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Abstract

Phleboviruses (order , family ) are globally emerging arboviruses with a wide spectrum of virulence. Sandfly fever Sicilian virus (SFSV) is one of the most ubiquitous members of the genus and associated with a self-limited, incapacitating febrile disease in travellers and military troops. The phleboviral NSs protein is an established virulence factor, acting as antagonist of the antiviral interferon (IFN) system. Consistently, we previously reported that SFSV NSs targets the induction of IFN mRNA synthesis by specifically binding to the DNA-binding domain of the IFN transcription factor IRF3. Here, we further characterized the effect of SFSV and its NSs towards IFN induction, and evaluated its potential to affect the downstream IFN-stimulated signalling and the subsequent transactivation of antiviral interferon-stimulated genes (ISGs). We found that SFSV dampened, but did not entirely abolish type I and type III IFN induction. Furthermore, SFSV NSs did not affect IFN signalling, resulting in substantial ISG expression in infected cells. Hence, although SFSV targets IRF3 to reduce IFN induction, it is not capable of entirely disarming the IFN system in the presence of high basal IRF3 and/or IRF7 levels, and we speculate that this significantly contributes to its low level of virulence.

Funding
This study was supported by the:
  • swedish research council (Award 2018-05766)
    • Principle Award Recipient: FriedemannWeber
  • bundesministerium für bildung und forschung (Award Infect-ERA, grant “ESCential”)
    • Principle Award Recipient: FriedemannWeber
  • deutsche forschungsgemeinschaft (Award 197785619–SFB 1021)
    • Principle Award Recipient: FriedemannWeber
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
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2021-11-02
2024-03-28
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References

  1. Alkan C, Bichaud L, de Lamballerie X, Alten B, Gould EA et al. Sandfly-borne phleboviruses of Eurasia and Africa: epidemiology, genetic diversity, geographic range, control measures. Antiviral Res 2013; 100:54–74 [View Article] [PubMed]
    [Google Scholar]
  2. Elliott RM, Brennan B. Emerging phleboviruses. Curr Opin Virol 2014; 5:50–57 [View Article] [PubMed]
    [Google Scholar]
  3. Wuerth JD, Weber F. Phleboviruses and the type I interferon response. Viruses 2016; 8: [View Article] [PubMed]
    [Google Scholar]
  4. Carhan A, Uyar Y, Ozkaya E, Ertek M, Dobler G et al. Characterization of a sandfly fever Sicilian virus isolated during a sandfly fever epidemic in Turkey. J Clin Virol 2010; 48:264–269 [View Article] [PubMed]
    [Google Scholar]
  5. Ergunay K, Ayhan N, Charrel RN. Novel and emergent sandfly-borne phleboviruses in Asia Minor: A systematic review. Rev Med Virol 2017; 27: [View Article] [PubMed]
    [Google Scholar]
  6. Ayhan N, Velo E, de Lamballerie X, Kota M, Kadriaj P et al. Detection of Leishmania infantum and a novel phlebovirus (balkan virus) from sand flies in Albania. Vector Borne Zoonotic Dis 2016; 16:802–806 [View Article] [PubMed]
    [Google Scholar]
  7. Marklewitz M, Dutari LC, Paraskevopoulou S, Page RA, Loaiza JR et al. Diverse novel phleboviruses in sandflies from the Panama Canal area, central Panama. J Gen Virol 2019; 100:938–949 [View Article] [PubMed]
    [Google Scholar]
  8. Marklewitz M, Tchouassi DP, Hieke C, Heyde V, Torto B et al. Insights into the evolutionary origin of Mediterranean sandfly fever viruses. mSphere 2020; 5: [View Article] [PubMed]
    [Google Scholar]
  9. Ohlendorf V, Marklewitz M, Kopp A, Yordanov S, Drosten C et al. Huge diversity of phleboviruses in ticks from Strandja Nature Park, Bulgaria. Ticks Tick Borne Dis 2019; 10:697–703 [View Article] [PubMed]
    [Google Scholar]
  10. Papa A, Velo E, Bino S. A novel phlebovirus in Albanian sandflies. Clin Microbiol Infect 2011; 17:585–587 [View Article] [PubMed]
    [Google Scholar]
  11. Bartelloni PJ, Tesh RB. Clinical and serologic responses of volunteers infected with phlebotomus fever virus (Sicilian type. Am J Trop Med Hyg 1976; 25:456–462 [View Article] [PubMed]
    [Google Scholar]
  12. Sabin AB. Experimental studies on Phlebotomus (pappataci, sandfly) fever during World War II. Arch Gesamte Virusforsch 1951; 4:367–410 [View Article] [PubMed]
    [Google Scholar]
  13. Alwassouf S, Christodoulou V, Bichaud L, Ntais P, Mazeris A et al. Seroprevalence of sandfly-borne phleboviruses belonging to three serocomplexes (Sandfly fever Naples, Sandfly fever Sicilian and Salehabad) in dogs from Greece and cyprus using neutralization test. PLoS Negl Trop Dis 2016; 10:e0005063 [View Article]
    [Google Scholar]
  14. Ayhan N, Sherifi K, Taraku A, Berxholi K, Charrel RN. High rates of neutralizing antibodies to toscana and sandfly fever sicilian viruses in Livestock, Kosovo. Emerg Infect Dis 2017; 23:989–992 [View Article] [PubMed]
    [Google Scholar]
  15. Eitrem R, Stylianou M, Niklasson B. High prevalence rates of antibody to three sandfly fever viruses (Sicilian, Naples, and Toscana) among Cypriots. Epidemiol Infect 1991; 107:685–691 [View Article] [PubMed]
    [Google Scholar]
  16. Sakhria S, Alwassouf S, Fares W, Bichaud L, Dachraoui K et al. Presence of sandfly-borne phleboviruses of two antigenic complexes (Sandfly fever Naples virus and Sandfly fever Sicilian virus) in two different bio-geographical regions of Tunisia demonstrated by a microneutralisation-based seroprevalence study in dogs. Parasit Vectors 2014; 7:476 [View Article] [PubMed]
    [Google Scholar]
  17. Tesh RB, Saidi S, Gajdamovic SJ, Rodhain F, Vesenjak-Hirjan J. Serological studies on the epidemiology of sandfly fever in the Old World. Bull World Health Organ 1976; 54:663–674 [PubMed]
    [Google Scholar]
  18. Eitrem R, Vene S, Niklasson B. Incidence of sand fly fever among Swedish United Nations soldiers on Cyprus during 1985. Am J Trop Med Hyg 1990; 43:207–211 [View Article] [PubMed]
    [Google Scholar]
  19. Eitrem R, Niklasson B, Weiland O. Sandfly fever among Swedish tourists. Scand J Infect Dis 1991; 23:451–457 [View Article] [PubMed]
    [Google Scholar]
  20. Kniha E, Obwaller AG, Dobler G, Poeppl W, Mooseder G et al. Phlebovirus seroprevalence in Austrian Army personnel returning from missions abroad. Parasit Vectors 2019; 12:416 [View Article] [PubMed]
    [Google Scholar]
  21. Papa A, Konstantinou G, Pavlidou V, Antoniadis A. Sandfly fever virus outbreak in Cyprus. Clin Microbiol Infect 2006; 12:192–194 [View Article] [PubMed]
    [Google Scholar]
  22. Shiraly R, Khosravi A, Farahangiz S. Seroprevalence of sandfly fever virus infection in military personnel on the western border of Iran. J Infect Public Health 2017; 10:59–63 [View Article] [PubMed]
    [Google Scholar]
  23. Alkan C, Erisoz Kasap O, Alten B, Lamballerie de, Charrel RN. Sandfly-Borne Phlebovirus Isolations from Turkey: New Insight into the Sandfly fever Sicilian and Sandfly fever Naples Species. PLoS Negl Trop Dis 2016; 10:e0004519 [View Article] [PubMed]
    [Google Scholar]
  24. Alkan C, Moin Vaziri V, Ayhan N, Badakhshan M, Bichaud L et al. Isolation and sequencing of Dashli virus, a novel sicilian-like virus in sandflies from Iran; Genetic and phylogenetic evidence for the creation of one novel species within the phlebovirus genus in the Phenuiviridae family. PLoS Negl Trop Dis 2017; 11:e0005978 [View Article]
    [Google Scholar]
  25. Weber M, Gawanbacht A, Habjan M, Rang A, Borner C et al. Incoming RNA virus nucleocapsids containing a 5’-triphosphorylated genome activate RIG-I and antiviral signaling. Cell Host Microbe 2013; 13:336–346 [View Article] [PubMed]
    [Google Scholar]
  26. Liu G, Gack MU. Distinct and orchestrated functions of RNA sensors in innate immunity. Immunity 2020; 53:26–42 [View Article] [PubMed]
    [Google Scholar]
  27. Yoneyama M, Onomoto K, Jogi M, Akaboshi T, Fujita T. Viral RNA detection by RIG-I-like receptors. Curr Opin Immunol 2015; 32:48–53 [View Article] [PubMed]
    [Google Scholar]
  28. Schoggins JW. Interferon-stimulated genes: what do they all do?. Annu Rev Virol 2019; 6:567–584 [View Article] [PubMed]
    [Google Scholar]
  29. do Valle TZ, Billecocq A, Guillemot L, Alberts R, Gommet C et al. A new mouse model reveals a critical role for host innate immunity in resistance to Rift Valley fever. J Immunol 2010; 185:6146–6156 [View Article] [PubMed]
    [Google Scholar]
  30. Frese M, Kochs G, Feldmann H, Hertkorn C, Haller O. Inhibition of bunyaviruses, phleboviruses, and hantaviruses by human MxA protein. J Virol 1996; 70:915–923 [View Article] [PubMed]
    [Google Scholar]
  31. Sandrock M, Frese M, Haller O, Kochs G. Interferon-induced rat Mx proteins confer resistance to Rift Valley fever virus and other arthropod-borne viruses. J Interferon Cytokine Res 2001; 21:663–668 [View Article] [PubMed]
    [Google Scholar]
  32. Bouloy M, Janzen C, Vialat P, Khun H, Pavlovic J et al. Genetic evidence for an interferon-antagonistic function of Rift Valley fever virus nonstructural protein NSs. J Virol 2001; 75:1371–1377 [View Article] [PubMed]
    [Google Scholar]
  33. Crance JM, Gratier D, Guimet J, Jouan A. Inhibition of sandfly fever Sicilian virus (Phlebovirus) replication in vitro by antiviral compounds. Res Virol 1997; 148:353–365 [View Article] [PubMed]
    [Google Scholar]
  34. Habjan M, Pichlmair A, Elliott RM, Overby AK, Glatter T et al. NSs protein of Rift Valley fever virus induces the specific degradation of the double-stranded RNA-dependent protein kinase. J Virol 2009; 83:4365–4375 [View Article] [PubMed]
    [Google Scholar]
  35. Kende M. Prophylactic and therapeutic efficacy of poly(I,C)-LC against Rift Valley fever virus infection in mice. J Biol Response Mod 1985; 4:503–511 [PubMed]
    [Google Scholar]
  36. Liu Y, Wu B, Paessler S, Walker DH, Tesh RB et al. The pathogenesis of severe fever with thrombocytopenia syndrome virus infection in alpha/beta interferon knockout mice: insights into the pathologic mechanisms of a new viral hemorrhagic fever. J Virol 2014; 88:1781–1786 [View Article] [PubMed]
    [Google Scholar]
  37. Mendenhall M, Wong MH, Skirpstunas R, Morrey JD, Gowen BB. Punta Toro virus (Bunyaviridae, Phlebovirus) infection in mice: strain differences in pathogenesis and host interferon response. Virology 2009; 395:143–151 [View Article] [PubMed]
    [Google Scholar]
  38. Morrill JC, Jennings GB, Cosgriff TM, Gibbs PH, Peters CJ. Prevention of Rift Valley fever in rhesus monkeys with interferon-alpha. Rev Infect Dis 1989; 11:S815–S825
    [Google Scholar]
  39. Morrill JC, Jennings GB, Johnson AJ, Cosgriff TM, Gibbs PH et al. Pathogenesis of Rift Valley fever in rhesus monkeys: role of interferon response. Arch Virol 1990; 110:195–212 [View Article] [PubMed]
    [Google Scholar]
  40. Peters CJ, Reynolds JA, Slone TW, Jones DE, Stephen EL. Prophylaxis of Rift Valley fever with antiviral drugs, immune serum, an interferon inducer, and a macrophage activator. Antiviral Res 1986; 6:285–297 [View Article] [PubMed]
    [Google Scholar]
  41. Sidwell RW, Huffman JH, Smee DF, Gilbert J, Gessaman A et al. Potential role of immunomodulators for treatment of phlebovirus infections of animals. Ann N Y Acad Sci 1992; 653:344–355 [View Article] [PubMed]
    [Google Scholar]
  42. Eifan S, Schnettler E, Dietrich I, Kohl A, Blomstrom AL. Non-structural proteins of arthropod-borne bunyaviruses: roles and functions. Viruses 2013; 5:2447–2468 [View Article] [PubMed]
    [Google Scholar]
  43. Ly HJ, Ikegami T. Rift Valley fever virus NSs protein functions and the similarity to other bunyavirus NSs proteins. Virol J 2016; 13:118 [View Article] [PubMed]
    [Google Scholar]
  44. Ikegami T, Narayanan K, Won S, Kamitani W, Peters CJ et al. Rift Valley fever virus NSs protein promotes post-transcriptional downregulation of protein kinase PKR and inhibits eIF2alpha phosphorylation. PLoS Pathog 2009; 5:e1000287 [View Article] [PubMed]
    [Google Scholar]
  45. Kainulainen M, Habjan M, Hubel P, Busch L, Lau S et al. Virulence factor NSs of rift valley fever virus recruits the F-box protein FBXO3 to degrade subunit p62 of general transcription factor TFIIH. J Virol 2014; 88:3464–3473 [View Article] [PubMed]
    [Google Scholar]
  46. Lihoradova OA, Indran SV, Kalveram B, Lokugamage N, Head JA et al. Characterization of Rift Valley fever virus MP-12 strain encoding NSs of Punta Toro virus or sandfly fever Sicilian virus. PLoS Negl Trop Dis 2013; 7:e2181 [View Article] [PubMed]
    [Google Scholar]
  47. Wuerth JD, Habjan M, Wulle J, Superti-Furga G, Pichlmair A et al. NSs Protein of Sandfly Fever Sicilian Phlebovirus Counteracts Interferon (IFN) Induction by Masking the DNA-Binding Domain of IFN Regulatory Factor 3. J Virol 2018; 92:23 [View Article]
    [Google Scholar]
  48. Gori Savellini G, Anichini G, Gandolfo C, Prathyumnan S, Cusi MG. Toscana virus non-structural protein NSS acts as E3 ubiquitin ligase promoting rig-i degradation. PLoS Pathog 2019; 15:e1008186 [View Article]
    [Google Scholar]
  49. Horisberger MA, de Staritzky K. A recombinant human interferon-alpha B/D hybrid with a broad host-range. J Gen Virol 1987; 68:945–948 [View Article] [PubMed]
    [Google Scholar]
  50. Yoneyama M, Suhara W, Fukuhara Y, Fukuda M, Nishida E et al. Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. EMBO J 1998; 17:1087–1095 [View Article] [PubMed]
    [Google Scholar]
  51. Kochs G, Garcia-Sastre A, Martinez-Sobrido L. Multiple anti-interferon actions of the influenza A virus NS1 protein. J Virol 2007; 81:7011–7021 [View Article] [PubMed]
    [Google Scholar]
  52. Weidmann M, Sanchez-Seco MP, Sall AA, Ly PO, Thiongane Y et al. Rapid detection of important human pathogenic Phleboviruses. J Clin Virol 2008; 41:138–142 [View Article] [PubMed]
    [Google Scholar]
  53. Bird BH, Bawiec DA, Ksiazek TG, Shoemaker TR, Nichol ST. Highly sensitive and broadly reactive quantitative reverse transcription-PCR assay for high-throughput detection of Rift Valley fever virus. J Clin Microbiol 2007; 45:3506–3513 [View Article] [PubMed]
    [Google Scholar]
  54. Holzer M, Schoen A, Wulle J, Muller MA, Drosten C et al. Virus- and interferon alpha-induced transcriptomes of cells from the microbat Myotis daubentonii. iScience 2019; 19:647–661 [View Article] [PubMed]
    [Google Scholar]
  55. Prescott J, Hall P, Acuna-Retamar M, Ye C, Wathelet MG et al. New World hantaviruses activate IFNlambda production in type I IFN-deficient vero E6 cells. PLoS One 2010; 5:e11159 [View Article] [PubMed]
    [Google Scholar]
  56. Kuri T, Habjan M, Penski N, Weber F. Species-independent bioassay for sensitive quantification of antiviral type I interferons. Virol J 2010; 7:50 [View Article] [PubMed]
    [Google Scholar]
  57. International Committee on Taxonomy of Viruses Virus Taxonomy: 2019 Release; 2019 https://talk.ictvonline.org/taxonomy/
  58. Chaudhary V, Zhang S, Yuen KS, Li C, Lui PY et al. Suppression of type I and type III IFN signalling by NSs protein of severe fever with thrombocytopenia syndrome virus through inhibition of STAT1 phosphorylation and activation. J Gen Virol 2015; 96:3204–3211 [View Article] [PubMed]
    [Google Scholar]
  59. Ning YJ, Wang M, Deng M, Shen S, Liu W et al. Viral suppression of innate immunity via spatial isolation of TBK1/IKKepsilon from mitochondrial antiviral platform. J Mol Cell Biol 2014; 6:324–337 [View Article] [PubMed]
    [Google Scholar]
  60. Qu B, Qi X, Wu X, Liang M, Li C et al. Suppression of the interferon and NF-kappaB responses by severe fever with thrombocytopenia syndrome virus. J Virol 2012; 86:8388–8401 [View Article] [PubMed]
    [Google Scholar]
  61. Santiago FW, Covaleda LM, Sanchez-Aparicio MT, Silvas JA, Diaz-Vizarreta AC et al. Hijacking of RIG-I signaling proteins into virus-induced cytoplasmic structures correlates with the inhibition of type I interferon responses. J Virol 2014; 88:4572–4585 [View Article] [PubMed]
    [Google Scholar]
  62. Rezelj VV, Li P, Chaudhary V, Elliott RM, Jin DY et al. Differential antagonism of human innate immune responses by tick-borne phlebovirus nonstructural proteins. mSphere 2017; 2: [View Article] [PubMed]
    [Google Scholar]
  63. Ning S, Pagano JS, Barber GN. IRF7: activation, regulation, modification and function. Genes Immun 2011; 12:399–414 [View Article] [PubMed]
    [Google Scholar]
  64. Marie I, Durbin JE, Levy DE. Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7. EMBO J 1998; 17:6660–6669 [View Article] [PubMed]
    [Google Scholar]
  65. Sato M, Hata N, Asagiri M, Nakaya T, Taniguchi T et al. Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. FEBS Lett 1998; 441:106–110 [View Article] [PubMed]
    [Google Scholar]
  66. Stewart CE, Randall RE, Adamson CS. Inhibitors of the interferon response enhance virus replication in vitro. PLOS ONE 2014; 9:e112014
    [Google Scholar]
  67. Wu X, Qi X, Qu B, Zhang Z, Liang M et al. Evasion of antiviral immunity through sequestering of TBK1/IKKepsilon/IRF3 into viral inclusion bodies. J Virol 2014; 88:3067–3076 [View Article] [PubMed]
    [Google Scholar]
  68. Pichlmair A, Kandasamy K, Alvisi G, Mulhern O, Sacco R et al. Viral immune modulators perturb the human molecular network by common and unique strategies. Nature 2012; 487:486–490 [View Article] [PubMed]
    [Google Scholar]
  69. Wuerth JD, Habjan M, Kainulainen M, Berisha B, Bertheloot D et al. eIF2B as a target for viral evasion of PKR-Mediated Translation Inhibition. mBio 2020; 11: [View Article] [PubMed]
    [Google Scholar]
  70. Proenca-Modena JL, Hyde JL, Sesti-Costa R, Lucas T, Pinto AK et al. Interferon-Regulatory Factor 5-dependent signaling restricts orthobunyavirus dissemination to the central nervous System. J Virol 2016; 90:189–205 [View Article] [PubMed]
    [Google Scholar]
  71. Nishiyama S, Slack OA, Lokugamage N, Hill TE, Juelich TL et al. Attenuation of pathogenic Rift Valley fever virus strain through the chimeric S-segment encoding sandfly fever phlebovirus NSs or a dominant-negative PKR. Virulence 2016; 7:871–881 [View Article] [PubMed]
    [Google Scholar]
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