Identification of Effective Genes in Feline Infectious Peritonitis and Drug Repurposing Using Systems Biology Approach

Document Type : Short communication

Authors

• Mohammad Ahmadi Ashtiyani ¹
• Jalal Shayegh ¹
• Ali Rezapour ²
• Habib MotieGhader ³

¹ Department of Veterinary Medicine, Faculty of Veterinary and Agricultural Science, Shabestar Branch, Islamic Azad University, Shabestar, Iran.

² Department of Animal Science, Faculty of Agriculture, Tabriz Branch, Islamic Azad University, Tabriz, Iran.

³ Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran.

10.22067/ijvst.2024.82835.1270

Abstract

FIP is a systemic infectious disease of cats of coronavirus origin. The lack of clear signs of the presence of the virus before clinical form presentation, and the absence of easy and inexpensive diagnostic tests to confirm virus presence are among the problems for controlling and preventing the spread of the virus. In addition, there is not yet any approved medications or treatment protocols for this disease. In this paper, the gene co-expression  network was first reconstructed and modulated using the STRING database and Cytoscape software. The GO and pathways of the modules were obtained using the DAVID and KEGG databases. The most important possible pathways are proteasome, protein processing in the endoplasmic reticulum, protein export, aminoacyl-tRNA biosynthesis, phagosome, tuberculosis, and T cell receptor signaling pathway. In the other part of the study, the gene-drug network regeneration strategy was used to identify a potential medicine reconstructed using the DGIdb database and Cytoscape software using the drug-gene network. BORTEZOMIB, CARFILZOMIB, OPROZOMIB, IXAZOMIB CITRATE, MARIZOMIB, BCG VACCINE, IC14, NELFINAVIR, and RITONAVIR are some of our recommended drugs for this disease. Although our computational strategy predicts repurposable candidate drugs against FIP, more detailed experimental trials and clinical analyses of drug performance, toxicity, and validation are necessary to achieve an accurate and improved treatment protocol.
 

Keywords

• Feline infectious peritonitis
• Systems biology
• Gene co-expression
• Drug repurposing
• Coronaviridae

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References

1.    Olsen M, Cook SE, Huang V, Pedersen N, Murphy BG. Perspectives: potential therapeutic options for SARS-CoV-2 patients based on feline infectious peritonitis strategies: central nervous system invasion and drug coverage. Int J Antimicrob Agents. 2020 Jun;55(6):105964. Doi: 10.1016/j.ijantimicag.2020.105964.
2.    Lin L, Yao D, Wu L, Fan F, Liu Y, Zhoul Z. Molecular epidemiology of type I and II feline coronavirus from cats with suspected feline infectious peritonitis in China between 2019 and 2021. Archives of Virology 2022; 167: 189–194.Doi: 10.3201/eid1807.120143.
3.     Pedersen NC. An update on feline infectious peritonitis: Virology and immunopathogenesis. Veterinary Journal. 2014; 201(2): 123–132. Doi: 10.1016/j.tvjl.2014.04.017.
4.    de Groot RJ, Baker SC, Baric R, et al. Coronaviridae - Positive Sense RNA Viruses - Positive Sense RNA Viruses (2011) - ICTV. Comité Internacional de Taxonomía de Virus (ICTV), https://talk.ictvonline.org/ictv-reports/ictv_9th_report/positive-sense-rna-viruses-2011/w/posrna_viruses/222/coronaviridae (2020, accessed 4 December 2021).
5.    AAddie D, Belák S, Boucraut-Baralon C, Egberink H, Frymus T, et al. Feline infectious peritonitis. ABCD guidelines on prevention and management. J Feline Med Surg. 2009 ;11(7):594-604. doi: 10.1016/j.jfms.2009.05.008. 6. 
6.    Tuanthap S, Chiteafea N, Rattanasrisomporn J, Choowongkomon K. Comparative sequence analysis of the accessory and nucleocapsid genes of feline coronavirus strains isolated from cats diagnosed with effusive feline infectious peritonitis. Arch Virol. 2021;166(10):2779-2787. Doi: 10.1007/s00705-021-05188-7
7.     elten S, Hartmann K. Diagnosis of Feline Infectious Peritonitis: A Review of the Current Literature. Viruses. 2019 Nov 15;11(11):1068. Doi: 10.3390/v11111068. 
8.     Takano T, Hohdatsu T, Hashida Y, Kaneko Y, Tanabe M, Koyama H. A "possible" involvement of TNF-alpha in apoptosis induction in peripheral blood lymphocytes of cats with feline infectious peritonitis. Vet Microbiol. 2007 Jan 31;119(2-4):121-31. Doi: 10.1016/j.vetmic.2006.08.033.
9.    Sherman BT, Hao M, Qiu J, Jiao X, Baseler MW, Lane HC, Imamichi T, Chang W. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022;50(W1):W216-W221. Doi: 10.1093/nar/gkac194.
10.    Zhang B, Horvath S. A general framework for weighted gene co-expression network analysis. Statistical Applications in Genetics and Molecular Biology; 4. Epub ahead of print 2005. Doi: 10.2202/1544-6115.1128.
11.     Malbon AJ, Russo G, Burgener C, Barker EN, Meli ML, Tasker S, Kipar A. The Effect of Natural Feline Coronavirus Infection on the Host Immune Response: A Whole-Transcriptome Analysis of the Mesenteric Lymph Nodes in Cats with and without Feline Infectious Peritonitis. Pathogens. 2020 Jun 29;9(7):524. Doi: 10.3390/pathogens9070524.
12.     Szklarczyk D, Gable AL, Nastou KC, Lyon D, Kirsch R, Pyysalo S, et al. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2021;49(D1):D605-D612. Doi: 10.1093/nar/gkaa1074. Erratum in: Nucleic Acids Res. 2021;49(18):10800. Doi: 10.1093/nar/gkab835. 
13.     Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003 Nov;13(11):2498-504. Doi: 10.1101/gr.1239303.
14.     Wang J, Zhong J, Chen G, Li M, Wu FX, Pan Y. ClusterViz: A Cytoscape APP for Cluster Analysis of Biological Network. IEEE/ACM Trans Comput Biol Bioinform. 2015 ;12(4):815-22. Doi: 10.1109/TCBB.2014.2361348. 
16.    Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000 ;25(1):25-9. Doi: 10.1038/75556
17.    Kanehisa M. Toward understanding the origin and evolution of cellular organisms. Protein Sci. 2019;28(11):1947-1951. Doi: 10.1002/pro.3715. 
18.     Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res. 2021;49(D1):D545-D551. Doi: 10.1093/nar/gkaa970. 
19.     Kanehisa M, Goto S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Research 2000; 28: 27–30.
20.     Freshour SL, Kiwala S, Cotto KC, Coffman AC, McMichael JF, Song JJ, et al. Integration of the Drug-Gene Interaction Database (DGIdb 4.0) with open crowdsource efforts. Nucleic Acids Res. 2021;49(D1):D1144-D1151. Doi: 10.1093/nar/gkaa1084. 
21.    Hari P, Matous JV, Voorhees PM, Shain KH, Obreja M, Frye J, et al. Oprozomib in patients with newly diagnosed multiple myeloma. Blood Cancer J. 2019;9(9):66. Doi: 10.1038/s41408-019-0232-6. 
22.    Kortuem KM, Stewart AK. Carfilzomib. Blood. 2013;121(6):893-7. Doi: 10.1182/blood-2012-10-459883. 
23.     Mujtaba T, Dou QP. Advances in the understanding of mechanisms and therapeutic use of bortezomib. Discov Med. 2011 ;12(67):471-80. 
24.    Offidani M, Corvatta L, Caraffa P, Gentili S, Maracci L, Leoni P. An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma. Onco Targets Ther. 2014;7:1793-800. Doi: 10.2147/OTT.S49187.
25.    Potts BC, Albitar MX, Anderson KC, Baritaki S, Berkers C, Bonavida B, et al. Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials. Curr Cancer Drug Targets. 2011;11(3):254-84. Doi: 10.2174/156800911794519716. 
26.    Adams J. The development of proteasome inhibitors as anticancer drugs. Cancer Cell. 2004;5(5):417-21. ِoi: 10.1016/s1535-6108(04)00120-5. 
27.     Schneider SM, Lee BH, Nicola AV. Viral entry and the ubiquitin-proteasome system. Cell Microbiol. 2021;23(2):e13276. Doi: 10.1111/cmi.13276. 
28    Raaben M, Posthuma CC, Verheije MH, te Lintelo EG, Kikkert M, Drijfhout JW, et al. The ubiquitin-proteasome system plays an important role during various stages of the coronavirus infection cycle. J Virol. 2010 ;84(15):7869-79. Doi: 10.1128/JVI.00485-10. 
29.     Bowdish DM, Sakamoto K, Kim MJ, Kroos M, Mukhopadhyay S, Leifer CA, et al. MARCO, TLR2, and CD14 are required for macrophage cytokine responses to mycobacterial trehalose dimycolate and Mycobacterium tuberculosis. PLoS Pathog. 2009;5(6):e1000474. Doi: 10.1371/journal.ppat.1000474. 
30.     Cubillos-Angulo JM, Fernandes CD, Araújo DN, Carmo CA, Arriaga MB, Andrade BB. The influence of single nucleotide polymorphisms of NOD2 or CD14 on the risk of Mycobacterium tuberculosis diseases: a systematic review. Syst Rev. 2021;10(1):174. Doi: 10.1186/s13643-021-01729-y. 
 31.    Won Y, Yang JI, Park S, Chun JS. Lipopolysaccharide Binding Protein and CD14, Cofactors of Toll-like Receptors, Are Essential for Low-Grade Inflammation-Induced Exacerbation of Cartilage Damage in Mouse Models of Posttraumatic Osteoarthritis. Arthritis Rheumatol. 2021;73(8):1451-1460. Doi: 10.1002/art.41679. 
32     Henderson RD, Agosti JM, McCombe PA, Thorpe K, Heggie S, Heshmat S, et al. Phase 1b dose-escalation, safety, and pharmacokinetic study of IC14, a monoclonal antibody against CD14, for the treatment of amyotrophic lateral sclerosis. Medicine (Baltimore). 2021;100(42):e27421. Doi: 10.1097/MD.0000000000027421. 
33.    Messner CB, Demichev V, Wendisch D, Michalick L, White M, Freiwald A, Tet al.Ultra-High-Throughput Clinical Proteomics Reveals Classifiers of COVID-19 Infection. Cell Syst. 2020 ;11(1):11-24.e4. Doi: 10.1016/j.cels.2020.05.012. 
34.    Bardsley-Elliot A, Plosker GL. Nelfinavir: an update on its use in HIV infection. Drugs. 2000;59(3):581-620. Doi: 10.2165/00003495-200059030-00014. 
35.     Hsieh LE, Lin CN, Su BL, Jan TR, Chen CM, Wang CH, et al. Synergistic antiviral effect of Galanthus nivalis agglutinin and nelfinavir against feline coronavirus. Antiviral Res. 2010 ;88(1):25-30. Doi: 10.1016/j.antiviral.2010.06.010. 
36.    Ohashi H, Watashi K, Saso W, Shionoya K, Iwanami S, Hirokawa T, et al. Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment. iScience. 2021;24(4):102367. Doi: 10.1016/j.isci.2021.102367. 
37.    Hsu A, Granneman GR, Bertz RJ. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet. 1998 Oct;35(4):275-91. Doi: 10.2165/00003088-199835040-00002. Erratum in: Clin Pharmacokinet 1998;35(6):473. 
38.    Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020;382(19):1787-1799. Doi: 10.1056/NEJMoa2001282. 
39.     Pedersen NC, Kim Y, Liu H, Galasiti Kankanamalage AC, Eckstrand C, Groutas WC, et al. Efficacy of a 3C-like protease inhibitor in treating various forms of acquired feline infectious peritonitis. J Feline Med Surg. 2018;20(4):378-392. Doi: 10.1177/1098612X17729626. 
40.    Murphy BG, Perron M, Murakami E, Bauer K, Park Y, Eckstrand C, et al. The nucleoside analog GS-441524 strongly inhibits feline infectious peritonitis (FIP) virus in tissue culture and experimental cat infection studies. Vet Microbiol. 2018;219:226-233. Doi: 10.1016/j.vetmic.2018.04.026. 
41.     Richman DD. Antiviral drug resistance. Antiviral Res. 2006 ;71(2-3):117-21. Doi: 10.1016/j.antiviral.2006.03.004. 
42.    Delaplace M, Huet H, Gambino A, Le Poder S. Feline Coronavirus Antivirals: A Review. Pathogens. 2021;10(9):1150. Doi: 10.3390/pathogens10091150. 
43.     McFee RB. COVID-19: Therapeutics and interventions currently under consideration. Dis Mon. 2020;66(9):101058. Doi: 10.1016/j.disamonth.2020.101058. 
44.     Amirian ES, Levy JK. Current knowledge about the antivirals remdesivir (GS-5734) and GS-441524 as therapeutic options for coronaviruses. One Health 2020; 9: 100128. Doi:10.1016/j.onehlt.2020.100128.
45.    Yan VC, Muller FL. Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment. ACS Med Chem Lett. 2020;11(7):1361-1366. Doi: 10.1021/acsmedchemlett.0c00316.