1887

Abstract

Anti-microbial compounds typically exert their action by directly interfering with one or more stages of the pathogen’s life cycle. However, some compounds also have secondary effects on the host that aid in pathogen clearance. Raltegravir is a human immunodeficiency virus (HIV)-integrase inhibitor that has been shown to alter the host immune response to HIV in addition to its direct antiviral effect. Interestingly, raltegravir can also directly inhibit the replication of various herpesviruses. However, the host-targeted effects of this drug in the context of a herpesvirus infection have not been explored. Here, we used felid alphaherpesvirus 1 (FHV-1), a close relative of human alphaherpesvirus 1 (HHV-1) that similarly causes ocular herpes, to characterize the host-targeted effects of raltegravir on corneal epithelial cells during an alphaherpesvirus infection. Using RNA deep sequencing, we found that raltegravir specifically boosts the expression of anti-angiogenic factors and promotes metabolic homeostasis in FHV-1-infected cells. In contrast, few changes in host gene transcription were found in uninfected cells. Importantly, we were able to demonstrate that these effects were specific to raltegravir and independent of the direct-acting antiviral effect of the drug, since treatment with the DNA polymerase inhibitor phosphonoacetic acid did not induce these host-targeted effects. Taken together, these results indicate that raltegravir has profound and specific effects on the host transcription profile of herpesvirus-infected cells that may contribute to the overall antiviral activity of the drug and could provide therapeutic benefits in vivo. Furthermore, this study provides a framework for future efforts evaluating the host-targeted effects of anti-microbial compounds.

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2018-06-19
2019-09-18
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References

  1. Razonable RR. Antiviral drugs for viruses other than human immunodeficiency virus. Mayo Clin Proc 2011;86:1009–1026 [CrossRef][PubMed]
    [Google Scholar]
  2. de Clercq E, Li G. Approved antiviral drugs over the past 50 years. Clin Microbiol Rev 2016;29:695–747 [CrossRef][PubMed]
    [Google Scholar]
  3. Labro MT. Immunomodulatory effects of antimicrobial agents. Part I: antibacterial and antiviral agents. Expert Rev Anti Infect Ther 2012;10:319–340 [CrossRef][PubMed]
    [Google Scholar]
  4. Boriskin YS, Leneva IA, Pécheur EI, Polyak SJ. Arbidol: a broad-spectrum antiviral compound that blocks viral fusion. Curr Med Chem 2008;15:997–1005 [CrossRef][PubMed]
    [Google Scholar]
  5. Perfetto B, Filosa R, de Gregorio V, Peduto A, La Gatta A et al. In vitro antiviral and immunomodulatory activity of arbidol and structurally related derivatives in herpes simplex virus type 1-infected human keratinocytes (HaCat). J Med Microbiol 2014;63:1474–1483 [CrossRef][PubMed]
    [Google Scholar]
  6. Redwan EM, Uversky VN, El-Fakharany EM, Al-Mehdar H. Potential lactoferrin activity against pathogenic viruses. C R Biol 2014;337:581–595 [CrossRef][PubMed]
    [Google Scholar]
  7. Wakabayashi H, Oda H, Yamauchi K, Abe F. Lactoferrin for prevention of common viral infections. J Infect Chemother 2014;20:666–671 [CrossRef][PubMed]
    [Google Scholar]
  8. Wakabayashi H, Kurokawa M, Shin K, Teraguchi S, Tamura Y et al. Oral lactoferrin prevents body weight loss and increases cytokine responses during herpes simplex virus type 1 infection of mice. Biosci Biotechnol Biochem 2004;68:537–544 [CrossRef][PubMed]
    [Google Scholar]
  9. Zheng Y, Qin Z, Ye Q, Chen P, Wang Z et al. Lactoferrin suppresses the Epstein-Barr virus-induced inflammatory response by interfering with pattern recognition of TLR2 and TLR9. Lab Invest 2014;94:1188–1199 [CrossRef][PubMed]
    [Google Scholar]
  10. Summa V, Petrocchi A, Bonelli F, Crescenzi B, Donghi M et al. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J Med Chem 2008;51:5843–5855 [CrossRef][PubMed]
    [Google Scholar]
  11. Ingale KB, Bhatia MS. HIV-1 integrase inhibitors: a review of their chemical development. Antivir Chem Chemother 2011;22:95–105 [CrossRef][PubMed]
    [Google Scholar]
  12. Mouscadet JF, Tchertanov L. Raltegravir: molecular basis of its mechanism of action. Eur J Med Res 2009;14:5–16 [CrossRef][PubMed]
    [Google Scholar]
  13. Ouyang Z, Buzon MJ, Zheng L, Sun H, Yu XG et al. Transcriptional changes in CD8(+) T cells during antiretroviral therapy intensified with raltegravir. Open Forum Infect Dis 2015;2:ofv045 [CrossRef][PubMed]
    [Google Scholar]
  14. Nadal M, Mas PJ, Mas PJ, Blanco AG, Arnan C et al. Structure and inhibition of herpesvirus DNA packaging terminase nuclease domain. Proc Natl Acad Sci USA 2010;107:16078–16083 [CrossRef][PubMed]
    [Google Scholar]
  15. Zhou B, Yang K, Wills E, Tang L, Baines JD. A mutation in the DNA polymerase accessory factor of herpes simplex virus 1 restores viral DNA replication in the presence of raltegravir. J Virol 2014;88:11121–11129 [CrossRef][PubMed]
    [Google Scholar]
  16. Maes R. Felid herpesvirus type 1 infection in cats: a natural host model for alphaherpesvirus pathogenesis. ISRN Vet Sci 2012;2012:1–14 [CrossRef][PubMed]
    [Google Scholar]
  17. Gaskell R, Dawson S, Radford A, Thiry E. Feline herpesvirus. Vet Res 2007;38:337–354 [CrossRef][PubMed]
    [Google Scholar]
  18. Pennington MR, Fort MW, Ledbetter EC, Van de Walle GR. A novel corneal explant model system to evaluate antiviral drugs against feline herpesvirus type 1 (FHV-1). J Gen Virol 2016;97:1414–1425 [CrossRef][PubMed]
    [Google Scholar]
  19. Giménez F, Suryawanshi A, Rouse BT. Pathogenesis of herpes stromal keratitis–a focus on corneal neovascularization. Prog Retin Eye Res 2013;33:1–9 [CrossRef][PubMed]
    [Google Scholar]
  20. Kaye S, Choudhary A. Herpes simplex keratitis. Prog Retin Eye Res 2006;25:355–380 [CrossRef][PubMed]
    [Google Scholar]
  21. Thompson MR, Xu D, Williams BR. ATF3 transcription factor and its emerging roles in immunity and cancer. J Mol Med 2009;87:1053–1060 [CrossRef][PubMed]
    [Google Scholar]
  22. Shu M, Du T, Zhou G, Roizman B. Role of activating transcription factor 3 in the synthesis of latency-associated transcript and maintenance of herpes simplex virus 1 in latent state in ganglia. Proc Natl Acad Sci USA 2015;112:E5420E5426 [CrossRef][PubMed]
    [Google Scholar]
  23. Shirwany NA, Zou MH. AMPK: a cellular metabolic and redox sensor. A minireview. Front Biosci 2014;19:447–474 [CrossRef][PubMed]
    [Google Scholar]
  24. Panayiotou C, Solaroli N, Karlsson A. The many isoforms of human adenylate kinases. Int J Biochem Cell Biol 2014;49:75–83 [CrossRef][PubMed]
    [Google Scholar]
  25. Huang SH, Tang A, Drisco B, Zhang SQ, Seeger R et al. Human dTMP kinase: gene expression and enzymatic activity coinciding with cell cycle progression and cell growth. DNA Cell Biol 1994;13:461–471 [CrossRef][PubMed]
    [Google Scholar]
  26. Munch-Petersen B. Enzymatic regulation of cytosolic thymidine kinase 1 and mitochondrial thymidine kinase 2: a mini review. Nucleosides Nucleotides Nucleic Acids 2010;29:363–369 [CrossRef][PubMed]
    [Google Scholar]
  27. Lu SC, Mato JM. S-Adenosylmethionine in cell growth, apoptosis and liver cancer. J Gastroenterol Hepatol 2008;23:S73–77 [CrossRef][PubMed]
    [Google Scholar]
  28. Nagai MA. Pleckstrin homology-like domain, family A, member 1 (PHLDA1) and cancer. Biomed Rep 2016;4:275–281 [CrossRef][PubMed]
    [Google Scholar]
  29. Patil K, Bellner L, Cullaro G, Gotlinger KH, Dunn MW et al. Heme oxygenase-1 induction attenuates corneal inflammation and accelerates wound healing after epithelial injury. Invest Ophthalmol Vis Sci 2008;49:3379 [CrossRef][PubMed]
    [Google Scholar]
  30. Halilovic A, Patil KA, Bellner L, Marrazzo G, Castellano K et al. Knockdown of heme oxygenase-2 impairs corneal epithelial cell wound healing. J Cell Physiol 2011;226:1732–1740 [CrossRef][PubMed]
    [Google Scholar]
  31. Santangelo R, Mancuso C, Marchetti S, di Stasio E, Pani G et al. Bilirubin: an endogenous molecule with antiviral activity in vitro. Front Pharmacol 2012;3:36 [CrossRef][PubMed]
    [Google Scholar]
  32. Espinoza JA, González PA, Kalergis AM. Modulation of antiviral immunity by heme oxygenase-1. Am J Pathol 2017;187:487–493 [CrossRef][PubMed]
    [Google Scholar]
  33. Soares MP, Bach FH. Heme oxygenase-1: from biology to therapeutic potential. Trends Mol Med 2009;15:50–58 [CrossRef][PubMed]
    [Google Scholar]
  34. Zhao J, Tan S, Liu F, Zhang Y, Su M et al. Heme oxygenase and ocular disease: a review of the literature. Curr Eye Res 2012;37:955–960 [CrossRef][PubMed]
    [Google Scholar]
  35. Castilho Á, Aveleira CA, Leal EC, Simões NF, Fernandes CR et al. Heme oxygenase-1 protects retinal endothelial cells against high glucose- and oxidative/nitrosative stress-induced toxicity. PLoS One 2012;7:e42428 [CrossRef][PubMed]
    [Google Scholar]
  36. Keese CR, Wegener J, Walker SR, Giaever I. Electrical wound-healing assay for cells in vitro. Proc Natl Acad Sci USA 2004;101:1554–1559 [CrossRef][PubMed]
    [Google Scholar]
  37. Pennington M, Ledbetter E, Van de Walle G. New paradigms for the study of ocular alphaherpesvirus infections: insights into the use of non-traditional host model systems. Viruses 2017;9:349 [CrossRef]
    [Google Scholar]
  38. Gutierrez AD, Balasubramanyam A. Dysregulation of glucose metabolism in HIV patients: epidemiology, mechanisms, and management. Endocrine 2012;41:1–10 [CrossRef][PubMed]
    [Google Scholar]
  39. Derakhshan M, Willcocks MM, Salako MA, Kass GE, Carter MJ. Human herpesvirus 1 protein US3 induces an inhibition of mitochondrial electron transport. J Gen Virol 2006;87:2155–2159 [CrossRef][PubMed]
    [Google Scholar]
  40. Abrantes JL, Alves CM, Costa J, Almeida FC, Sola-Penna M et al. Herpes simplex type 1 activates glycolysis through engagement of the enzyme 6-phosphofructo-1-kinase (PFK-1). Biochim Biophys Acta 2012;1822:1198–1206 [CrossRef][PubMed]
    [Google Scholar]
  41. Varanasi SK, Donohoe D, Jaggi U, Rouse BT. Manipulating glucose metabolism during different stages of viral pathogenesis can have either detrimental or beneficial effects. J Immunol 2017;199:1748–1761 [CrossRef][PubMed]
    [Google Scholar]
  42. Yadav SS, Narayan G. Role of ROBO4 signalling in developmental and pathological angiogenesis. Biomed Res Int 2014;2014:1–9 [CrossRef][PubMed]
    [Google Scholar]
  43. Wang W, Li GY, Zhu JY, Huang DB, Zhou HC et al. Overexpression of AGGF1 is correlated with angiogenesis and poor prognosis of hepatocellular carcinoma. Med Oncol 2015;32:131 [CrossRef][PubMed]
    [Google Scholar]
  44. Stiebel-Kalish H, Gaton DD, Weinberger D, Loya N, Schwartz-Ventik M et al. A comparison of the effect of hyaluronic acid versus gentamicin on corneal epithelial healing. Eye 1998;12:829–833 [CrossRef][PubMed]
    [Google Scholar]
  45. Gomes JA, Amankwah R, Powell-Richards A, Dua HS. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br J Ophthalmol 2004;88:821–825 [CrossRef][PubMed]
    [Google Scholar]
  46. Sandri-Goldin RM. The many roles of the regulatory protein ICP27 during herpes simplex virus infection. Front Biosci 2008;13:5241–5256 [CrossRef][PubMed]
    [Google Scholar]
  47. Sandri-Goldin RM. The many roles of the highly interactive HSV protein ICP27, a key regulator of infection. Future Microbiol 2011;6:1261–1277 [CrossRef][PubMed]
    [Google Scholar]
  48. Rivas HG, Schmaling SK, Gaglia MM. Shutoff of host gene expression in influenza a virus and herpesviruses: similar mechanisms and common themes. Viruses 2016;8:102 [CrossRef][PubMed]
    [Google Scholar]
  49. Rutkowski AJ, Erhard F, L'Hernault A, Bonfert T, Schilhabel M et al. Widespread disruption of host transcription termination in HSV-1 infection. Nat Commun 2015;6:7126 [CrossRef][PubMed]
    [Google Scholar]
  50. Sandmeyer LS, Keller CB, Bienzle D. Culture of feline corneal epithelial cells and infection with feline herpesvirus-1 as an investigative tool. Am J Vet Res 2005;66:205–209 [CrossRef][PubMed]
    [Google Scholar]
  51. Baddal B, Muzzi A, Censini S, Calogero RA, Torricelli G et al. Dual RNA-seq of nontypeable haemophilus influenzae and host cell transcriptomes reveals novel insights into host-pathogen cross talk. MBio 2015;6:e01765-15 [CrossRef][PubMed]
    [Google Scholar]
  52. Jeffers V, Gao H, Checkley LA, Liu Y, Ferdig MT et al. Garcinol inhibits GCN5-mediated lysine acetyltransferase activity and prevents replication of the parasite toxoplasma gondii. Antimicrob Agents Chemother 2016;60:2164–2170 [CrossRef][PubMed]
    [Google Scholar]
  53. Baer A, Lundberg L, Swales D, Waybright N, Pinkham C et al. Venezuelan equine encephalitis virus induces apoptosis through the unfolded protein response activation of EGR1. J Virol 2016;90:3558–3572 [CrossRef][PubMed]
    [Google Scholar]
  54. Walton TE, Gillespie JH. Feline viruses. VII. Immunity to the feline herpesvirus in kittens inoculated experimentally by the aerosol method. Cornell Vet 1970;60:232–239[PubMed]
    [Google Scholar]
  55. Pennington MR, van de Walle GR. Electric cell-substrate impedance sensing to monitor viral growth and study cellular responses to infection with alphaherpesviruses in real time. mSphere 2017;2:e00039-17 [CrossRef][PubMed]
    [Google Scholar]
  56. Kirkconnell KS, Paulsen MT, Magnuson B, Bedi K, Ljungman M. Capturing the dynamic nascent transcriptome during acute cellular responses: the serum response. Biol Open 2016;5:837–847 [CrossRef][PubMed]
    [Google Scholar]
  57. Martin M. Cutadapt removes adapter sequences from high-througput sequencing reads. EMBnet.journal 2011;17:10–12
    [Google Scholar]
  58. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods 2012;9:357–359 [CrossRef][PubMed]
    [Google Scholar]
  59. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R et al. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol 2013;14:R36 [CrossRef][PubMed]
    [Google Scholar]
  60. Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol 2010;28:511–515 [CrossRef][PubMed]
    [Google Scholar]
  61. Trapnell C, Hendrickson DG, Sauvageau M, Goff L, Rinn JL et al. Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol 2013;31:46–53 [CrossRef][PubMed]
    [Google Scholar]
  62. Mi H, Muruganujan A, Thomas PD. PANTHER in 2013: modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees. Nucleic Acids Res 2013;41:D377–D386 [CrossRef][PubMed]
    [Google Scholar]
  63. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 2017;45:D362–D368 [CrossRef][PubMed]
    [Google Scholar]
  64. Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC et al. Primer3–new capabilities and interfaces. Nucleic Acids Res 2012;40:e115 [CrossRef][PubMed]
    [Google Scholar]
  65. Hübner D, Jahn K, Pinkert S, Böhnke J, Jung M et al. Infection of iPSC lines with miscarriage-associated coxsackievirus and measles virus and teratogenic rubella virus as a model for viral impairment of early human embryogenesis. ACS Infect Dis 2017;3:886–897 [CrossRef][PubMed]
    [Google Scholar]
  66. Bussche L, Harman RM, Syracuse BA, Plante EL, Lu YC et al. Microencapsulated equine mesenchymal stromal cells promote cutaneous wound healing in vitro. Stem Cell Res Ther 2015;6:66 [CrossRef][PubMed]
    [Google Scholar]
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