System Biology Approach to Identify the Hub Genes and Pathways Associated with Human H5N1 Infection

Introduction: H5N1 is a highly pathogenic avian influenza virus that can infect humans and has an estimated fatality rate of 53%. As shown by the current situation of the COVID-19 pandemic, emerging and re-emerging viruses such as H5N1 have the potential to cause another pandemic. Thus, this study outlined the hub genes and pathways associated with H5N1 infection in humans. Methods: The genes associated with H5N1 infection in humans were retrieved from the NCBI Gene database using “H5N1 virus infection” as the keyword. The genes obtained were investigated for protein–protein interaction (PPI) using STRING version 11.5 and studied for functional enrichment analysis using DAVID 2021. Further, the PPI network was visualised and analysed using Cytoscape 3.7.2, and the hub genes were obtained using the local topological analysis method of the cytoHubba plugin. Results: A total of 39 genes associated with H5N1 infection in humans significantly interacted with each other, forming a PPI network with 38 nodes and 149 edges modulating 74 KEGG pathways, 76 biological processes, 13 cellular components, and 22 molecular functions. Further, the PPI network analysis revealed that 33 nodes interacted, forming 1056 shortest paths at 0.282 network density, along with a 1.947 characteristic path length. The local topological analysis predicted IFNA1, IRF3, CXCL8, CXCL10, IFNB1, and CHUK as the critical hub genes in human H5N1 infection. Conclusion: The hub genes associated with the H5N1 infection and their pathways could serve as diagnostic, prognostic, and therapeutic targets for H5N1 infection among humans.

[1]  A. Keshri,et al.  Immunoinformatics Approaches for Vaccine Design: A Fast and Secure Strategy for Successful Vaccine Development , 2023, Vaccines.

[2]  B. Padhi,et al.  Camel Virus (MERS) Reported from Qatar: A Threat to the FIFA-2022 and Middle East. , 2022, QJM : monthly journal of the Association of Physicians.

[3]  B. Padhi,et al.  Rabies on Rise in Africa amid COVID and Monkeypox: A Global Health Concern. , 2022, QJM : monthly journal of the Association of Physicians.

[4]  B. Padhi,et al.  Visceral leishmaniasis outbreak in Kenya—a setback to the elimination efforts , 2022, New microbes and new infections.

[5]  K. Dhama,et al.  Marburg virus re-emerged in 2022: recently detected in Ghana, another zoonotic pathogen coming up amid rising cases of Monkeypox and ongoing COVID-19 pandemic- global health concerns and counteracting measures , 2022, The veterinary quarterly.

[6]  Yue Zhang,et al.  Identification of Critical Genes and Pathways for Influenza A Virus Infections via Bioinformatics Analysis , 2022, Viruses.

[7]  Suowen Xu,et al.  Endothelial Cells as a Key Cell Type for Innate Immunity: A Focused Review on RIG-I Signaling Pathway , 2022, Frontiers in Immunology.

[8]  Brad T. Sherman,et al.  DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update) , 2022, Nucleic Acids Res..

[9]  Jianguo Wu,et al.  AP-1 signaling pathway promotes pro-IL-1β transcription to facilitate NLRP3 inflammasome activation upon influenza A virus infection , 2022, Virulence.

[10]  T. Kuiken,et al.  Avian influenza overview September – December 2021 , 2021, EFSA journal. European Food Safety Authority.

[11]  Suh-Chin Wu,et al.  Site-Specific Glycan-Masking/Unmasking Hemagglutinin Antigen Design to Elicit Broadly Neutralizing and Stem-Binding Antibodies Against Highly Pathogenic Avian Influenza H5N1 Virus Infections , 2021, Frontiers in Immunology.

[12]  Jiayou Zhang,et al.  Identifying Potential Candidate Hub Genes and Functionally Enriched Pathways in the Immune Responses to Quadrivalent Inactivated Influenza Vaccines in the Elderly Through Co-Expression Network Analysis , 2020, Frontiers in Immunology.

[13]  P. Horby,et al.  Serological evidence of human infections with highly pathogenic avian influenza A(H5N1) virus: a systematic review and meta-analysis , 2020, BMC Medicine.

[14]  Nadezhda T. Doncheva,et al.  The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets , 2020, Nucleic Acids Res..

[15]  Guangli Lu,et al.  Novel vaccine design based on genomics data analysis: A review , 2020, Scandinavian journal of immunology.

[16]  K. Ridge,et al.  The cGAS-STING pathway: The role of self-DNA sensing in inflammatory lung disease , 2020, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  Asif M. Khan,et al.  Dynamics of Influenza A (H5N1) virus protein sequence diversity , 2020, PeerJ.

[18]  R. Fouchier,et al.  Phenotypic Effects of Substitutions within the Receptor Binding Site of Highly Pathogenic Avian Influenza H5N1 Virus Observed during Human Infection , 2020, Journal of Virology.

[19]  D. Odimegwu,et al.  Immunoinformatics and Vaccine Development: An Overview , 2020, ImmunoTargets and therapy.

[20]  Yongpeng Xie,et al.  Identification of DDX58 and CXCL10 as Potential Biomarkers in Acute Respiratory Distress Syndrome. , 2019, DNA and cell biology.

[21]  M. Duan,et al.  The induction and consequences of Influenza A virus-induced cell death , 2018, Cell Death & Disease.

[22]  Song-Liang Wang,et al.  Evolution of Influenza A Virus by Mutation and Re-Assortment , 2017, International Journal of Molecular Sciences.

[23]  Zhijian J. Chen,et al.  Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing , 2016, Nature Immunology.

[24]  Yu Sun,et al.  Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis , 2015, Journal of receptor and signal transduction research.

[25]  Guozhong Zhang,et al.  Regulatory roles of c-jun in H5N1 influenza virus replication and host inflammation. , 2014, Biochimica et biophysica acta.

[26]  M. Oldstone,et al.  Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection , 2014, Proceedings of the National Academy of Sciences.

[27]  Jian Li,et al.  The antigenic architecture of the hemagglutinin of influenza H5N1 viruses. , 2013, Molecular immunology.

[28]  C. Clegg,et al.  Clinical vaccine development for H5N1 influenza , 2013, Expert review of vaccines.

[29]  G. Rimmelzwaan,et al.  Evasion of Influenza A Viruses from Innate and Adaptive Immune Responses , 2012, Viruses.

[30]  J. Hibbert,et al.  CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications , 2011, Cytokine & Growth Factor Reviews.

[31]  S. Akira,et al.  Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. , 2011, Immunity.

[32]  Y. Guan,et al.  Induction of Proinflammatory Cytokines in Primary Human Macrophages by Influenza A Virus (H5N1) Is Selectively Regulated by IFN Regulatory Factor 3 and p38 MAPK1 , 2009, The Journal of Immunology.

[33]  Timothy M. Uyeki,et al.  Incubation Period for Human Cases of Avian Influenza A (H5N1) Infection, China , 2008, Emerging infectious diseases.

[34]  K. Ikuta,et al.  H5N1 Avian Influenza Virus Induces Apoptotic Cell Death in Mammalian Airway Epithelial Cells , 2008, Journal of Virology.

[35]  C. Korteweg,et al.  Pathology, Molecular Biology, and Pathogenesis of Avian Influenza A (H5N1) Infection in Humans , 2008, The American Journal of Pathology.

[36]  F. Hayden,et al.  Update on avian influenza A (H5N1) virus infection in humans. , 2008, The New England journal of medicine.

[37]  R. Webster,et al.  Higher polymerase activity of a human influenza virus enhances activation of the hemagglutinin-induced Raf/MEK/ERK signal cascade , 2007, Virology Journal.

[38]  Gabriel Núñez,et al.  Intracellular NOD-like receptors in host defense and disease. , 2007, Immunity.

[39]  T. Tumpey,et al.  Highly Pathogenic Avian Influenza H5N1 Viruses Elicit an Attenuated Type I Interferon Response in Polarized Human Bronchial Epithelial Cells , 2007, Journal of Virology.

[40]  K. Ungchusak,et al.  Apoptosis and Pathogenesis of Avian Influenza A (H5N1) Virus in Humans , 2007, Emerging infectious diseases.

[41]  Y. Guan,et al.  Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells , 2005, Respiratory research.

[42]  R. Webster,et al.  Molecular Determinants within the Surface Proteins Involved in the Pathogenicity of H5N1 Influenza Viruses in Chickens , 2004, Journal of Virology.

[43]  J. Peiris,et al.  Re-emergence of fatal human influenza A subtype H5N1 disease , 2004, The Lancet.

[44]  L. Mitnaul,et al.  Balanced Hemagglutinin and Neuraminidase Activities Are Critical for Efficient Replication of Influenza A Virus , 2000, Journal of Virology.

[45]  OUP accepted manuscript , 2022, Nucleic Acids Research.

[46]  R. Jou,et al.  Incubation Period for Human Cases of Avian Influenza A (H5N1) Infection, China , 2019 .

[47]  Brad T. Sherman,et al.  Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources , 2008, Nature Protocols.

[48]  K. Ikuta,et al.  H5N1 Avian Influenza Virus Induces Apoptotic Cell Death in Mammalian Airway Epithelial Cells (cid:1) † , 2008 .

[49]  F. Hayden.  Writing Committee of the Second World Health Organization (WHO) Consultation on Clinical Aspects of Human Infection with Avian Influenza A(H5N1) Virus , 2007 .

[50]  J. Snick,et al.  Interleukin-6: an overview. , 1990, Annual review of immunology.

[51]  J. Van Snick.  Interleukin-6: an overview. , 1990, Annual review of immunology.