Scientists at Sanford Burnham Prebys have identified a set of human genes
that fight SARS-CoV-2 infection, the virus that causes COVID-19. Knowing
which genes help control viral infection can greatly assist researchers'
understanding of factors that affect disease severity and also suggest
possible therapeutic options. The genes in question are related to
interferons, the body's frontline virus fighters.
The study was published in the journal Molecular Cell.
"We wanted to gain a better understanding of the cellular response to
SARS-CoV-2, including what drives a strong or weak response to infection,"
says Sumit K. Chanda, Ph.D., professor and director of the Immunity and
Pathogenesis Program at Sanford Burnham Prebys and lead author of the study.
"We've gained new insights into how the virus exploits the human cells it
invades, but we are still searching for its Achille's heel so that we can
develop optimal antivirals."
Soon after the start of the pandemic, clinicians found that a weak
interferon response to SARS-CoV-2 infection resulted in some of the more
severe cases of COVID-19. This knowledge led Chanda and his collaborators to
search for the human genes that are triggered by interferons, known as
interferon-stimulated genes (ISGs), which act to limit SARS-CoV-2 infection.
Based on knowledge gleaned from SARS-CoV-1, the virus that caused a deadly,
but relatively brief, outbreak of disease from 2002 to 2004, and knowing
that it was similar to SARS-CoV-2, the investigators were able to develop
laboratory experiments to identify the ISGs that control viral replication
in COVID-19.
"We found that 65 ISGs controlled SARS-CoV-2 infection, including some that
inhibited the virus' ability to enter cells, some that suppressed
manufacture of the RNA that is the virus's lifeblood, and a cluster of genes
that inhibited assembly of the virus," says Chanda. "What was also of great
interest was the fact that some of the ISGs exhibited control across
unrelated viruses, such as seasonal flu, West Nile and HIV, which leads to
AIDS".
"We identified eight ISGs that inhibited both SARS-CoV-1 and CoV-2
replication in the subcellular compartment responsible for protein
packaging, suggesting this vulnerable site could be exploited to clear viral
infection," says Laura Martin-Sancho, Ph.D., a senior postdoctoral associate
in the Chanda lab and first author of this study. "This is important
information, but we still need to learn more about the biology of the virus
and investigate if genetic variability within these ISGs correlates with
COVID-19 severity."
As a next step, the researchers will look at the biology of SARS-CoV-2
variants that continue to evolve and threaten vaccine efficacy.
Martin-Sancho notes that they have already started gathering variants for
laboratory investigation,
"It's vitally important that we don't take our foot off the pedal of basic
research efforts now that vaccines are helping control the pandemic,"
concludes Chanda. "We've come so far so fast because of investment in
fundamental research at Sanford Burnham Prebys and elsewhere, and our
continued efforts will be especially important when, not if, another viral
outbreak occurs."
Reference:
Functional Landscape of SARS-CoV-2 Cellular Restriction. Molecular Cell, 2021;
DOI:
10.1016/j.molcel.2021.04.008