Since its emergence in late 2019, SARS-CoV-2, the causative agent of COVID-19, has undergone extensive genomic evolution, leading to the emergence of multiple variants with varying transmissibility, immune evasion capabilities, and pathogenic potential. Understanding the molecular interactions between viral and host proteins—the SARS-CoV-2 protein interactome—has been instrumental in elucidating the virus’s mechanisms of infection, immune modulation, and replication.
Beyond the acute phase of infection, a significant proportion of individuals experience persistent symptoms collectively termed Long COVID, which includes neurological complications such as brain fog, cognitive impairment, and fatigue. While the underlying molecular mechanisms remain unclear, emerging evidence suggests that viral persistence, immune dysregulation, and inflammatory responses may contribute to these long-term sequelae. Investigating how SARS-CoV-2 proteins interact with host neural and immune pathways is crucial for developing targeted interventions to mitigate Long COVID’s impact and improve patient outcomes.
Over the past five years, advances in proteomics, structural biology, and systems biology have provided unprecedented insights into the virus-host interface. High-throughput mass spectrometry, cryo-electron microscopy, and computational modeling have revealed key viral protein interactions that drive pathogenesis and immune evasion. These discoveries have not only expanded our understanding of coronavirus biology but have also facilitated the identification of novel therapeutic targets.
This review summarizes the current landscape of the SARS-CoV-2 protein interactome, highlighting key host factors exploited by the virus, emerging trends in viral evolution, and potential avenues for antiviral intervention. By integrating recent findings, we aim to provide a comprehensive resource for researchers exploring new strategies to combat SARS-CoV-2 and future pandemic threats.
The 30kb SARS-CoV-2 genome encodes 16 non-structural proteins (Nsp1-16), four structural proteins (spike, envelope, nucleocapsid, membrane), and nine putative accessory factors7. Many of these proteins and polypeptides have a number or interaction partners in particular in lung cells, the virus’ primary infection site. These interactions with the host cell determine the virus’ ability to infect the cell, reproduce its genome and trigger the production and release of new virus particles. In addition, several virus proteins appear to have interaction partners affecting innate immune pathways such as the interferon signaling pathway, NF-kappa B inflammatory response, type I interferon production, and IRF-3 activation.
At least some of the members of the third group of SARS-CoV-2 proteins, the nine accessory factors (Orf3a-10), have been implicated in driving progression of COVID-19. Orf3a induces apoptosis and is thought to activate NF-kB and the NLRP3 inflammasome involved in pyroptosis, a highly inflammatory form of apoptosis. The type I interferon (IFN) antagonists Orf6 and Orf9b inhibit the IFN alpha and beta signaling, two key players of the antiviral innate immune response.
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