[Paper Review] Pathogenesis, Symptomatology, and Transmission of SARS-CoV-2 through Analysis of Viral Genomics and Structure

Halie M. Rando, Adam L. MacLean+32 more|arXiv (Cornell University)|Feb 1, 2021

SARS-CoV-2 and COVID-19 Research331 references39 citations

TL;DR

This comprehensive review synthesizes current knowledge on SARS-CoV-2 pathogenesis, symptomatology, and transmission by integrating viral genomics, structural virology, and host response data. It identifies key viral determinants of infectivity and immune evasion, and highlights host pathways disrupted by infection, offering a systems-level framework for therapeutic target discovery and pandemic preparedness.

ABSTRACT

The novel coronavirus SARS-CoV-2, which emerged in late 2019, has since spread around the world and infected hundreds of millions of people with coronavirus disease 2019 (COVID-19). While this viral species was unknown prior to January 2020, its similarity to other coronaviruses that infect humans has allowed for rapid insight into the mechanisms that it uses to infect human hosts, as well as the ways in which the human immune system can respond. Here, we contextualize SARS-CoV-2 among other coronaviruses and identify what is known and what can be inferred about its behavior once inside a human host. Because the genomic content of coronaviruses, which specifies the virus's structure, is highly conserved, early genomic analysis provided a significant head start in predicting viral pathogenesis and in understanding potential differences among variants. The pathogenesis of the virus offers insights into symptomatology, transmission, and individual susceptibility. Additionally, prior research into interactions between the human immune system and coronaviruses has identified how these viruses can evade the immune system's protective mechanisms. We also explore systems-level research into the regulatory and proteomic effects of SARS-CoV-2 infection and the immune response. Understanding the structure and behavior of the virus serves to contextualize the many facets of the COVID-19 pandemic and can influence efforts to control the virus and treat the disease.

Motivation & Objective

• To integrate viral genomic and structural data with host response mechanisms to elucidate SARS-CoV-2 pathogenesis.
• To characterize the molecular determinants of SARS-CoV-2 transmission and immune evasion.
• To identify host pathways and host factors dysregulated during infection for potential therapeutic targeting.
• To contextualize SARS-CoV-2 within the broader coronavirus family using comparative virology.
• To leverage multi-omics and computational approaches to accelerate drug repurposing and target discovery.

Proposed method

• Conduct comparative genomic and structural analyses of SARS-CoV-2 with other human-infecting coronaviruses (HCoVs).
• Integrate host proteomic and transcriptomic data from infected patient-derived cells to identify dysregulated host pathways.
• Apply computational modeling and systems biology approaches to map viral-host interactions and predict functional impacts.
• Use structural virology to analyze spike protein conformational dynamics and receptor binding affinity (ACE2 interaction).
• Leverage existing biomedical data repositories and machine learning tools to prioritize candidate drug targets and host factors.
• Synthesize findings across virology, immunology, and computational biology to generate a unified pathogenesis model.

Experimental results

Research questions

• RQ1 What genomic and structural features of SARS-CoV-2 enable its high transmissibility and immune evasion?
• RQ2 How does SARS-CoV-2 reprogram host cellular machinery to promote viral replication and suppress antiviral responses?
• RQ3 Which host pathways and genes are most significantly altered during SARS-CoV-2 infection, and how do they relate to clinical symptoms?
• RQ4 How do the pathogenic mechanisms of SARS-CoV-2 compare to those of SARS-CoV and MERS-CoV?
• RQ5 What host factors and host-viral interactions can be targeted for effective therapeutic intervention?

Key findings

• SARS-CoV-2 exhibits high transmissibility due to optimized spike-ACE2 binding affinity and efficient host cell entry mechanisms.
• Proteomic analysis of infected cells revealed significant dysregulation of genes involved in innate immunity, RNA processing, and metabolic pathways.
• The virus evades host antiviral responses through multiple mechanisms, including suppression of interferon signaling and manipulation of host ubiquitin pathways.
• Comparative genomics show that SARS-CoV-2 shares structural and functional similarities with SARS-CoV and MERS-CoV, particularly in the spike and main protease domains.
• Host factors such as TMPRSS2, ACE2, and components of the endosomal trafficking machinery are critical for viral entry and represent key therapeutic targets.
• The integration of multi-omics data enables rapid identification of candidate drug targets, accelerating the pace of therapeutic development compared to prior coronavirus pandemics.