Study identifies human genes enabling SARS-CoV-2 infection

Last Updated on May 2, 2023 by Joseph Gut – thasso

01 May, 2023 – SARS-CoV-2, like other respiratory viruses, typically initiates infection in the throat and sinuses. But it often spreads from the respiratory tract to other parts of the body, such as the gut, liver, heart, kidneys, brain, blood vessels and pancreas. Infections in these tissues are frequently seen in severe COVID-19 disease and can cause fatal complications including blood clots and organ failure.

Since there exists a very broad variety of the responses of patients when confronted with exposure (which is not the same as actual infection) to SARS-CoV-2, the question comes up, why certain patients get never infected upon exposure to the virus, while others do? Are there predisposing genetic factors involved? The answer may be yes, there are.

In fact, in a recent study which appeared March 13 in Nature Cell Biology, researchers used multiple models of small three-dimensional clumps of human tissue, called organoids, to search for general host factors that influence infections by SARS-CoV-2, the coronavirus that causes COVID-19. They identified CIART as a strong SARS-CoV-2-enabling factor in organoids modeling both lung and heart tissue. The researchers traced CIART’s permissive effect on SARS-CoV-2 infection to its stimulation of the synthesis of small molecules called fatty acids.

CIART (Circadian Associated Repressor Of Transcription) is a protein coding gene. Diseases known to be associated with CIART include Gallbladder Benign Neoplasm and Gallbladder Adenoma. Gene Ontology (GO) annotations related to this gene include core promoter sequence-specific DNA binding and E-box binding.

In the present study, the researchers identified CIART as a key factor in the establishment of the viral infection that causes COVID-19, and demonstrated the power of a multi-organoid approach by revealing a pathway that could be targeted with future drugs to treat or prevent SARS-CoV-2 infection across multiple organ systems. Different human organs tend to respond differently to SARS-CoV-2 infection. Thus, starting with human stem cells, the researchers grew organoids to model bronchial airway tissue, gas-exchanging alveoli tissue deep in the lungs, and heart muscle, all of which are known to be infectible by SARS-CoV-2. The researchers exposed these organoids to different quantities of the SARS-CoV-2 and identified 18 genes that become consistently more active during infection in the selected  organoids and at different viral doses.

The scientists deleted then these genes from the organoids, one by one, to see the effect on virus levels. The results suggested that while 13 of the genes appear to have some role in enabling SARS-CoV-2 so that virus levels are lower when they are absent, the strongest enabler by far was the CIART gene. The latter encodes a transcription factor protein that normally works in the cell nucleus to regulate the activity of other genes. It had never before been linked to COVID-19 disease. Further tests indicated that the CIART gene normally enhances the ability of SARS-CoV-2 to reproduce by boosting the production of certain fatty acids via a pathway known as the RXR pathway. Treating the organoids with experimental RXR inhibitor compounds before exposure to SARS-CoV-2 effectively blocked the virus’s ability to establish infection in the tissues. The findings suggest that targeting RXR or its upstream controller, the CIART protein, could be an effective way to treat SARS-CoV-2 infection, or even to prevent it over the short-term.

The true novelty of these approaches, according to the research team, would be that it alters the host side of the virus-host interaction. Most antiviral approaches to SARS-CoV-2 have focused on targeting some component of the virus itself, but, unfortunately, the virus usually evolves rapidly around that (see all the SARS-CoV-2 variants that aready exist or ar in the  expected making). It may be a lot harder for the virus to adapt to changes on the host side. Research now continues to study how CIART influences the viral life cycle, and how best to block its infection-enhancing effect.

Pleas note that thasso in this context already had a couple of articles in the past which mostly addressed the possible genetics behind the COVId-19 disease such as Rare cases of anaphylaxis with COVID-19 vaccines, Could DNA testing help the most seriously affected Covid-19 patients?, Covid-19 Vaccines: Is there genetic predisposition for thrombosis?, Do genomic regions influence the severity of Covid-19 disease?, Serious adverse events after Covid-19 vaccination occur but are very rare, or Genetic links revealed between severe COVID-19 and other diseases, and so on. Also, on thasso, under resources-useful links, you will find a section called Covid-19 (Diseases, Vaccines, Recovery) with links  to most informative Covid-19 resources .

See here a sequence on aspects of host and/or viral genetics in infection:

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