Platelets mediate inflammatory monocyte activation by SARS-CoV-2 spike protein

Abstract

Infection with SARS-CoV-2, the causative agent of COVID-19, causes mild to moderate disease in most patients but carries a risk of morbidity and mortality.Seriously affected individuals manifest disorders of hemostasis and a cytokine storm, but it is not understood how these manifestations of severe COVID-19 are linked. Here, we showed that the SARS-CoV-2 Spike protein engaged the CD42b receptor to activate platelet via two distinct signaling pathways, and promoted platelet-monocyte communication through the engagement of P-selectin/PGSL-1 and CD40L/CD40, which led to pro-inflammatory cytokine production by monocytes. These results explain why hypercoagulation, monocyte activation and a cytokine storm are correlated in severely affected COVID-19 patients, and suggest a potential target for therapeutic intervention.

Platelet‐leukocyte interactions in COVID‐19: Contributions to hypercoagulability, inflammation, and disease severity

“…In vitro infection of platelets from healthy volunteers shows that platelets recognize and respond to SARS‐CoV‐2 becoming activated 21,28,41,42 . Similar results have been observed in platelets exposed to recombinant Spike protein and Spike‐containing pseudovirus 21,41,43 . SARS‐CoV‐2‐induced platelet activation in vitro is inhibited by competition with recombinant ACE‐2, suggesting platelet activation through the Spike receptor‐binding domain 41 .…”

“…19 Platelets activated by SARS-CoV-2 Spike protein also bind to monocytes through P-selectin and CD40-L, and signal proinflammatory monocyte activation with high IL-1β expression. 43 Similarly, results from our group show that platelets from COVID-19 patients or in vitro-infected platelets also induce a proinflammatory program in monocytes, which is induced by P-selectin and integrin α IIb /β 3 binding and is amplified by TF signaling. 46 Platelet activation and monocyte TF expression positively correlate with plasma levels of D-dimers, supporting a role in hypercoagulability.…”

“…Mechanistically, platelets from severe COVID‐19 patients induced monocyte TF expression depending on P‐selectin and integrin α IIb /β 3 signaling (Figure 1C). 19 Platelets activated by SARS‐CoV‐2 Spike protein also bind to monocytes through P‐selectin and CD40‐L, and signal proinflammatory monocyte activation with high IL‐1β expression 43 . Similarly, results from our group show that platelets from COVID‐19 patients or in vitro‐infected platelets also induce a proinflammatory program in monocytes, which is induced by P‐selectin and integrin α IIb /β 3 binding and is amplified by TF signaling 46 .…”

“…Different studies using similar techniques to detect ACE‐2 have shown that platelets express 28,41 and do not express ACE‐2 20,21,23,27,42 . Alternative receptors for SARS‐CoV‐2 attachment in platelets, including CD147 and CD42b, have been proposed 21,27,42,43 21 .…”

Platelets as Key Factors in Inflammation: Focus on CD40L/CD40

“…Interestingly they observed that the soluble CD40L plasma level decreased overtime while that of sCD62P increased significantly, highlighting the importance of the inflammatory kinetics in COVID-19. Finally, Tianyang Li et al (140) have defined a mechanism that may be a potential therapeutic target in severe COVID-19. They showed that hypercoagulation and the cytokine storm in severe COVID-19 were linked through the Spike-CD42b interaction that activates platelets, the CD40L-CD40 and the P-selectin-PSGL-1 interactions that bind them to monocytes, and the strong induction of IL-1b in monocytes.…”