Junqueira Caroline, Crespo Ângela, Ranjbar Shahin, Ingber Jacob, Parry Blair, Ravid Sagi, de Lacerda Luna B, Lewandrowski Mercedes, Clark Sarah, Ho Felicia, Vora Setu M, Leger Valerie, Beakes Caroline, Margolin Justin, Russell Nicole, Gehrke Lee, Adhikari Upasana Das, Henderson Lauren, Janssen Erin, Kwon Douglas, Sander Chris, Abraham Jonathan, Filbin Michael, Goldberg Marcia B, Wu Hao, Mehta Gautam, Bell Steven, Goldfeld Anne E, Lieberman Judy
medRxiv. 2021 Mar 8:2021.03.06.21252796. doi: 10.1101/2021.03.06.21252796.
SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in some patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes are sentinel blood cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators. Here we show that ~10% of blood monocytes in COVID-19 patients are dying and infected with SARS-CoV-2. Monocyte infection, which depends on antiviral antibodies, activates NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD cleavage and relocalization. Signs of pyroptosis (IL-1 family cytokines, LDH) in the plasma correlate with development of severe disease. Moreover, expression quantitative trait loci (eQTLs) linked to higher expression increase the risk of severe COVID-19 disease (odds ratio, 1.3, p<0.005). These findings taken together suggest that antibody-mediated SARS-CoV-2 infection of monocytes triggers inflammation that contributes to severe COVID-19 disease pathogenesis.
Antibody-mediated SARS-CoV-2 infection of monocytes activates inflammation and cytokine release.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）可导致急性呼吸窘迫，在某些患者中可进展为多器官功能衰竭和死亡。尽管重症冠状病毒病（COVID-19）与过度炎症有关，但SARS-CoV-2如何引发炎症尚不清楚。单核细胞是一种哨兵血细胞，可感知侵入性感染以形成炎性小体，从而激活半胱天冬酶-1和gasdermin D（GSDMD）孔道，导致炎性死亡（细胞焦亡）以及白细胞介素-1家族细胞因子（强效炎性介质）的加工和释放。在此我们表明，COVID-19患者中约10%的血液单核细胞正在死亡并感染了SARS-CoV-2。单核细胞感染依赖于抗病毒抗体，可激活NLRP3和AIM2炎性小体、半胱天冬酶-1以及GSDMD的切割和重新定位。血浆中的细胞焦亡迹象（白细胞介素-1家族细胞因子、乳酸脱氢酶）与重症疾病的发展相关。此外，与较高表达相关的表达定量性状位点（eQTL）会增加患重症COVID-19疾病的风险（优势比，1.3，p<0.005）。综合这些发现表明，抗体介导的SARS-CoV-2对单核细胞的感染会引发炎症，这对重症COVID-19疾病的发病机制有影响。
抗体介导的SARS-CoV-2对单核细胞的感染会激活炎症和细胞因子释放。
