SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release

Abstract

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 GSDMD 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.

Diabetes and coronavirus (SARS-CoV-2): Molecular mechanism of Metformin intervention and the scientific basis of drug repurposing

“…An in vitro study conducted in monocytes under increasing glucose concentrations showed elevated viral load, ACE2, and interleukin (IAU : PleasenotethatILhasbeendefine L)-1β expression with SARS-CoV-2 infection [34]. In parallel, unpublished reports on clinical samples confirmed SARS-CoV-2 infection in monocytes and indication of pyroptosis in monocytes isolated from COVID-19 patients [35]. Unlike the infections with other respiratory viruses, a glycolytic trait was identified in monocytes infected with SARS-CoV-2.…”

Severe Clinical Worsening in COVID-19 and Potential Mechanisms of Immune-Enhanced Disease

“…While monocytes derived from healthy donors were inefficiently infected by SARS-CoV-2, pre-incubation with anti-spike antibody or patient plasma was reported to enhance productive infection of monocytes. This effect was abrogated by Ig depletion of patient plasma ( 50 ). Moreover, positive- and negative-strand SARS-CoV-2 RNA is detected in alveolar macrophages recovered from BALF of intubated patients with severe COVID-19, and in monocyte-derived macrophage and DC subsets that do not express ACE2 ( 51 ).…”

Inflammasome activation at the crux of severe COVID-19

“…All of these cell types are competent to activate inflammasomes and undergo pyroptosis 55 – 57 . Interestingly, monocytes from patients with COVID-19 showed no increase in staining for annexin V, yet about ~10% took up small dyes, a sign of disrupted plasma membranes, which is a pattern indicative of pyroptosis or other forms of programmed necrosis 58 .…”

“…Support for the hypothesis that IL-1β acts as a pleiotropic proinflammatory cytokine to unleash the inflammatory response is provided by the in vitro observation that exogenous IL-1 receptor antagonist (IL-1RA) completely abolishes IL-6 and TNF secretion in SARS-CoV-2-infected primary monocytes 65 . Another strong indication of inflammasome activation in COVID-19 is the fact that IL-18, the processing and secretion of which depend on inflammasome and GSDMD activation, is associated with severe COVID-19 and has emerged as a highly predictive biomarker of death 52 , 58 , 61 , 66 , 67 .…”