D-dimer and CoV-2 spike-immune complexes contribute to the production of PGE2 and proinflammatory cytokines in monocytes

Abstract

An overreactive inflammatory response and coagulopathy are observed in patients with severe form of COVID-19. Since increased levels of D-dimer (DD) are associated with coagulopathy in COVID-19, we explored whether DD contributes to the aberrant cytokine responses. Here we show that treatment of healthy human monocytes with DD induced a dose dependent increase in production of pyrogenic mediator, Prostaglandin E2 (PGE2) and inflammatory cytokines, IL-6 and IL-8. The DD-induced PGE2 and inflammatory cytokines were enhanced significantly by co-treatment with immune complexes (IC) of SARS CoV2 recombinant S protein or of pseudovirus containing SARS CoV-2 S protein (PVCoV2) coated with spike-specific chimeric monoclonal antibody (MAb) containing mouse variable and human Fc regions. The production of PGE2 and cytokines in monocytes activated with DD and ICs was sensitive to the inhibitors of β2 integrin and FcγRIIa, and to the inhibitors of calcium signaling, Mitogen-Activated Protein Kinase (MAPK) pathway, and tyrosine-protein kinase. Importantly, strong increase in PGE2 and in IL-6/IL-8/IL-1β cytokines was observed in monocytes activated with DD in the presence of IC of PVCoV2 coated with plasma from hospitalized COVID-19 patients but not from healthy donors. The IC of PVCoV2 with convalescent plasma induced much lower levels of PGE2 and cytokines compared with plasma from hospitalized COVID-19 patients. PGE2 and IL-6/IL-8 cytokines produced in monocytes activated with plasma-containing IC, correlated well with the levels of spike binding antibodies and not with neutralizing antibody titers. Our study suggests that a combination of high levels of DD and high titers of spike-binding antibodies that can form IC with SARS CoV2 viral particles might accelerate the inflammatory status of lung infiltrating monocytes leading to increased lung pathology in patients with severe form of COVID-19.

Persistent Presence of Spike protein and Viral RNA in the Circulation of Individuals with Post-Acute Sequelae of COVID-19

“…It is now widely recognized that endothelial dysfunction and micro-thromboses play a significant role in acute infection and we see further evidence of this with our finding that D-dimer is positively correlated with circulating levels of total plasma Spike protein (p=0.0249) and EV-associated Spike protein (p<0.01) across all three groups of acute COVID-19 severity. D-dimer is a marker of coagulopathy 30, 31 and is highly correlated with the COVID-19 disease severity 32, 33 . Park et al 32 recently reported that D-Dimer can also form immune complexes with SARS-CoV-2 Spike protein and bound antibodies resulting in activation of monocytes to produce proinflammatory cytokines.…”

“…D-dimer is a marker of coagulopathy 30, 31 and is highly correlated with the COVID-19 disease severity 32, 33 . Park et al 32 recently reported that D-Dimer can also form immune complexes with SARS-CoV-2 Spike protein and bound antibodies resulting in activation of monocytes to produce proinflammatory cytokines. Moreover, endothelial dysfunction may be caused by both direct infection of endothelial cells 34 and by the SARS-CoV-2 components in the bloodstream 35 .…”

Pharmacological Activities of Fingerroot Extract and Its Phytoconstituents Against SARS-CoV-2 Infection in Golden Syrian Hamsters

“…The increased level of PGE 2 in the plasma of COVID-19 patients associated with disease severity, due to its immunosuppressive effect and the disruption of the immune response. 43 , 44 Interestingly, our finding exhibited twofold reduction of PGE 2 level in lung tissues at day 4 post-infection. Thus, fingerroot extract could suppress inflammatory cytokine production in the infected hamsters.…”

Discovery of host-directed modulators of virus infection by probing the SARS-CoV-2–host protein–protein interaction network

“…We experimentally tested seven selected compounds that inhibit the VIPs BRD4, IMPDH2 and HDAC2, along with spautin-1, which inhibits the NIP USP10 and the VIP USP13 ( Table 2 ). The compounds were first tested for modulation of SARS-CoV-2 infection in HEK293T cells that overexpress the key SARS-CoV-2 host factors ACE2 and TMPRSS2 [ 32 ]. Confirmatory experiments were performed in Calu 3 human lung cells [ 33 ], which are well-established targets for SARS-CoV-2 [ 28 ].…”