected with mock or a MOI of 0.5 SARS-CoV-2 for 24 hours. Scale bar: 100 μm.
The results showed the importance of furin as a mediator of SARS-CoV-2 infection and demonstrated that a common variant in the FURIN gene is capable of influencing SARS-CoV-2 infection in vitro.
More specifically, the CRISPR / Cas9-mediated allelic conversion of the rs4702 variant from AA to GG resulted in decreased expression of the target cis FURIN gene in neurons and alveolar cells, and a reduction in SARS-CoV infection. -two.
What are the implications of the study?
The study findings have shown that a single noncoding SNP (single nucleotide polymorphism) is sufficient to impact SARS-CoV-2 infection in human neurons and alveolar cells, say Brennand and colleagues.
“Therefore, we provide a proof-of-principle finding that common genetic variation can affect viral infection and thus contribute to clinical heterogeneity in SARS-CoV-2,” the team writes.
The researchers say the results suggest that uncovering the genetic underpinnings of the SARS-CoV-2 results could help predict susceptibility to COVID-19, as well as facilitate the development of precision prevention and treatment approaches.
“Ongoing genetic studies will help better identify people at high risk, predict clinical complications, and facilitate the discovery of drugs that can treat the disease,” they conclude.
*Important news
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behavior, or be treated as established information.
