Network perturbation analysis in human bronchial epithelial cells following SARS-CoV2 infection

Giuseppe Nunnari; Cristina Sanfilippo; Paola Castrogiovanni; Rosa Imbesi; Giovanni Li Volti; Ignazio Barbagallo; Giuseppe Musumeci; Michelino Di Rosa

doi:10.1016/j.yexcr.2020.112204

Network perturbation analysis in human bronchial epithelial cells following SARS-CoV2 infection

Exp Cell Res. 2020 Oct 15;395(2):112204. doi: 10.1016/j.yexcr.2020.112204. Epub 2020 Jul 28.

Authors

Giuseppe Nunnari¹, Cristina Sanfilippo², Paola Castrogiovanni³, Rosa Imbesi⁴, Giovanni Li Volti⁵, Ignazio Barbagallo⁶, Giuseppe Musumeci⁷, Michelino Di Rosa⁸

Affiliations

¹ Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. Electronic address: gnunnari@unime.it.
² IRCCS Centro Neurolesi Bonino Pulejo, Strada Statale 113, C.da Casazza, 98124, Messina, Italy. Electronic address: cristina.sanfilippo@irccsme.it.
³ Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, Italy. Electronic address: pacastro@unict.it.
⁴ Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, Italy. Electronic address: roimbesi@unict.i.
⁵ Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 97, 95125, Catania, Italy. Electronic address: livolti@unict.it.
⁶ Department of Drug Sciences, University of Catania, Viale Andrea Doria, 6, 95125, Catania, Italy. Electronic address: ignazio.barbagallo@unict.it.
⁷ Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, Italy. Electronic address: g.musumeci@unict.it.
⁸ Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, Italy. Electronic address: mdirosa@unict.it.

Abstract

Background: SARS-CoV2, the agent responsible for the current pandemic, is also causing respiratory distress syndrome (RDS), hyperinflammation and high mortality. It is critical to dissect the pathogenetic mechanisms in order to reach a targeted therapeutic approach.

Methods: In the present investigation, we evaluated the effects of SARS-CoV₂ on human bronchial epithelial cells (HBEC). We used RNA-seq datasets available online for identifying SARS-CoV₂ potential genes target on human bronchial epithelial cells. RNA expression levels and potential cellular gene pathways have been analyzed. In order to identify possible common strategies among the main pandemic viruses, such as SARS-CoV₂, SARS-CoV1, MERS-CoV, and H1N1, we carried out a hypergeometric test of the main genes transcribed in the cells of the respiratory tract exposed to these viruses.

Results: The analysis showed that two mechanisms are highly regulated in HBEC: the innate immunity recruitment and the disassembly of cilia and cytoskeletal structure. The granulocyte colony-stimulating factor (CSF3) and dynein heavy chain 7, axonemal (DNAH7) represented respectively the most upregulated and downregulated genes belonging to the two mechanisms highlighted above. Furthermore, the carcinoembryonic antigen-related cell adhesion molecule 7 (CEACAM7) that codifies for a surface protein is highly specific of SARS-CoV₂ and not for SARS-CoV1, MERS-CoV, and H1N1, suggesting a potential role in viral entry. In order to identify potential new drugs, using a machine learning approach, we highlighted Flunisolide, Thalidomide, Lenalidomide, Desoximetasone, xylazine, and salmeterol as potential drugs against SARS-CoV₂ infection.

Conclusions: Overall, lung involvement and RDS could be generated by the activation and down regulation of diverse gene pathway involving respiratory cilia and muscle contraction, apoptotic phenomena, matrix destructuration, collagen deposition, neutrophil and macrophages recruitment.

Keywords: Bioinformatics; CEACAM7; COVID-19; CSF3; DNAH7; Innate immunity; Respiratory cilia; SARS-CoV(2); c8orf4.

MeSH terms

Bronchi / metabolism*
Bronchi / pathology
COVID-19
Carcinoembryonic Antigen / genetics
Carcinoembryonic Antigen / metabolism
Coronavirus Infections / genetics*
Coronavirus Infections / metabolism
Drug Discovery / methods
Dyneins / genetics
Dyneins / metabolism
GPI-Linked Proteins / genetics
GPI-Linked Proteins / metabolism
Gene Regulatory Networks*
Granulocyte Colony-Stimulating Factor / genetics
Granulocyte Colony-Stimulating Factor / metabolism
Humans
Immunity, Innate
Machine Learning
Pandemics
Pneumonia, Viral / genetics*
Pneumonia, Viral / metabolism
Respiratory Mucosa / metabolism*
Transcriptome*
Up-Regulation

Substances

CEACAM7 protein, human
Carcinoembryonic Antigen
GPI-Linked Proteins
Granulocyte Colony-Stimulating Factor
DNAH7 protein, human
Dyneins