Long‐lived macrophage reprogramming drives spike protein‐mediated inflammasome activation in COVID‐19

Abstract

Innate immunity triggers responsible for viral control or hyperinflammation in COVID‐19 are largely unknown. Here we show that the SARS‐CoV‐2 spike protein (S‐protein) primes inflammasome formation and release of mature interleukin‐1β (IL‐1β) in macrophages derived from COVID‐19 patients but not in macrophages from healthy SARS‐CoV‐2 naïve individuals. Furthermore, longitudinal analyses reveal robust S‐protein‐driven inflammasome activation in macrophages isolated from convalescent COVID‐19 patients, which correlates with distinct epigenetic and gene expression signatures suggesting innate immune memory after recovery from COVID‐19. Importantly, we show that S‐protein‐driven IL‐1β secretion from patient‐derived macrophages requires non‐specific monocyte pre‐activation in vivo to trigger NLRP3‐inflammasome signaling. Our findings reveal that SARS‐CoV‐2 infection causes profound and long‐lived reprogramming of macrophages resulting in augmented immunogenicity of the SARS‐CoV‐2 S‐protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling.

Inflammatory Response in COVID-19 Patients Resulting from the Interaction of the Inflammasome and SARS-CoV-2

“…The interplay between ACE2 and SARS-CoV-2 also triggers the NLRP3 inflammasome [ 23 ]. The SARS-CoV-2 S protein was recently shown to prime inflammasome formation and drive NLRP3 inflammasome activation in macrophages derived from patients with COVID-19 [ 8 ]. The SARS-CoV-2 S1 protein increases the NLRP3 level and caspase-1 activity in human PBMCs [ 9 ].…”

“…Higher IL-1β levels are observed in the plasma of severely ill patients with COVID-19 [ 28 ]. The SARS-CoV-2 S protein promotes NLRP3 inflammasome activation and IL-1β secretion in COVID-19 patient-derived macrophages, and stimulation of the S protein upregulates both IL-1β and TNF-α; however, TNF-α is secreted in an NLRP3 inflammasome-independent manner [ 8 ]. In RNA sequencing, the SARS-CoV-2 S protein is observed to upregulate innate immunity-associated genes and several signalling pathways, including pro-inflammatory pathways, the NOD-like receptor, and the inflammasome signalling pathway.…”

“…In RNA sequencing, the SARS-CoV-2 S protein is observed to upregulate innate immunity-associated genes and several signalling pathways, including pro-inflammatory pathways, the NOD-like receptor, and the inflammasome signalling pathway. In particular, the S protein increases TLR2 in CD14 + macrophages, and the S protein is correlated with a high level of TLR2 in cells derived from patients with COVID-19 [ 8 ]. In a single-cell RNA sequencing analysis, the upregulation of caspase expression in immune cells is observed in blood from patients with COVID-19.…”

“…S protein-induced inflammasome activation is reversed by treatment with MCC950, and the release of IL-1β is also blocked in spite of S-protein exposure. Similarly, treatment with VX-765 (a caspase-1 inhibitor) suppresses NLRP inflammasome activation and the secretion of IL-1β [ 8 ]. Additionally, the development of nanovesicles through biomedical engineering may prevent the cytokine storm that occurs in patients with COVID-19 [ 60 ].…”

“…There have been a growing number of studies on inflammasome activation induced by SARS-CoV-2 infection and COVID-19 severity in patients [ 2 , 7 ]. In particular, the SARS-CoV-2 S protein primes and drives the activation of the nucleotide-binding oligomerisation domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, and the SARS-CoV-2 S1 protein triggers inflammasome activity alone [ 8 , 9 ]. The inflammasome is a macromolecular immune complex in cells, and it is involved in the extracellular release of IL-1β and IL-18 as well as in pyroptotic cell death [ 10 ].…”