Mast cells promote viral entry of SARS-CoV-2 via formation of chymase/spike protein complex

Liu, Shuang; Suzuki, Yoshito; Takemasa, Erika; Watanabe, Ryusuke; Mogi, Masaki

doi:10.1016/j.ejphar.2022.175169

Cited by 17 publications

(12 citation statements)

References 24 publications

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“…Interestingly, a recent study in mast cell-deficient mice showed that that a lack of mast cells may lead to increased viral uptake of upper respiratory tract cells, leading to development of more severe clinical disease. Furthermore, these mast cell-deficient mice also exhibited persistent infection in the post-acute setting ( 35 ). Together with the interpretation of our findings, these studies suggest that a defect in mast cell responses may contribute to severe COVID-19 disease.…”

Section: Discussionmentioning

confidence: 99%

Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity

et al. 2023

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BackgroundDysregulated immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are thought to underlie the progression of coronavirus disease 2019 (COVID-19) to severe disease. We sought to determine whether early host immune-related gene expression could predict clinical progression to severe disease.MethodsWe analysed the expression of 579 immunological genes in peripheral blood mononuclear cells taken early after symptom onset using the NanoString nCounter and compared SARS-CoV-2 negative controls with SARS-CoV-2 positive subjects with mild (SARS+ Mild) and Moderate/Severe disease to evaluate disease outcomes. Biobanked plasma samples were also assessed for type I (IFN-α2a and IFN-β), type II (IFN-γ) and type III (IFN-λ1) interferons (IFNs) as well as 10 additional cytokines using multiplex immunoassays.ResultsWe identified 19 significantly deregulated genes in 62 SARS-CoV-2 positive subject samples within 5 days of symptom onset and 58 SARS-CoV-2 negative controls and found that type I interferon (IFN) signalling (MX1, IRF7, IFITM1, IFI35, STAT2, IRF4, PML, BST2, STAT1) and genes encoding proinflammatory cytokines (TNF, TNFSF4, PTGS2 and IL1B) were upregulated in both SARS+ groups. Moreover, we found that FCER1, involved in mast cell activation, was upregulated in the SARS+ Mild group but significantly downregulated in the SARS+ Moderate/Severe group. In both SARS+ groups we discovered elevated interferon type I IFN-α2a, type II IFN and type III IFN λ1 plasma levels together with higher IL-10 and IL-6. These results indicate that those with moderate or severe disease are characterised by deficiencies in a mast cell response together with IFN hyper-responsiveness, suggesting that early host antiviral immune responses could be a cause and not a consequence of severe COVID-19.ConclusionsThis study suggests that early host immune responses linking defects in mast cell activation with host interferon responses correlates with more severe outcomes in COVID-19. Further characterisation of this pathway could help inform better treatment for vulnerable individuals.

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Section: Discussionmentioning

confidence: 99%

Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity

et al. 2023

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“…MCs are among the first immune cells to be activated in response to penetration of the SARS-CoV-2 virus [80]. However, the study conducted by Liu et al should be mentioned, which suggests that MCs contribute to SARS-CoV-2 entry by generating the chymase/spike protein complex, highlighting a possible dual role of MCs in the pathology of COVID-19 [81].…”

Section: Role Of Mast Cells In Pathologymentioning

confidence: 98%

Mast Cell Activation Syndrome Update—A Dermatological Perspective

Mihele

Nistor

Bruma

et al. 2023

JPM

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Mast cells (MCs) are infamous for their role in potentially fatal anaphylaxis reactions. In the last two decades, a more complex picture has emerged, as it has become obvious that MCs are much more than just IgE effectors of anaphylaxis. MCs are defenders against a host of infectious and toxic aggressions (their interactions with other components of the immune system are not yet fully understood) and after the insult has ended, MCs continue to play a role in inflammation regulation and tissue repair. Unfortunately, MC involvement in pathology is also significant. Apart from their role in allergies, MCs can proliferate clonally to produce systemic mastocytosis. They have also been implicated in excessive fibrosis, keloid scaring, graft rejection and chronic inflammation, especially at the level of the skin and gut. In recent years, the term MC activation syndrome (MCAS) was proposed to account for symptoms caused by MC activation, and clear diagnostic criteria have been defined. However, not all authors agree with these criteria, as some find them too restrictive, potentially leaving much of the MC-related pathology unaccounted for. Here, we review the current knowledge on the physiological and pathological roles of MCs, with a dermatological emphasis, and discuss the MCAS classification.

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“…MCAS therefore may be a direct result of continued coagulopathy, even if activation was initiated via antigen exposure. Spike protein persistence may be a chronic MCAS trigger [168]. Thus, whilst MCAS appears to be a co-pathology in some Long COVID patients, mitigating the coagulopathy could have dual benefit via reducing (inappropriate/damaging) mast cell activation whilst mitigating thrombogenesis.…”

Section: Co-pathologiesmentioning

confidence: 99%

Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis

Carroll

2023

Preprint

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Long COVID describes an array of often debilitating symptoms in the aftermath of SARS-CoV-2 infection, with similar symptomatology affecting some people post-vaccination. With an estimated > 200 million Long COVID patients worldwide and cases still rising, the effects on quality of life and the economy are significant, thus warranting urgent attention to understand the pathophysiology. Herein we describe our perspective that Long COVID is a continuation of acute COVID-19 pathology, whereby coagulopathy is the main driver of disease and can cause or exacerbate other pathologies common in Long COVID, such as mast cell activation syndrome and dysautonomia. Considering the SARS-CoV-2 spike protein can independently induce fibrinaloid microclots, platelet activation, and endotheliitis, we predict that persistent spike protein will be a key mechanism driving the continued coagulopathy in Long COVID. We discuss several treatment targets to address the coagulopathy, and predict that (particularly early) treatment with combination anticoagulant and antiplatelet drugs will bring significant relief to many patients, supported by a case study. To help focus attention on such treatment targets, we propose Long COVID should be referred to as Spike protein Induced Thrombotic Vasculitis (SITV). These ideas require urgent testing, especially as the world tries to co-exist with COVID-19.

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Mast cells promote viral entry of SARS-CoV-2 via formation of chymase/spike protein complex

Cited by 17 publications

References 24 publications

Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity

Dysregulated early transcriptional signatures linked to mast cell and interferon responses are implicated in COVID-19 severity

Mast Cell Activation Syndrome Update—A Dermatological Perspective

Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis

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