Could it be that an actual glitch in type 1 interferon (IFN) signaling is associated with people who experienced more severe SARS-CoV-2 disease progression? Put another way, was an individual, case by case abnormal reaction the explanation behind why some people get deathly ill behind COVID-19 while others don’t even notice they’re sick? The recent COVID Human Genetic Effort (CHGE) study may have some answers.

Set up in February 2020 by Jean-Laurent Casanova of Rockefeller University and Helen Su of the National Institute of Allergy and Infectious Diseases (NIAID), the study team sought to better understand why some COVID-19 patients become deathly ill while others are asymptomatic.  TrialSite provides a research breakdown of this lab work conducted in the laboratory of infectious diseases of Jean-Laurent Casanova and Laurent Abel.

Where did this research occur?

France and the USA.

What’s the source of the data?

Biosamples from a large number of patients in France. Researcher Paul Bastard, winner of the inaugural Michelson Philanthropies & Science Prize for Immunology rode his bike to Paris hospitals to collect the samples as part of the study.Subscribe to the Trialsitenews “COVID-19” ChannelNo spam – we promise

What did the results of the analyses reveal?

After conducting sequencing studies from a large pool of the samples, the study authors found consistently that hospitalized patients suffering from severe COVID-19 had a glitch in type I interferon (IFN) signaling.

Normally, Type I IFNs are secreted by infected cells to help fight off viruses. Yet in some of the patients, the research team found that they developed an autoimmune response with autoantibodies attacking type I IFNs blocking their antiviral effect. This abnormal reaction can contribute to worsening SARS-CoV-2-triggered conditions. 

What’s the research takeaway?

Specific autoantibody responses against IFN could be a driver triggering more severe COVID-19, particularly in older patients but also in younger people who present with life-threatening COVID-19.  Could this be a clue as to why COVID-19 is fatal for some and not others?

Is age also a factor?

Yes. The study team reports that the triggering of autoantibodies against IFNs in COVID-19 patients appears to intensify with age. 

What precision-therapy-based advancement is now possible?

A screening tool that could help identify patients facing the highest risk of life-threatening complications.

According to Researcher Paul Bastard, a technique called ELISA could possibly be employed for screening autoantibodies against type I IFNs.

What other factors did the team identify based on the French samples?

One potential second factor associated with severe COVID-19 outcomes includes a rare mutation in genes controlling for type I IFNs. The authors noted that a gene that encodes the receptor TLR7, involved in initiating type I IFN responses, is also screen able—although more challenging.

What is COVID Human Genetic Effort (CHGE)?

CHGE or the COVID Human Genetic Effort is an international consortium aiming to discover the human genetic and immunological bases of the various clinical forms of SARS-CoV-2 infection. CHGE searches for:

(I) Monogenic or digenic inborn errors of immunity (IEI), rare or common, underlying severe forms of COVID-19 in previously healthy individuals, including severe pneumonia, multisystem inflammatory syndrome in children (MIS-C), Long COVID, COVID Toes, etc.

(ii) Phenocopies of these monogenic IEI, such as auto-antibodies neutralizing gene products of loci whose variants underlie these IEI (e.g., auto-antibodies to type I IFNs mimicking inborn errors of type I IFNs).

(iii) Single-gene variants, rare or common, which make certain individuals resistant to the infection by the SARS-CoV2 itself, despite repeated exposure, or resistant to the development of clinical manifestations despite infection.

With these three projects, the COVID Human Genetic Effort aims to discover truly causative genetic and/or immunological anomalies, rare or common, and decipher in depth the molecular, cellular, and immunological mechanisms by which they cause resistance to viral infection or disease, or predisposition to one or another form of severe disease (Casanova JL & Su HC Cell 2020).

Lead Research/investigator

Paul Bastard, PhD, Imagine Institute, INSERM, University of Paris

Jean-Laurent Casanova, MD, PhD, Rockefeller University

Helen Su, MD, PhD, National Institute of Allergy and Infectious Diseases

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