{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T13:43:16Z","timestamp":1780926196444,"version":"3.54.1"},"reference-count":52,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Measles, hepatitis C, and COVID-19 are significant human diseases caused by RNA viruses. While vaccines exist to prevent infections, there are a small number of currently available therapeutic agents that can effectively treat these diseases after infection occurs. This study explores a new therapeutic strategy using a small molecule designated polyprenyl immunostimulant (PI) to increase innate immune responses and combat viral infections. Using a multi-disciplinary approach, this study quantifies the effects of PI in mice and THP-1 cells using flow cytometry to identify immune phenotypic markers and mass spectroscopy to monitor the metabolomic profiles of immune cells perturbed by PI treatment. The metabolomic studies identified that sphinganine and ceramide, which are precursors of sphingosine-1-phosphate (S1P), were the common metabolites upregulated in THP-1 and mice blood. Sphingosine-1-phosphate can mediate the trafficking of T cells, whereas ceramide can signal the activation and proliferation of T cells, thereby modulating the mammalian host\u2019s immunity. To demonstrate proof-of-principle, a case study was conducted to examine the benefit of administering PI to improve the outcomes of a feline co-infected with two distinct RNA viruses\u2014feline leukemia virus and feline infectious peritonitis virus. Both viruses produce deadly symptoms that closely resemble RNA viruses that infect humans. The results identify quantifiable cellular and metabolic markers arising from PI treatment that can be used to establish a platform measuring the efficacy of PI in modulating the innate immune system.<\/jats:p>","DOI":"10.3390\/cells14100752","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T07:44:57Z","timestamp":1747813497000},"page":"752","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Utilization of Flow Cytometry, Metabolomic Analyses and a Feline Infectious Peritonitis Case Study to Evaluate the Physiological Impact of Polyprenyl Immunostimulant"],"prefix":"10.3390","volume":"14","author":[{"given":"Irene","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amar","family":"Desai","sequence":"additional","affiliation":[{"name":"CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshay","family":"Patil","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2697-1297","authenticated-orcid":false,"given":"Yan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelley","family":"Pozza-Adams","sequence":"additional","affiliation":[{"name":"Tremont Animal Clinic, 2885 W 25th St, Cleveland, OH 44113, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0318-0951","authenticated-orcid":false,"given":"Anthony J","family":"Berdis","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Banerjee, A., Kulcsar, K., Misra, V., Frieman, M., and Mossman, K. (2019). Bats and Coronaviruses. Viruses, 11.","DOI":"10.3389\/fimmu.2020.00026"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/s41579-018-0118-9","article-title":"Origin and evolution of pathogenic coronaviruses","volume":"17","author":"Cui","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-4939-2438-7_1","article-title":"Coronaviruses: An overview of their replication and pathogenesis","volume":"1282","author":"Fehr","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.virusres.2007.03.012","article-title":"A review of studies on animal reservoirs of the SARS coronavirus","volume":"133","author":"Shi","year":"2008","journal-title":"Virus Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0065-3527(06)66005-3","article-title":"The molecular biology of coronaviruses","volume":"66","author":"Masters","year":"2006","journal-title":"Adv. Virus Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/B978-0-12-385885-6.00009-2","article-title":"Coronavirus pathogenesis","volume":"81","author":"Weiss","year":"2011","journal-title":"Adv. Virus Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"76","DOI":"10.2174\/1874357901004010076","article-title":"Understanding Human Coronavirus HCoV-NL63","volume":"4","author":"Fielding","year":"2010","journal-title":"Open Virol. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/bs.aivir.2018.01.001","article-title":"Hosts and Sources of Endemic Human Coronaviruses","volume":"100","author":"Corman","year":"2018","journal-title":"Adv. Virus Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11325","DOI":"10.1128\/JVI.05512-11","article-title":"Molecular epidemiology of human coronavirus OC43 reveals evolution of different genotypes over time and recent emergence of a novel genotype due to natural recombination","volume":"85","author":"Lau","year":"2011","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1128\/JCM.02614-05","article-title":"Coronavirus HKU1 and other coronavirus infections in Hong Kong","volume":"44","author":"Lau","year":"2006","journal-title":"J. Clin. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2940","DOI":"10.1128\/JCM.00636-10","article-title":"Epidemiology and clinical presentations of the four human coronaviruses 229E, HKU1, NL63, and OC43 detected over 3 years using a novel multiplex real-time PCR method","volume":"48","author":"Gaunt","year":"2010","journal-title":"J. Clin. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Chafekar, A., and Fielding, B.C. (2018). MERS-CoV: Understanding the Latest Human Coronavirus Threat. Viruses, 10.","DOI":"10.20944\/preprints201711.0198.v2"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.antiviral.2013.08.016","article-title":"Clinical management and infection control of SARS: Lessons learned","volume":"100","author":"Cheng","year":"2013","journal-title":"Antivir. Res."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Desforges, M., Le Coupanec, A., Dubeau, P., Bourgouin, A., Lajoie, L., Dube, M., and Talbot, P.J. (2019). Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?. Viruses, 12.","DOI":"10.3390\/v12010014"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1186\/s12985-015-0439-5","article-title":"MERS coronavirus: Diagnostics, epidemiology and transmission","volume":"12","author":"Mackay","year":"2015","journal-title":"Virol. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e792","DOI":"10.1016\/j.ijid.2013.07.002","article-title":"Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV)\u2014Possible lessons from a systematic review of SARS-CoV therapy","volume":"17","author":"Momattin","year":"2013","journal-title":"Int. J. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1196\/annals.1408.002","article-title":"The molecular biology of SARS coronavirus","volume":"1102","author":"Satija","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Song, Z., Xu, Y., Bao, L., Zhang, L., Yu, P., Qu, Y., Zhu, H., Zhao, W., Han, Y., and Qin, C. (2019). From SARS to MERS, Thrusting Coronaviruses into the Spotlight. Viruses, 11.","DOI":"10.3390\/v11010059"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1128\/MMBR.69.4.635-664.2005","article-title":"Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus","volume":"69","author":"Weiss","year":"2005","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"313","DOI":"10.4014\/jmb.2003.03011","article-title":"Current Status of Epidemiology, Diagnosis, Therapeutics, and Vaccines for Novel Coronavirus Disease 2019 (COVID-19)","volume":"30","author":"Ahn","year":"2020","journal-title":"J. Microbiol. Biotechnol."},{"key":"ref_21","first-page":"11","article-title":"The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak\u2014An update on the status","volume":"7","author":"Guo","year":"2020","journal-title":"Mil. Med. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"146443","DOI":"10.1016\/j.gene.2022.146443","article-title":"Mind the feline coronavirus: Comparison with SARS-CoV-2","volume":"825","author":"Gao","year":"2022","journal-title":"Gene"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1111\/j.1748-5827.1998.tb03691.x","article-title":"Feline infectious peritonitis","volume":"39","author":"Barr","year":"1998","journal-title":"J. Small Anim. Pract."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1177\/0300985814522077","article-title":"Feline infectious peritonitis: Still an enigma?","volume":"51","author":"Kipar","year":"2014","journal-title":"Vet. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.tvjl.2014.04.016","article-title":"An update on feline infectious peritonitis: Diagnostics and therapeutics","volume":"201","author":"Pedersen","year":"2014","journal-title":"Vet. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102537","DOI":"10.1016\/j.autrev.2020.102537","article-title":"The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease","volume":"19","author":"McGonagle","year":"2020","journal-title":"Autoimmun. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zanza, C., Romenskaya, T., Manetti, A.C., Franceschi, F., La Russa, R., Bertozzi, G., Maiese, A., Savioli, G., Volonnino, G., and Longhitano, Y. (2022). Cytokine Storm in COVID-19: Immunopathogenesis and Therapy. Medicina, 58.","DOI":"10.3390\/medicina58020144"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"73","DOI":"10.5582\/ddt.2020.01015","article-title":"Rapid review for the anti-coronavirus effect of remdesivir","volume":"14","author":"Li","year":"2020","journal-title":"Drug Discov. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1056\/NEJMoa2007764","article-title":"Remdesivir for the Treatment of COVID-19\u2014Final Report","volume":"383","author":"Beigel","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Tian, L., Pang, Z., Li, M., Lou, F., An, X., Zhu, S., Song, L., Tong, Y., Fan, H., and Fan, J. (2022). Molnupiravir and Its Antiviral Activity Against COVID-19. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.855496"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3087","DOI":"10.1111\/jvim.17187","article-title":"Open label clinical trial of orally administered molnupiravir as a first-line treatment for naturally occurring effusive feline infectious peritonitis","volume":"38","author":"Reagan","year":"2024","journal-title":"J. Vet. Intern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Legendre, A.M., Kuritz, T., Heidel, R.E., and Baylor, V.M. (2017). Polyprenyl Immunostimulant in Feline Rhinotracheitis: Randomized Placebo-Controlled Experimental and Field Safety Studies. Front. Vet. Sci., 4.","DOI":"10.3389\/fvets.2017.00024"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Cerna, P., Ayoob, A., Baylor, C., Champagne, E., Hazanow, S., Heidel, R.E., Wirth, K., Legendre, A.M., and Gunn-Moore, D.A. (2022). Retrospective Survival Analysis of Cats with Feline Infectious Peritonitis Treated with Polyprenyl Immunostimulant That Survived over 365 Days. Pathogens, 11.","DOI":"10.3390\/pathogens11080881"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.jfms.2008.12.002","article-title":"Effect of Polyprenyl Immunostimulant on the survival times of three cats with the dry form of feline infectious peritonitis","volume":"11","author":"Legendre","year":"2009","journal-title":"J. Feline Med. Surg."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Legendre, A.M., Kuritz, T., Galyon, G., Baylor, V.M., and Heidel, R.E. (2017). Polyprenyl Immunostimulant Treatment of Cats with Presumptive Non-Effusive Feline Infectious Peritonitis In a Field Study. Front. Vet. Sci., 4.","DOI":"10.3389\/fvets.2017.00007"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Sykes, J.E., and Hartmann, K. (2014). Feline Leukemia Virus Infection. Canine Feline Infect. Dis., 224\u2013238.","DOI":"10.1016\/B978-1-4377-0795-3.00022-3"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Tasker, S., Addie, D.D., Egberink, H., Hofmann-Lehmann, R., Hosie, M.J., Truyen, U., Bel\u00e1k, S., Boucraut-Baralon, C., Frymus, T., and Lloret, A. (2023). Feline Infectious Peritonitis: European Advisory Board on Cat Diseases Guidelines. Viruses, 15.","DOI":"10.3390\/v15091847"},{"key":"ref_38","unstructured":"Kuritz, T. (2018). Methods and Compositions for Modulation of Innate Immunity. (No. 9,872,867), U.S. Patent."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5379","DOI":"10.1038\/s41467-018-07387-4","article-title":"Integrin CD11b activation drives anti-tumor innate immunity","volume":"9","author":"Schmid","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1111\/tbed.13856","article-title":"Feline infectious peritonitis (FIP) and coronavirus disease 19 (COVID-19): Are they similar?","volume":"68","author":"Paltrinieri","year":"2021","journal-title":"Transbound. Emerg. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.intimp.2014.08.002","article-title":"THP-1 cell line: An in vitro cell model for immune modulation approach","volume":"23","author":"Chanput","year":"2014","journal-title":"Int. Immunopharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Liu, G., Lee, D.P., Schmidt, E., and Prasad, G.L. (2019). Pathway Analysis of Global Metabolomic Profiles Identified Enrichment of Caffeine, Energy, and Arginine Metabolism in Smokers but Not Moist Snuff Consumers. Bioinform. Biol. Insights, 13.","DOI":"10.1177\/1177932219882961"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1038\/s12276-023-01018-9","article-title":"Functional roles of sphingolipids in immunity and their implication in disease","volume":"55","author":"Lee","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Starr, T., Bauler, T.J., Malik-Kale, P., and Steele-Mortimer, O. (2018). The phorbol 12-myristate-13-acetate differentiation protocol is critical to the interaction of THP-1 macrophages with Salmonella Typhimurium. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193601"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Cerna, P., Dow, S., Wheat, W., Chow, L., Hawley, J., and Lappin, M.R. (2024). Comparison of Antiviral Immune Responses in Healthy Cats Induced by Two Immune Therapeutics. Pathogens, 13.","DOI":"10.3390\/pathogens13070602"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Roy, M., Jacque, N., Novicoff, W., Li, E., Negash, R., and Evans, S.J.M. (2022). Unlicensed Molnupiravir is an Effective Rescue Treatment Following Failure of Unlicensed GS-441524-like Therapy for Cats with Suspected Feline Infectious Peritonitis. Pathogens, 11.","DOI":"10.3390\/pathogens11101209"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Zuzzi-Krebitz, A.M., Buchta, K., Bergmann, M., Krentz, D., Zwicklbauer, K., Dorsch, R., Wess, G., Fischer, A., Matiasek, K., and Honl, A. (2024). Short Treatment of 42 Days with Oral GS-441524 Results in Equal Efficacy as the Recommended 84-Day Treatment in Cats Suffering from Feline Infectious Peritonitis with Effusion\u2014A Prospective Randomized Controlled Study. Viruses, 16.","DOI":"10.3390\/v16071144"},{"key":"ref_48","first-page":"41","article-title":"Case studies on RetroMAD1\u2122, an orally administered recombinant chimeric protein to treat naturally infected Feline Leukemia Virus (FeLV) cats","volume":"2","author":"Ung","year":"2019","journal-title":"Arch. Vet. Sci. Med."},{"key":"ref_49","unstructured":"Martin, C.R., Patel, V.B., and Preedy, V.R. (2023). Chapter 31\u2014Restoration of myelination in the central nervous system via specific dietary bioactive lipids: An opportunity to halt disease progression in multiple sclerosis. Diet and Nutrition in Neurological Disorders, Academic Press."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e83073","DOI":"10.7554\/eLife.83073","article-title":"Cell-intrinsic ceramides determine T cell function during melanoma progression","volume":"11","author":"Hose","year":"2022","journal-title":"Elife"},{"key":"ref_51","first-page":"81","article-title":"The Revival of an \u201cOld\u201d Marker: CD4\/CD8 Ratio","volume":"19","author":"Bruno","year":"2017","journal-title":"AIDS Rev."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Sweet, A.N., Andre, N.M., Stout, A.E., Licitra, B.N., and Whittaker, G.R. (2022). Clinical and Molecular Relationships between COVID-19 and Feline Infectious Peritonitis (FIP). Viruses, 14.","DOI":"10.3390\/v14030481"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/10\/752\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:36:19Z","timestamp":1760031379000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/10\/752"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,21]]},"references-count":52,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["cells14100752"],"URL":"https:\/\/doi.org\/10.3390\/cells14100752","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,21]]}}}