Free SARS-CoV-2 Spike Protein S1 Particles May Play a Role in the Pathogenesis of COVID-19 Infection

Letarov, Andrey V.; Babenko, Vladislav V.; Kulikov, Eugene E.

doi:10.1134/s0006297921030032

Cited by 46 publications

(51 citation statements)

References 32 publications

(54 reference statements)

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“…If this hypothesis is correct, the virus can directly cause acidosis, and this regulation should be added to the scheme on Figure 1 . Letarov and co-authors proposed that the particles released because of spontaneous activation of S1 spikes can bind to the receptor and cause a decrease in the representation of ACE2 on uninfected cells, which can lead to a local imbalance of the renin-angiotensin system and even greater activation of thrombosis [ 78 ].…”

Section: Hypotheses Of Covid-19 Related Acidosismentioning

confidence: 99%

The Role of Acidosis in the Pathogenesis of Severe Forms of COVID-19

Nechipurenko

Semyonov

Lavrinenko

et al. 2021

Biology

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COVID-19 has specific characteristics that distinguish this disease from many other infections. We suggest that the pathogenesis of severe forms of COVID-19 can be associated with acidosis. This review article discusses several mechanisms potentially linking the damaging effects of COVID-19 with acidosis and shows the existence of a vicious cycle between the development of hypoxia and acidosis in COVID-19 patients. At the early stages of the disease, inflammation, difficulty in gas exchange in the lungs and thrombosis collectively contribute to the onset of acidosis. In accordance with the Verigo-Bohr effect, a decrease in blood pH leads to a decrease in oxygen saturation, which contributes to the exacerbation of acidosis and results in a deterioration of the patient’s condition. A decrease in pH can also cause conformational changes in the S-protein of the virus and thus lead to a decrease in the affinity and avidity of protective antibodies. Hypoxia and acidosis lead to dysregulation of the immune system and multidirectional pro- and anti-inflammatory reactions, resulting in the development of a “cytokine storm”. In this review, we highlight the potential importance of supporting normal blood pH as an approach to COVID-19 therapy.

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Section: Hypotheses Of Covid-19 Related Acidosismentioning

confidence: 99%

The Role of Acidosis in the Pathogenesis of Severe Forms of COVID-19

Nechipurenko

Semyonov

Lavrinenko

et al. 2021

Biology

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“…S1 shedding was also reported to play a role in virion infectivity as the introduction of a D614G mutation significantly enhanced infectivity due to an increased S-protein density in the virion 44 . Finally, others have identified potential mechanisms leading to S-antigen shedding in viral infection and proposed a link between the presence of circulating S-antigen and disease severity 45 . Alternatively, IgG auto-antibodies of diverse specificity might cause the formation of the CD16 triggering sICs we herein identified.…”

Section: Circulating Sics Contribute To Covid-19 Disease Severitymentioning

confidence: 99%

Circulating multimeric immune complexes drive immunopathology in COVID-19

Ankerhold

Giese

Kolb

et al. 2021

Preprint

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A dysregulated immune response with high levels of SARS-CoV-2 specific IgG antibodies is a common and distinctive feature of severe or critical COVID-19. Although a robust IgG response is typically considered to be beneficial, an overshooting activation mediated by immune receptors recognizing the Fc part of IgG (FcγRs) is thought to be detrimental and associated with immunopathology. However, direct evidence of FcγR driven immunopathology in COVID-19 is still sparse. Here, we used a cell-based FcγR activation reporter system to systematically analyze SARS-CoV-2 specific IgG responses and IgG-mediated FcγRIII (CD16) activation profiles in COVID-19 patient cohorts categorized by severity of disease. We found that increased CD16 activation by SARS-CoV-2 specific IgG is associated with a known pro-inflammatory IgG modification, namely afucosylation. Further, we identified CD16-reactive soluble IgG immune complexes (sICs) to be present in the serum of COVID-19 patients and show that the resulting CD16 activation by sICs is strongly related to disease severity. Our results provide evidence that CD16 activation by pro-inflammatory SARS-CoV-2 specific IgG together with circulating sICs is a major contributor to COVID-19 immunopathology. These findings highlight the importance of FcγR driven immunopathology in COVID-19. Further, our data highly warrant the development of targeted intervention strategies against IgG driven immunopathology following SARS-CoV-2 infection.

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“…S1 proteins can also cross the blood-brainbarrier [23]. Free S1 particles may also play a role in the pathogenesis of the disease [24,25]. Free spike protein can potentially be released due to spontaneous "firing" of the S protein trimers on the surface of virions, and infected cells liberates free receptor binding domaincontaining S1 particles [24].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19

et al. 2021

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Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) -induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation. Using platelet poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to β and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.

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Free SARS-CoV-2 Spike Protein S1 Particles May Play a Role in the Pathogenesis of COVID-19 Infection

Cited by 46 publications

References 32 publications

The Role of Acidosis in the Pathogenesis of Severe Forms of COVID-19

The Role of Acidosis in the Pathogenesis of Severe Forms of COVID-19

Circulating multimeric immune complexes drive immunopathology in COVID-19

SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19

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