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http://conacyt.repositorioinstitucional.mx/jspui/handle/1000/3366| Confronting the COVID-19 Pandemic with Systems Biology | |
| Erica Teixeira Prates. Michael R Garvin. Mirko Pavicic. Piet Jones. Manesh Shah. Christiane Alvarez. David Kainer. Omar Demerdash. B Kirtley Amos. Armin Geiger. Daniel Jacobson. | |
| Acceso Abierto | |
| Atribución-NoComercial-SinDerivadas | |
| 10.1101/2020.04.06.028712 | |
| BackgroundThe magnitude and severity of the COVID-19 pandemic cannot be overstated. Although the mortality rate is less than SARS and MERS, the global outbreak has already resulted in orders of magnitude more deaths. In order to tackle the complexities of this disease, a Systems Biology approach can provide insights into the biology of the virus and mechanisms of disease. MethodsUsing a Systems Biology approach, we have integrated genomic, transcriptomic, proteomic, and molecular evolution data layers to understand its impact on host cells. We overlay these analyses with high-resolution structural models and atomistic molecular dynamics simulations conducted on the Summit supercomputer at the Oak Ridge National Laboratory. FindingsTranscriptomic and proteomic data indicate little to no expression of ACE2 in lung tissue. Molecular modeling simulations support ACE2 as the receptor for SARS-CoV-2, but ACE may also act as a receptor for the virus and may be important for entry of SARS-CoV-1. Gene expression data from bronchoalveolar lavage samples from COVID-19 patients identify upregulation of renin, angiotensin, and the angiotensin 1-7 receptor MAS as well as a cellular landscape consistent with large-scale dissolution of lung parenchyma tissues, likely comprised of all lung epithelial cell types as well as lymphatic endothelial cells, but an absence of cells, such as macrophages, normally essential for host defense. InterpretationOur analyses indicate that the commonly accepted view that SARS-CoV-2 enters host cells via ACE2 expressed in the lung is unlikely because ACE2 is undetectable there. Instead, given the greater target space of ACE2-positive nasal, oral, and gastrointestinal tissues, a more likely scenario suggests initial infection in those tissues is followed by a secondary infection via migration through the lymphatic system and bloodstream to the lung microvasculature. The elimination of macrophages and complete lack of activated cytokine signature in COVID-19 lung samples suggest that a major component of SARS-CoV-2s virulence is its net effect of causing a functional immune deficiency syndrome. Our structural analysis of the SARS-CoV-2 proteome suggests involvement of the highly conserved nsp5 protein as part of a major mechanism that suppresses the nuclear factor transcription factor kappa B (NF-{kappa}B) pathway, eliminating the host cells interferon-based antiviral response. FundingOak Ridge National Laboratory, Laboratory Directed Research & Development Fund, LOIS:10074 Office of Biological and Environmental Research, United States Department of Energy Office of Science, COVID-19 Testing Research & Development Priorities, ERKPA09. National Institutes of Health, U24 HL148865: the LungMap Consortium Research in context Evidence before this studyWe searched PubMed, medRxiv, bioRxiv, arXiv, NCBI GEO & SRA, PDB, Genotype-Tissue Expression Portal, Proteomics DataBase, ALlele FREquency Database, Global Initiative on Sharing All Influenza Data, Human Cell Landscape, Tabula Muris, Google and Google Scholar for peer-reviewed articles, preprints, datasets and research reports on all aspects of coronavirus and the genes, gene/protein expression and cell types mentioned in this manuscript up to April 3, 2020. Added value of this studyBy synthesizing information from a wide variety of data types, sources and scales (from atoms, alleles, transcripts, proteins, protein complexes, cells, tissues, organs and individuals to populations) with a Systems Biology approach we have provided mechanistic insight into the route of infection and spread of SARS-CoV-2 in the human body. In addition, this has provided insights into the bodys responses to the virus, including a broader view of the role of the Renin-Angiotensin-System, and the likely targeted tissues and cell types that are responsible for COVID-19 symptoms. We have posited that ACE can be an alternate receptor for SARS-CoV-1 in some tissues and discussed how this may explain the behavior of SARS-CoV-2 in comparison to SARS-CoV-1. We have also used gene expression levels across organs and individuals to explain some of the possible causes for the different responses observed in individuals across the human population. Furthermore, we have elucidated the effects of COVID-19 on specific cell types in lung tissue. By predicting the structures of the entire SARS-CoV-2 proteome and doing a thorough structure-based mutational analysis of all SARS-CoV-2 proteins we have been able to provide functional insights as to the likely impacts of these mutations on transmission, virulence and pathogenicity which will serve as a significant resource to the scientific community for further investigation and validation. Implications of all the available evidenceThis study provides greater comprehension of the mechanistic and molecular underpinnings of COVID-19. In so doing it contributes to the understanding of the evolution of the virus and its varying effects on human hosts. This enhanced understanding has implications on disease spread and prevention, provides preliminary evidence for the design of new studies into the causes of susceptibility and severity of illness and provides information that will aid in the development of drugs (targeting viral and human proteins), vaccines, and diagnostic methodologies. | |
| www.biorxiv.org | |
| 2020 | |
| Artículo | |
| https://www.biorxiv.org/content/10.1101/2020.04.06.028712v2.full.pdf | |
| Inglés | |
| VIRUS RESPIRATORIOS | |
| Aparece en las colecciones: | Artículos científicos |
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