Likely molecular mechanisms of SARS-CoV-2 pathogenesis are revealed by
network biology
These molecular insights may foster effective therapies using existing
drugs for patients with COVID-19

Date:
September 23, 2020
Source:
University of Alabama at Birmingham
Summary:
Researchers have built an interactome that includes the
lung-epithelial cell host interactome integrated with a SARS-CoV-2
interactome. Applying network biology analysis tools to this
human/SARS-CoV-2 interactome has revealed potential molecular
mechanisms of pathogenesis for SARS-CoV-2, the virus responsible
for the COVID-19 pandemic. The research identified 33 high-value
SARS-CoV-2 therapeutic targets, which are possibly involved in
viral entry, proliferation and survival to establish infection
and facilitate disease progression.



FULL STORY ========================================================================== Viral and bacterial pathogens wield pathogenic or virulent proteins that interact with high-value targets inside human cells, attacking what is
known as the host interactome. The host interactome is the network map
of all the protein-protein interactions inside cells.


==========================================================================
Such networks have been studied in organisms as diverse as plants,
humans and roundworms, and they show a similarity to social networks
like Facebook or airline route maps. In Facebook, a few people will
have a huge number of friend connections, some will have many, and a
vast majority will have much fewer.

Similarly, airlines have a few hubs that many passengers pass through
on the way to their destinations.

Host interactomes show a limited number of high-powered hubs -- where
a protein has a large number of connections -- and a limited number
of important bottlenecks, which are sites with a large number of short
paths to a node.

These are key targets for pathogens as they seek to seize control of
the infected cell, so it can rewire the cell's flow of information and
cause disease.

University of Alabama at Birmingham researchers, led by Shahid Mukhtar,
Ph.D., associate professor of biology in the UAB College of Arts and
Sciences, have now built an interactome that includes the lung-epithelial
cell host interactome integrated with a SARS-CoV-2 interactome. Applying network biology analysis tools to this human/SARS-CoV-2 interactome has revealed potential molecular mechanisms of pathogenesis for SARS-CoV-2,
the virus responsible for the COVID-19 pandemic. The UAB research,
published in the journal iScience, identified 33 high-value SARS-CoV-2 therapeutic targets, which are possibly involved in viral entry,
proliferation and survival to establish infection and facilitate disease progression. These molecular insights may foster effective therapies,
using combinations of existing drugs, for patients with COVID-19.

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

The UAB researchers took many steps to generate the Calu-3-specific
human-SARS- CoV-2 interactome, or CSI, that was the starting point for
their network biology analyses.



==========================================================================
They began from a comprehensive human interactome of experimentally
validated protein-protein interactions, posted online in 2015, and then manually curated other protein-protein interactions from four subsequent interactome studies.

The resulting human interactome contained 18,906 nodes and 444,633
"edges" - - the term for the links between protein nodes.

From two 2020 studies, the researchers compiled an exhaustive list of 394
host proteins that interact with the novel human coronavirus; these host proteins were called SARS-CoV-2 interacting proteins, or SIPs. The SIPs included 332 human proteins associated with the peptides of SARS-CoV-2
and 62 host proteins interacting with the viral factors of other human coronaviruses, including SARSCoV and MERS-CoV, the causes of SARS and
MERS, which could also aid understanding the molecular pathogenesis of SARS-CoV-2 By querying these 394 SIPs in the human interactome, they
generated a subnetwork of 12,852 nodes and 84,100 edges that covered
first and second neighbors of the 373 SIPs.

Finally, they filtered these interactions in the context of temporal
changes during COVID-19 infection, using a high-resolution temporal transcriptome derived from cultured human airway epithelial cells, or
Calu-3, treated with SARSCoV and SARS-CoV-2 over time. Integrating this
Calu-3 expression data with the SIPs-derived protein-protein interaction subnetwork resulted in a Calu-3- specific human-SARS-CoV-2 interactome,
or CSI, that contained 214 SIPs interacting with their first and second neighbors, and forming a network of 4,176 nodes and 18,630 edges.

The CSI had a power law degree distribution with a few nodes harboring increased connectivity compared to a random network, and thus exhibited properties of a scale-free network, similar to the other, previously
generated human-viral interactomes.



==========================================================================
The robust, high-quality CSI was then further utilized for network-aided architectural and functional pathway analyses.

Topological clustering and pathway enrichment analysis showed that the
SARS- CoV-2 virus attacks central nodes of the host-viral network that participate in core functional pathways. Network centrality analyses
discovered 33 high-value SARS-CoV-2 targets for possible drug therapy;
these targets are possibly involved in viral entry, proliferation and
survival to establish infection and facilitate disease progression. A probabilistic modeling framework elucidated critical regulatory circuitry
and molecular events pertinent to COVID-19, particularly the host
modifying responses and cytokine storm.

"In summary," Mukhtar said, "our integrative network topology analyses
led us to elucidate the underlying molecular mechanisms and pathways of SARS-CoV- 2 pathogenesis." Mukhtar's lab continues to work on network
medicine and artificial intelligence to battle COVID-19 and other human inflammatory diseases.

Co-first authors of the study, "Integrative network biology framework elucidates molecular mechanisms of SARS-CoV-2 pathogenesis," are graduate students Nilesh Kumar and Bharat Mishra, UAB Department of Biology.

Other co-authors, along with Mukhtar, are Adeel Mehmood, UAB departments
of Biology and Computer Science; and Mohammad Athar, Department of
Dermatology, UAB School of Medicine.

Support came from National Science Foundation grant IOS-1557796 and
National Institutes of Health grant ES030246.


========================================================================== Story Source: Materials provided by
University_of_Alabama_at_Birmingham. Original written by Jeff
Hansen. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Nilesh Kumar, Bharat Mishra, Adeel Mehmood, Mohammad Athar, M Shahid
Mukhtar. Integrative Network Biology Framework Elucidates Molecular
Mechanisms of SARS-CoV-2 Pathogenesis. iScience, 2020; 23 (9):
101526 DOI: 10.1016/j.isci.2020.101526 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200923124732.htm

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