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.

中文翻译：

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Perforin、COVID-19 和可能的致病性自身炎症反馈回路

在 COVID-19 感染期间，自然杀伤 (NK) 细胞功能降低会导致病毒清除受损和免疫反应失调。这种失调导致细胞因子过度产生、中性粒细胞/淋巴细胞比率升高和单核细胞增多症。这反过来又增加了 IL-6 的表达，从而促进了疤痕和血栓的形成。过量的IL-6还通过下调穿孔素表达导致NK功能进一步降低，从而形成致病性自身炎症反馈回路。细胞毒性穿孔素/颗粒酶系统是 NK 细胞和细胞毒性 T 淋巴细胞消除病毒感染宿主细胞的主要机制，也是它们在调节对微生物感染的免疫反应中的核心作用。这里，我们提供的流行病学证据表明穿孔素表达与对 COVID-19 的耐药性之间存在关联。此外，我们概述了致病性自身炎症反馈回路的运作方式以及该回路与严重 COVID-19 相关基因的关系。这种自身炎症循环可能适用于协同多模式治疗。