Interferons May Hold the Key to the Severity of COVID-19
By Sahana Shankar, Ph.D. Candidate
A COVID-19 diagnosis can result in a wide spectrum of clinical conditions ranging from asymptomatic, mild flu-like symptoms, severe pulmonary distress to multiple organ failure. Since discovering the SARS-CoV-2 virus in January 2020, there have been numerous studies to understand how it manifests differently in the global population. Much work has been done on emerging strains of the virus based on geographies, risk factors that make certain groups more susceptible, how the immune system responds to COVID-19, how long patients can develop neutralizing antibodies, and the risk of second infections.
A recent publication led by Dr. Qian Zhang from the lab of Dr. Jean-Laurent Casanova at Rockefeller University and Dr. Helen Su at the National Institute of Allergy and Infectious Diseases focuses on how some people might have inborn immunity defects in the interferon pathway. In a study involving 659 COVID-19 patients, the authors show that these defects make them highly at risk for COVID-19 and are resistant to traditional therapy. All participants in the study were hospitalized for severe pneumonia caused by SARS-CoV-2.
Interferons (IFNs) are considered antiviral superheroes of our immune system, which can detect specific patterns of viral DNA and induce cytokines to clear the viral infection. They are broadly classified into types I, II, and III. Type I interferons are known to recognize and fight the influenza virus effectively.
Since the SARS-CoV-2 virus is genetically similar to the Influenza virus, the researchers tested the patients’ genome for any defects in interferon genes. Analyzing the whole genome sequence of over 600 COVID-19 patients, the authors looked for genetic errors and found that 13 loci in core genes of the interferon-mediated immune pathway showed over 100 variants. Further analysis revealed that 12 of the candidate loci were autosomal, and one was X-linked. There were no copy number variations for these genes.
Some of the identified variants (3.5%) were predicted to be loss-of-function, and some were missense or in-frame indels. Comparing these variants with a sample set of 534 controls of mild SARS-CoV-2 infection, they found only one loss-of-function variation at the 13 candidate loci, suggesting that these variants are enriched in severe COVID-19 cases. A random experimental analysis of 113 of the variants in overexpression systems confirmed that 24 of them were deleterious due to loss /reduced expression, and 89 were biochemically neutral.
Since most of the enriched loss-of-function-variants were known to be essential for TLR3- / IRF7-dependent interferon activation, the authors zeroed in on TLR-3 and IRF7 receptors as key markers for interferon deficiency. They demonstrated that patients with low expression of either marker could not produce detectable interferons against SARS-CoV-2. While the IRF7 deficiency caused a reduction in type I IFNs, TLR3 was important for fibroblast-driven IFN immunity, indicating that patients with mutations in the TLR3-/IRF7-dependent IFN pathway are more vulnerable to COVID-19.
In an accompanying research study published back-to-back with this study in Science, the Casanova lab from Rockefeller University also provided some clues as to how men and women respond differently to COVID-19 due to the presence of auto-antibodies against type I IFNs, which was reported in 12.5% of male patients as compared to 2.6% female patients.
“These findings provide compelling evidence that the disruption of type I interferon is often the cause of life-threatening COVID-19. And at least in theory, such interferon problems could be treated with existing medications and interventions,” Casanova said in a statement. “COVID-19 may now be the best understood acute infectious disease in terms of having a molecular and genetic explanation for nearly 15 percent of critical cases across diverse ancestries.”
These two papers are the first of results published from the COVID Human Genetic Effort (CHGE), a multi-national consortium that involves data collection and analysis across more than 50 sequencing hubs, more than 100 participating labs and hospitals around the world. The mission of CHGE is to identify genetic pathways involved in COVID-19 in patients that get severely ill and develop new preventative and therapeutic strategies.
Editor: Rajaneesh K. Gopinath, Ph.D.
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