Silence of the Genes or their products
Why Some Patients Have Severe COVID? Why More Males dies of COVID and Why the disease is more mortal in elderlies? The genetics underlying severe COVID-19There is a crucial role of type I IFNs that offers protective immunity against SARS-CoV-2. After the initial infection, small amounts of IFNs are induced by the virus that become crucial in offering a protection against severe disease. However, few patients have developed neutralizing auto-Abs against type I IFNs, like inborn errors of type I IFN production. This sways the balance in favor of the virus and results in devastating disease due to absence of innate and adaptive immune responses.
Two pathways in which these genes can be perturbed are –
1) Genetic mutations resulting in deletion or functional compromise of the type I IFNs.
2) Development of antibobodies to type I IFNs. The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs).
Individuals who lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Adaptive autoimmunity impairs innate and intrinsic antiviral immunity.
A crucial role of type I IFNs in protective immunity against SARS-CoV-2. These auto-Abs against type I IFNs were clinically silent until the patients were infected with SARS-CoV-2—a poor inducer of type I IFNs which suggests that the small amounts of IFNs induced by the virus are important for protection against severe disease. At least 10% of patients with life-threatening COVID-19 pneumonia have neutralizing auto-Abs against type I IFNs. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system. Genetics may determine the clinical course of the infection. High titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified.
A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least
a) 2.6% of women and
b) 12.5% of men.
Provide an explanation for the excess of men among patients with life-threatening COVID-19 and the increase in risk with age. They also provide a means of identifying individuals at risk of developing life-threatening COVID-19 and ensuring their enrolment in vaccine trials. Finally, they pave the way for prevention and treatment, including plasmapheresis, plasmablast depletion, and recombinant type I IFNs not targeted by the auto-Abs (e.g., IFN-β).2) At least 10% of patients with life-threatening COVID-19 pneumonia have neutralizing auto-Abs against type I IFNs. With our accompanying description of patients with inborn errors of type I IFNs and life-threatening COVID-19, this study highlights the crucial role of type I IFNs in protective immunity against SARS-CoV-2.These auto-Abs against type I IFNs were clinically silent until the patients were infected with SARS-CoV-2—a poor inducer of type I IFNs which suggests that the small amounts of IFNs induced by the virus are important for protection against severe disease. The neutralizing auto-Abs against type I IFNs, like inborn errors of type I IFN production, tip the balance in favor of the virus, which results in devastating disease with insufficient, and even perhaps deleterious, innate and adaptive immune responses.
At least for now, a piece of puzzle is solved. We now know that if Type 1 IFN develop auto-antibodies, or have mutations in the genes, or any (gene) silencing ensues, then it is possible, you may have individual vulnerability. The last aspect, silencing of the genes through methylation, though not yet proven may be potentially possible. Let us wait for science to unravel more.
What is typically called as translational medicine, it takes time to transfer the technological advances from laboratories to bed side. However, with COVID-19, we have seen a significantly reduced latency from lab to bed side (bed side here means for common use in practice).
Science 23 Oct 2020: Vol. 370, Issue 6515, eabd4585; DOI: 10.1126/science.abd4585