The double edged interferon riddle in COVID-19 pathogenesis
- PDF / 602,905 Bytes
- 2 Pages / 595.276 x 790.866 pts Page_size
- 54 Downloads / 145 Views
Open Access
LETTER
The double edged interferon riddle in COVID‑19 pathogenesis Rahul Gupta*
Dear Editor, In their recent article [1], Jalkanen et al. discuss about the prospective usage of interferon beta 1 in managing COVID-19 and substantiating usage of intravenous route of administration over subcutaneous route. I would like to humbly add some views to it: there has been two varying reported type I interferon responses in COVID19 pathogenesis [2]: one stating the suppression of host antiviral type I interferons (IFNs) and interferon stimulated genes (ISGs) and other stating increased expression of different ISGs, with further inductions of chemokines and cytokines [2]. The viral Nsps (particularly Nsp1) and the ORFs (particularly ORF 6) are known to antagonise the host antiviral IFNs initially by suppressing/delaying their expressions, leading to viral persistence and propagating inflammations. Hence, neither type I IFN nor type III IFN, which are known hard-wired for providing antiviral immunity, was activated in early stages of COVID19. However, SARS-CoV-2 at 2 days post-infection (dpi), induced ISGs having antiviral action (Rsad2, Ifit, Mx2, Oas3, etc.) and at 7dpi, ISGs having potentiating IFN mediated inflammatory signalling (Ifihi,Irf7,Stat1,Ifnar1/ 2,Tyk2,etc.) [3]. As the disease progresses towards severity, the IFNs exacerbate the pathophysiology with specific inflammatory signatures [2]. Hence, cellular response to type 1 IFN (thru ISGs) towards later stages of infection is immunopathogenic. Neutrophils provide the first line of innate immune defence. Neutrophil attracting chemokines (CXCL1, *Correspondence: [email protected] Kolkata, India
CXCL2, CXCL8, S100A9) and cognate receptor (CXCR2) were found to be activated in early stages (1–3 dpi) [3]. COVID-19 is manifested with necrophilia having high neutrophil-to-lymphocyte ratio. Type 1 IFNs are known to inhibit neutrophil migration by downregulating neutrophil chemoattractants production (CXCL1/2) [4]. Other than phagocytosis, neutrophils have another capacity to contain pathogens, by forming neutrophil extracellular traps (NETs). NETs are mesh-like structures of DNA and proteins from degrading neutrophils (by neutrophil elastase) which entrap pathogens. Interestingly against leishmania, IFNAR−/− mice showed enhanced neutrophil elastase activity, with better infiltrations. Aberrant production of NETs have been known to cause severe COVID-like pathophysiologies—thrombosis, lung damage, ARDS, multiorgan damage, etc. [5]. Indeed, severe COVID-19 patients reported of higher amount of NETosis remnants like cell-free DNA, myeloperoxidase-DNA and citrullinated histone H3 [5]. These molecules further propagate inflammation by inducing IL-1β production thru inflammasome activation. The initial type 1IFN suppression could lead to enhanced infiltration of neutrophils, NET formation and ensuing pathophysiologies. Early administration of IFNβ has proved beneficial [1, 2]; hence, the “double edged sword” be tried prudently with respect to time and dosage. Ac
Data Loading...
