Interferons can explain why males & older people are more vulnerable to #COVID19.
(Nature, 2 Nov 2020)
Main causes for vulnerability:
IFN-1 deficiencies and autoantibodies to IFN-1.
[A] First, what are Interferons (IFN)?
(1) IFN are cytokines (immune signaling molecules).
(2) Function: Provide innate immune defences by mounting an initial rapid antiviral response.
(3) IFN-I family = IFN-α, IFN-β and IFN-ω.
(4) IFN-I are induced when a cell detects viral RNA through sensors/receptors (Toll like receptors – TLR3, TLR7 and TLR8 found in endosomes inside the cells).
(5) The IFN-I molecules then bind to the cell-surface receptors IFNAR 1 & 2 and block the viral replication and spread.
[B] IFN-I deficiencies lead to uncontrolled viral replication and spread.
Genetic defects leading to IFN-1 deficiency:
(1) TLR3 : Mutations of genes belonging to TLR3 and IFN-I signalling pathways render the gene products incapable of producing or responding to IFN-I.
(2) TLR7: Loss-of-function mutation in TLR7 gene.
[C] IFN-1 Auto-antibodies have the potential to affect the course of SARS-CoV-2 infection.
(1) IFN-1 auto-antibodies are typically seen in older males, which comprise the characteristic vulnerable population of #SARSCoV2. These autoantibodies are different from the standard autoimmune diseases because the latter is seen more in females.
(2) Anti-IFN-I antibodies might arise as a consequence of faulty B-cell- tolerance checkpoints. (Defects in the selection process)
(3) Many such genes are available on X chromosomes. Males would be more vulnerable because they depend on a single copy of these genes on their X chromosome, unlike females, who have a back-up gene copy on a second X chromosome.