Persistence of Viral RNA, Pneumocyte Syncytia and Thrombosis Are Hallmarks of Advanced COVID-19 Pathology

Bussani, Rossana; Schneider, Edoardo; Zentilin, Lorena; Collesi, Chiara; Ali, Hashim; Braga, Luca; Volpe, Maria Concetta; Colliva, Andrea; Zanconati, Fabrizio; Berlot, Giorgio; Silvestri, Furio; Zacchigna, Serena; Giacca, Mauro

doi:10.2139/ssrn.3654168

Cited by 41 publications

(64 citation statements)

References 22 publications

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“…Mid-term consequences of COVID-19 are not limited to lung disease and cover a wide range of organ systems: the underlining mechanism could be some kind of microcirculatory impairment [36,37]. We propose that studies should be addressed in this direction.…”

Section: Discussionmentioning

confidence: 99%

Surviving COVID-19 in Bergamo province: a post-acute outpatient re-evaluation

et al. 2021

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Bergamo province was badly hit by the coronavirus disease 2019 (COVID-19) epidemic. We organised a public-funded, multidisciplinary follow-up programme for COVID-19 patients discharged from the emergency department or from the inpatient wards of ‘Papa Giovanni XXIII’ Hospital, the largest public hospital in the area. As of 31 July, the first 767 patients had completed the first post-discharge multidisciplinary assessment. Patients entered our programme at a median time of 81 days after discharge. Among them, 51.4% still complained of symptoms, most commonly fatigue and exertional dyspnoea, and 30.5% were still experiencing post-traumatic psychological consequences. Impaired lung diffusion was found in 19%. Seventeen per cent had D-dimer values two times above the threshold for diagnosis of pulmonary embolism (two unexpected and clinically silent pulmonary thrombosis were discovered by investigating striking D-dimer elevation). Survivors of COVID-19 exhibit a complex array of symptoms, whose common underlying pathology, if any, has still to be elucidated: a multidisciplinary approach is fundamental, to address the different problems and to look for effective solutions.

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Section: Discussionmentioning

confidence: 99%

Surviving COVID-19 in Bergamo province: a post-acute outpatient re-evaluation

et al. 2021

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“…The S2 subunit of S mediates both viral-cell fusion and cell-cell fusion [40][41][42], with cell-cell fusion readily observed both in a laboratory setting and in the lungs of SARS-CoV-2 infected patients [40][41][42][43][44][45]. To better understand the requirements and contribution of cellular proteases to S2 mediated cell-cell fusion, we performed syncytia and reporter gene assays.…”

Section: Spike Mediated Cell-cell Fusionmentioning

confidence: 99%

“…However, when S1/S2 border cleavage is blocked, viral entry can be mediated through endosomal compartments with proteolytic cleavage carried out by a member of the cathepsin family, similar to the entry pathway of SARS-CoV [10,35,[37][38][39]. In addition to promoting virus-cell fusion during viral particle entry, S can also promote cell-cell fusion, a pathogenic effect observed in the lungs of COVID-19 patients where neighboring cells fuse together to form large multi-nucleated cells, termed syncytia [40][41][42][43][44][45]. While the role of cellular proteases and S cleavage in viral entry is being extensively investigated, insight into the cleavage requirements for cell-cell fusion in SARS-CoV-2 remains more limited.…”

Section: Introductionmentioning

confidence: 99%

Effect of mutations in the SARS-CoV-2 spike protein on protein stability, cleavage, and cell-cell fusion function

Barrett

Neal

Edmonds

et al. 2021

Preprint

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The SARS-CoV-2 spike protein (S) is the sole viral protein responsible for both viral binding to a host cell and the membrane fusion event needed for cell entry. In addition to facilitating fusion needed for viral entry, S can also drive cell-cell fusion, a pathogenic effect observed in the lungs of SARS-CoV-2 infected patients. While several studies have investigated S requirements involved in viral particle entry, examination of S stability and factors involved in S cell-cell fusion remain limited. We demonstrate that S must be processed at the S1/S2 border in order to mediate cell-cell fusion, and that mutations at potential cleavage sites within the S2 subunit alter S processing at the S1/S2 border, thus preventing cell-cell fusion. We also identify residues within the internal fusion peptide and the cytoplasmic tail that modulate S cell-cell fusion. Additionally, we examine S stability and protein cleavage kinetics in a variety of mammalian cell lines, including a bat cell line related to the likely reservoir species for SARS-CoV-2, and provide evidence that proteolytic processing alters the stability of the S trimer. This work therefore offers insight into S stability, proteolytic processing, and factors that mediate S cell-cell fusion, all of which help give a more comprehensive understanding of this highly sought-after therapeutic target.

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“…As mentioned, recent reports show that infected syncytia are frequently observed in lung tissues of SARS-CoV-2-infected patients with acute respiratory syndrome, and immunohistochemistry analyses have identified that these MGCs mainly originate from cell-cell fusion of alveolar epithelial cells. In addition, these SARS-CoV-2-mediated syncytia could also derive from cell-cell fusion of infected alveolar macrophages, target cells that certainly play a crucial role for the systemic hyper-inflammation known as “cytokine storm” (or macrophage activation syndrome) observed in patients with critical disease manifestations [ 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ]. Some authors even suggest that abnormal cellular syncytia are hallmarks of COVID-19 lung pathology, and it is obvious that some of these giant cells correspond to syncytial histiocytic cells as confirmed by positive CD68 expression, a specific marker of myeloid cells, including monocytes and macrophages [ 127 ].…”

Section: Introductionmentioning

confidence: 99%

Virus-Mediated Cell-Cell Fusion

Leroy

Han

Woottum

et al. 2020

IJMS

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Cell-cell fusion between eukaryotic cells is a general process involved in many physiological and pathological conditions, including infections by bacteria, parasites, and viruses. As obligate intracellular pathogens, viruses use intracellular machineries and pathways for efficient replication in their host target cells. Interestingly, certain viruses, and, more especially, enveloped viruses belonging to different viral families and including human pathogens, can mediate cell-cell fusion between infected cells and neighboring non-infected cells. Depending of the cellular environment and tissue organization, this virus-mediated cell-cell fusion leads to the merge of membrane and cytoplasm contents and formation of multinucleated cells, also called syncytia, that can express high amount of viral antigens in tissues and organs of infected hosts. This ability of some viruses to trigger cell-cell fusion between infected cells as virus-donor cells and surrounding non-infected target cells is mainly related to virus-encoded fusion proteins, known as viral fusogens displaying high fusogenic properties, and expressed at the cell surface of the virus-donor cells. Virus-induced cell-cell fusion is then mediated by interactions of these viral fusion proteins with surface molecules or receptors involved in virus entry and expressed on neighboring non-infected cells. Thus, the goal of this review is to give an overview of the different animal virus families, with a more special focus on human pathogens, that can trigger cell-cell fusion.

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Persistence of Viral RNA, Pneumocyte Syncytia and Thrombosis Are Hallmarks of Advanced COVID-19 Pathology

Cited by 41 publications

References 22 publications

Surviving COVID-19 in Bergamo province: a post-acute outpatient re-evaluation

Surviving COVID-19 in Bergamo province: a post-acute outpatient re-evaluation

Effect of mutations in the SARS-CoV-2 spike protein on protein stability, cleavage, and cell-cell fusion function

Virus-Mediated Cell-Cell Fusion

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