UAB researchers’ insights may promote effective treatment with existing drugs in patients with coronavirus

Viral and bacterial pathogens carry pathogenic or toxic proteins that interact with high-value targets in human cells and attack what is known as host interacting factors. The host interaction is a network map of all protein-protein interactions in the cell.

Such networks have been studied in a variety of organisms such as plants, humans and roundworms, and show similarities to social networks such as Facebook and airline route maps. On Facebook, a few people will have a huge number of friends, some will have many friends, and the majority will be much less. Similarly, airlines have several hubs, and many passengers pass on their way to their destination.

Host interactions represent a limited number of high-performance hubs (when proteins have many connections) and a limited number of important bottlenecks that are sites with many short paths to nodes. .. For pathogens that seek to take control of infected cells, they are important targets for the pathogen and can rewire the flow of information in the cell and cause disease.

University of Alabama at Birmingham Researcher led by Dr. Shahid Mukhtar, biology At UAB University of Arts and SciencesConstructed an interactome containing a lung epithelial cell host interactome integrated with the SARS-CoV-2 interactome. Applying a network biology analysis tool to this human / SARS-CoV-2 interaction revealed a potential molecular mechanism for the etiology of SARS-CoV-2, the virus responsible for the COVID-19 pandemic. .. UAB the studyPublished in the journal iScience, we have identified 33 high-value SARS-CoV-2 therapeutic targets. They are involved in virus invasion, proliferation, and survival, establishing infection and promoting disease progression. These molecular insights may promote effective treatment with existing drug combinations in patients with COVID-19.

So far, in 2019, the SARS-CoV-2 virus has killed about 1 million people worldwide and 200,000 in the United States.

UAB researchers have taken many steps to generate the Calu-3-specific human-SARS-CoV-2 interactome (CSI), which is the starting point for the analysis of network biology.

They started with a comprehensive human interaction of ly validated protein-protein interactions, posted online in 2015, and then manually manipulated other protein-protein interactions from four subsequent interactome studies. Curated with. The resulting human interaction contained 18,906 nodes and 444,633 “edges” (a term for links between protein nodes).

From two 2020 studies, researchers have compiled a complete list of 394 host proteins that interact with the novel human coronavirus. These host proteins were called SARS-CoV-2 interacting proteins, or SIPs. SIP contains 332 human proteins associated with the SARS-CoV-2 peptide and 62 host proteins that interact with viral factors of other human coronaviruses, including SARSCoV and MERS-CoV. And you can understand the cause of MERS. Molecular cause of SARS-CoV-2

By querying these 394 SIPs in a human interaction, we generated a subnet of 12,852 nodes and 84,100 edges covering the first and second neighbors of the 373 SIP.

Finally, they are derived from cultured human airway epithelial cells or Calu-3 that have been filtered over time in the context of temporal changes during COVID-19 infection and treated over time with SARSCoV and SARS-CoV-2. I used a high resolution temporal transcriptome. When this Calu-3 expression data is integrated with SIPs-derived protein-protein interaction subnetworks, a Calu-3-specific human-SARS-CoV-2 interactome containing 214 SIPs that interact with the first and second neighbors. , Or CSI occurs, forming a network of 4,176 nodes and 18,630 edges.

The CSI had a law distribution that should include several nodes with improved connectivity compared to a random network, so it, like other previously generated human virus interactomes, has the properties of a scale-free network. Shown.

Later, robust, high-quality CSI was further leveraged for network-assisted architecture and functional pathway analysis.

Topology clustering and pathway enhancement analysis showed that the SARS-CoV-2 virus attacks the central node of the host virus network that participates in the core functional pathway. Network-centric analysis revealed 33 high-value SARS-CoV-2 targets with potential drug therapy. These targets are involved in virus invasion, proliferation, and survival to establish infection and accelerate disease progression. The stochastic modeling framework has elucidated key regulatory circuits and molecular events associated with COVID-19, especially host modified responses and cytokine storms.

“In summary, Muhtar said:” Our integrated network topology analysis has allowed us to elucidate the molecular mechanisms and pathways underlying the pathogenesis of SARS-CoV-2. “Muhtar Our laboratory is working on network medicine and artificial intelligence to combat COVID-19 and other human inflammatory diseases.

Co-first author of Investigation“The Integrated Network Biology Framework elucidates the molecular mechanism of SARS-CoV-2 etiology,” said Nilesh Kumar and Bharat Mishra, graduate students of the UAB Biology Department.

Other co-authors with Mukhtar include Adeel Mehmood, UAB Biology of Biology, Computer ScienceAnd Mohammad Atar, Dermatology, UAB School of medicine..

Support was provided by the National Science Foundation grant IOS-1557796 and the National Institutes of Health grant ES030246.

This press release is University of Alabama at Birmingham.. The views expressed here are those of the author himself.