In silico and in vitro studies reveal complement system drives coagulation cascade in SARS-CoV-2 pathogenesis

Tiwari, Ritudhwaj; Mishra, Anurag; Mikaeloff, Flora; Gupta, Soham; Mirazimi, Alì; Byrareddy, Siddappa N.; Neogi, Ujjwal; Nayak, Debasis

doi:10.1016/j.csbj.2020.11.005

Cited by 26 publications

(26 citation statements)

References 57 publications

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“…The predicted interactions are highlighted based on their functional importance during SARS-CoV-2 infection and prioritized based on other related RNA viruses' available information. In the similar line we also predicted the host complement system driving the coagulation process in SARS-CoV-2 infection (Tiwari et al, 2020). While, in this study, these interacting proteins revealed that SARS-CoV-2 might use the clathrin-mediated endocytosis pathway for its entry.…”

Section: Introductionsupporting

confidence: 78%

Structural similarity-based prediction of host factors associated with SARS-CoV-2 infection and pathogenesis

Tiwari

Mishra

Gupta

et al. 2021

Journal of Biomolecular Structure and Dynamics

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The current pandemic resulted from SARS-CoV-2 still remains as the major public health concern globally. The precise mechanism of viral pathogenesis is not fully understood, which remains a major hurdle for medical intervention. Here we generated an interactome profile of protein-protein interactions based on host and viral protein structural similarities information. Further computational biological study combined with Gene enrichment analysis predicted key enriched pathways associated with viral pathogenesis. The results show that axon guidance, membrane trafficking, vesicle-mediated transport, apoptosis, clathrin-mediated endocytosis, Vpu mediated degradation of CD4 T cell, and interferon-gamma signaling are key events associated in SARS-CoV-2 life cycle. Further, degree centrality analysis reveals that IRF1/9/7, TP53, and CASP3, UBA52, and UBC are vital proteins for IFN-γ-mediated signaling, apoptosis, and proteasomal degradation of CD4, respectively. We crafted chronological events of the virus life cycle. The SARS-CoV-2 enters through clathrin-mediated endocytosis, and the genome is trafficked to the early endosomes in a RAB5-dependent manner. It is predicted to replicate in a double-membrane vesicle (DMV) composed of the endoplasmic reticulum, autophagosome, and ERAD machinery. The SARS-CoV-2 down-regulates host translational machinery by interacting with protein kinase R, PKR-like endoplasmic reticulum kinase, and heme-regulated inhibitor and can phosphorylate eIF2a. The virion assembly occurs in the ER-Golgi intermediate compartment (ERGIC) organized by the spike and matrix protein. Collectively, we have established a spatial link between viral entry, RNA synthesis, assembly, pathogenesis, and their associated diverse host factors, those could pave the way for therapeutic intervention.

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Section: Introductionsupporting

confidence: 78%

Structural similarity-based prediction of host factors associated with SARS-CoV-2 infection and pathogenesis

Tiwari

Mishra

Gupta

et al. 2021

Journal of Biomolecular Structure and Dynamics

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“…Overall, our data indicate that increased glucose levels but not mannose levels has an effect on viral replication in vitro. 1 3 Several studies, including ours, have shown an effect of SARS-CoV-2 infection on complement and coagulation cascades and thrombosis as unique features of COVID-19 infection [7,19,20].…”

Section: Role Of Increased Sugars In Sars-cov-2 Infection and The Commentioning

confidence: 78%

“…It is made 1 6 across the cell membrane [32]. We observed a significant increase in surface expression (MFI) of Plasma mannose emerges as a robust biomarker of disease severity and can also lead to activation of the lectin complement system at a later stage of infection [20]. In addition to mannose, we also observed increased levels of MBL in both COVID-19 patients and convalescent patients compared to the COVID-19 negative individuals.…”

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confidence: 71%

“…Temporal transcriptomic and proteomic profiling of SARS-CoV-2 infected Huh7 cells have also revealed an upregulation of proteins involved in complement activation at a later stage of infection [20]. Since complement component C4 is part of the cascade that leads to C3 activation in the classical and MBL pathways, we also studied whether increased glucose/mannose in the media during infection affected upstream events of C3 activation (Fig 6c).…”

Section: Role Of Increased Sugars In Sars-cov-2 Infection and The Commentioning

confidence: 98%

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Implications of central carbon metabolism in SARS-CoV-2 replication and disease severity

Krishnan

Nordqvist

Ambikan

et al. 2021

Preprint

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Viruses hijack host metabolic pathways for their replicative advantage. Several observational trans-omics analyses associated carbon and amino acid metabolism in coronavirus disease 2019 (COVID-19) severity in patients but lacked mechanistic insights. In this study, using patient- derived multi-omics data and in vitro infection assays, we aimed to understand i) role of key metabolic pathways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and ii) its association with disease severity. Our data suggests that monocytes are key to the altered immune response during COVID-19. COVID-19 infection was associated with increased plasma glutamate levels, while glucose and mannose levels were determinants of the disease severity. Monocytes showed altered expression pattern of carbohydrate and amino acid transporters, GLUT1 and xCT respectively in severe COVID-19. Furthermore, lung epithelial cells (Calu-3) showed a strong acute metabolic adaptation following infection in vitro by modulating central carbon metabolism. We found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, our study highlights that the virus utilizes and re-wires pathways governing central carbon metabolism leading to metabolic toxicity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

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“…Previous proteomics-based studies have observed that SARS-CoV-2 causes global proteomic changes after 48hpi specifically in pathways related to ErbB, HIF-1, mTOR and TNF signaling (Appelberg et al, 2020), complement system and coagulation cascades (Tiwari et al, 2020) and interferon signaling (Unpublished data). In order to understand the delayed changes in Huh7 cells (Huh7 48h ) compared to Calu-3 and Caco2 cells, we extracted the proteomics data set from our earlier study (Appelberg et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

Tropism of SARS-CoV-2 in commonly used laboratory cell lines and their proteomic landscape during infection

Saccon

Chen

Mikaeloff

et al. 2020

Preprint

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In silico and in vitro studies reveal complement system drives coagulation cascade in SARS-CoV-2 pathogenesis

Cited by 26 publications

References 57 publications

Structural similarity-based prediction of host factors associated with SARS-CoV-2 infection and pathogenesis

Structural similarity-based prediction of host factors associated with SARS-CoV-2 infection and pathogenesis

Implications of central carbon metabolism in SARS-CoV-2 replication and disease severity

Tropism of SARS-CoV-2 in commonly used laboratory cell lines and their proteomic landscape during infection

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