Perforin, COVID‐19 and a possible pathogenic auto‐inflammatory feedback loop

Cunningham, Louise Kimber Ian Basketter David Simmonds Peter McSweeney Sheila Tziotzios Christos McFadden John P.

During COVID‐19 infection, reduced function of natural killer (NK) cells can lead to both compromised viral clearance and dysregulation of the immune response. Such dysregulation leads to overproduction of cytokines, a raised neutrophil/lymphocyte ratio and monocytosis. This in turn increases IL‐6 expression, which promotes scar and thrombus formation. Excess IL‐6 also leads to a further reduction in NK function through downregulation of perforin expression, therefore forming a pathogenic auto‐inflammatory feedback loop. The perforin/granzyme system of cytotoxicity is the main mechanism through which NK cells and cytotoxic T lymphocytes eliminate virally infected host cells, as well as being central to their role in regulating immune responses to microbial infection. Here, we present epidemiological evidence suggesting an association between perforin expression and resistance to COVID‐19. In addition, we outline the manner in which a pathogenic auto‐inflammatory feedback loop could operate and the relationship of this loop to genes associated with severe COVID‐19. Such an auto‐inflammatory loop may be amenable to synergistic multimodal therapy. [ABSTRACT FROM AUTHOR] Copyright of Scandinavian Journal of Immunology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)