Kyasanur Forest disease virus (KFDV) is a highly pathogenic tick-borne flavivirus enzootic to India. In humans, KFDV causes a severe febrile disease. In some infected individuals, hemorrhagic manifestations, such as bleeding from the nose and gums and gastrointestinal bleeding with hematemesis and/or blood in the stool, have been reported. However, the mechanisms underlying these hemorrhagic complications remain unknown, and there is no information about the specific target cells for KFDV. We investigated the interaction of KFDV with vascular endothelial cells (ECs) and monocyte-derived dendritic cells (moDCs), which are key targets for several other hemorrhagic viruses. Here, we report that ECs are permissive to KFDV infection, which leads to their activation, as demonstrated by the upregulation of E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 at the mRNA and protein levels. Increased expression of these adhesive molecules correlated with increased leukocyte adhesion. Infected ECs upregulated the expression of interleukin (IL)-6 but not IL-8. Additionally, moDCs were permissive to KFDV infection, leading to increased release of IL-6 and tumor necrosis factor-α. Supernatants from KFDV-infected moDCs caused EC activation, as measured by leukocyte adhesion. The results indicate that ECs and moDCs can be targets for KFDV and that both direct and indirect mechanisms can contribute to EC activation.

Department of Virology Veterinary Research Institute Hudcova 70 CZ 62100 Brno Czech Republic

Faculty of Science University of South Bohemia Branisovska 31 CZ 37005 Ceske Budejovice Czech Republic

Institute of Parasitology Biology Centre of the Czech Academy of Sciences Branisovska 31 CZ 37005 Ceske Budejovice Czech Republic

NIAID Integrated Research Facility 8200 Research Plaza Ft Detrick Frederick MD 21702 USA

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Trapido H, Rajagopalan PK, Work TH, Varma MG. Kyasanur Forest disease. VIII. Isolation of Kyasanur Forest disease virus from naturally infected ticks of the genus Haemaphysalis. Indian J. Med. Res. 1959;47:133–138. PubMed

Holbrook MR. Kyasanur forest disease. Antivir. Res. 2012;96:353–362. doi: 10.1016/j.antiviral.2012.10.005. PubMed DOI PMC

Yadav PD, et al. Outbreak of Kyasanur Forest disease in Thirthahalli, Karnataka, India, 2014. Int. J. Infect. Dis. 2014;26:132–134. doi: 10.1016/j.ijid.2014.05.013. PubMed DOI

Ajesh K, Nagaraja BK, Sreejith K. Kyasanur forest disease virus breaking the endemic barrier: An investigation into ecological effects on disease emergence and future outlook. Zoonoses Public. Health. 2017;64:e73–e80. doi: 10.1111/zph.12349. PubMed DOI

Růžek D, Yakimenko VV, Karan LS, Tkachev SE. Omsk haemorrhagic fever. Lancet. 2010;376:2104–2113. doi: 10.1016/S0140-6736(10)61120-8. PubMed DOI

Muraleedharan M. Kyasanur Forest Disease (KFD): rare disease of zoonotic origin. J. Nepal Health Res Counc. 2016;14:214–218. PubMed

Pavri K. Clinical, clinicopathologic, and hematologic features of Kyasanur Forest disease. Rev. Infect. Dis. 1989;11(Suppl 4):S854–S859. doi: 10.1093/clinids/11.Supplement_4.S854. PubMed DOI

Work TH, et al. Kyasanur forest disease. III. A preliminary report on the nature of the infection and clinical manifestations in human beings. Indian J. Med Sci. 1957;11:619–645. PubMed

Work TH. Virological aspects of Kyasanur Forest disease. J. Indian Med. Assoc. 1958;31:111–113. PubMed

Wadia RS. Neurological involvement in Kyasanur Forest disease. Neurol. India. 1975;23:115–120. PubMed

Sawatsky B, McAuley AJ, Holbrook MR, Bente DA. Comparative pathogenesis of Alkhumra hemorrhagic fever and Kyasanur forest disease viruses in a mouse model. PLoS Negl. Trop. Dis. 2014;8:e2934. doi: 10.1371/journal.pntd.0002934. PubMed DOI PMC

Zivcec M, Safronetz D, Feldmann H. Animal models of tick-borne hemorrhagic Fever viruses. Pathogens. 2013;2:402–421. doi: 10.3390/pathogens2020402. PubMed DOI PMC

Lahoti J. A., Mishra R., Singh S. K. in: Viral Hemorrhagic Fevers (eds Singh, S. K. & Ruzek, D.) 63–80 (CRC Press, Boca Raton, 2014).

Dalrymple N. A., Gorbunova E., Gavrilovskaya I., Mackow E. R. in: Viral Hemorrhagic Fevers (eds Singh, S. K. & Ruzek, D.) 43–62 (CRC Press, Boca Raton, 2014).

Connolly-Andersen AM, et al. Crimean-Congo hemorrhagic fever virus activates endothelial cells. J. Virol. 2011;85:7766–7774. doi: 10.1128/JVI.02469-10. PubMed DOI PMC

Vestweber D. Adhesion and signaling molecules controlling the transmigration of leukocytes through endothelium. Immunol. Rev. 2007;218:178–196. doi: 10.1111/j.1600-065X.2007.00533.x. PubMed DOI

Connolly-Andersen AM, Douagi I, Kraus AA, Mirazimi A. Crimean Congo hemorrhagic fever virus infects human monocyte-derived dendritic cells. Virology. 2009;390:157–162. doi: 10.1016/j.virol.2009.06.010. PubMed DOI

Ho LJ, et al. Infection of human dendritic cells by dengue virus causes cell maturation and cytokine production. J. Immunol. 2001;166:1499–1506. doi: 10.4049/jimmunol.166.3.1499. PubMed DOI

Raftery MJ, Kraus AA, Ulrich R, Krüger DH, Schönrich G. Hantavirus infection of dendritic cells. J. Virol. 2002;76:10724–10733. doi: 10.1128/JVI.76.21.10724-10733.2002. PubMed DOI PMC

Madani TA. Alkhumra virus infection, a new viral hemorrhagic fever in Saudi Arabia. J. Infect. 2005;51:91–97. doi: 10.1016/j.jinf.2004.11.012. PubMed DOI

Cosgriff TM, Lewis RM. Mechanisms of disease in hemorrhagic fever with renal syndrome. Kidney Int. Suppl. 1991;35:S72–S79. PubMed

Nolte KB, et al. Hantavirus pulmonary syndrome in the United States: a pathological description of a disease caused by a new agent. Hum. Pathol. 1995;26:110–120. doi: 10.1016/0046-8177(95)90123-X. PubMed DOI

Pensiero MN, Sharefkin JB, Dieffenbach CW, Hay J. Hantaan virus infection of human endothelial cells. J. Virol. 1992;66:5929–5936. PubMed PMC

Lei HY, et al. Immunopathogenesis of dengue virus infection. J. Biomed. Sci. 2001;8:377–388. doi: 10.1007/BF02255946. PubMed DOI

Ergonul O, Tuncbilek S, Baykam N, Celikbas A, Dokuzoguz B. Evaluation of serum levels of interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha in patients with Crimean-Congo hemorrhagic fever. J. Infect. Dis. 2006;193:941–944. doi: 10.1086/500836. PubMed DOI

Papa A, et al. Cytokine levels in Crimean-Congo hemorrhagic fever. J. Clin. Virol. 2006;36:272–276. doi: 10.1016/j.jcv.2006.04.007. PubMed DOI

Guo J, et al. Cytokine response to Hantaan virus infection in patients with hemorrhagic fever with renal syndrome. J. Med. Virol. 2017;89:1139–1145. doi: 10.1002/jmv.24752. PubMed DOI

Wauquier N, Becquart P, Padilla C, Baize S, Leroy EM. Human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis. PLoS Negl. Trop. Dis. 2010;4:e837. doi: 10.1371/journal.pntd.0000837. PubMed DOI PMC

Lukashevich IS, et al. Lassa and Mopeia virus replication in human monocytes/macrophages and in endothelial cells: different effects on IL-8 and TNF-alpha gene expression. J. Med. Virol. 1999;59:552–560. doi: 10.1002/(SICI)1096-9071(199912)59:4<552::AID-JMV21>3.0.CO;2-A. PubMed DOI PMC

Biffl WL, et al. Interleukin-8 increases endothelial permeability independent of neutrophils. J. Trauma. 1995;39:98–102. doi: 10.1097/00005373-199507000-00013. PubMed DOI

Talavera D, Castillo AM, Dominguez MC, Gutierrez AE, Meza I. IL8 release, tight junction and cytoskeleton dynamic reorganization conducive to permeability increase are induced by dengue virus infection of microvascular endothelial monolayers. J. Gen. Virol. 2004;85(Pt 7):1801–1813. doi: 10.1099/vir.0.19652-0. PubMed DOI

Raghupathy R, et al. Elevated levels of IL-8 in dengue hemorrhagic fever. J. Med. Virol. 1998;56:280–285. doi: 10.1002/(SICI)1096-9071(199811)56:3<280::AID-JMV18>3.0.CO;2-I. PubMed DOI

Hutchinson KL, Rollin PE. Cytokine and chemokine expression in humans infected with Sudan Ebola virus. J. Infect. Dis. 2007;196(Suppl 2):S357–S363. doi: 10.1086/520611. PubMed DOI

Bowick G. C. in: Viral Hemorrhagic Fevers (eds Singh, S. K. & Ruzek, D.) 31–42 (CRC Press, Boca Raton, 2014).

Roebuck KA, Finnegan A. Regulation of intercellular adhesion molecule-1 (CD54) gene expression. J. Leukoc. Biol. 1999;66:876–888. doi: 10.1002/jlb.66.6.876. PubMed DOI

Rothlein R, Dustin ML, Marlin SD, Springer TA. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J. Immunol. 1986;137:1270–1274. PubMed

Yang CR, Hsieh SL, Ho FM, Lin WW. Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-kappa B-dependent upregulation of intercellular adhesion molecule-1, VCAM-1, and IL-8 expression. J. Immunol. 2005;174:1647–1656. doi: 10.4049/jimmunol.174.3.1647. PubMed DOI

Colden-Stanfield M, Ratcliffe D, Cramer EB, Gallin EK. Characterization of influenza virus-induced leukocyte adherence to human umbilical vein endothelial cell monolayers. J. Immunol. 1993;151:310–321. PubMed

Shahgasempour S, Woodroffe SB, Garnett HM. Alterations in the expression of ELAM-1, ICAM-1 and VCAM-1 after in vitro infection of endothelial cells with a clinical isolate of human cytomegalovirus. Microbiol. Immunol. 1997;41:121–129. doi: 10.1111/j.1348-0421.1997.tb01177.x. PubMed DOI

Saijets S, Ylipaasto P, Vaarala O, Hovi T, Roivainen M. Enterovirus infection and activation of human umbilical vein endothelial cells. J. Med. Virol. 2003;70:430–439. doi: 10.1002/jmv.10413. PubMed DOI

Zanone MM, et al. Persistent infection of human microvascular endothelial cells by coxsackie B viruses induces increased expression of adhesion molecules. J. Immunol. 2003;171:438–446. doi: 10.4049/jimmunol.171.1.438. PubMed DOI

Arnold R, König W. Respiratory syncytial virus infection of human lung endothelial cells enhances selectively intercellular adhesion molecule-1 expression. J. Immunol. 2005;174:7359–7367. doi: 10.4049/jimmunol.174.11.7359. PubMed DOI

Bosch I, et al. Increased production of interleukin-8 in primary human monocytes and in human epithelial and endothelial cell lines after dengue virus challenge. J. Virol. 2002;76:5588–5597. doi: 10.1128/JVI.76.11.5588-5597.2002. PubMed DOI PMC

Feldmann H, et al. Filovirus-induced endothelial leakage triggered by infected monocytes/macrophages. J. Virol. 1996;70:2208–2214. PubMed PMC

Connolly-Andersen AM, Magnusson KE, Mirazimi A. Basolateral entry and release of Crimean-Congo hemorrhagic fever virus in polarized MDCK-1 cells. J. Virol. 2007;81:2158–2164. doi: 10.1128/JVI.02070-06. PubMed DOI PMC

Mahanty S, et al. Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses. J. Immunol. 2003;170:2797–2801. doi: 10.4049/jimmunol.170.6.2797. PubMed DOI

Schnittler HJ, Feldmann H. Molecular pathogenesis of filovirus infections: role of macrophages and endothelial cells. Curr. Top. Microbiol. Immunol. 1999;235:175–204. PubMed

Villinger F, et al. Markedly elevated levels of interferon (IFN)-gamma, IFN-alpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-alpha associated with fatal Ebola virus infection. J. Infect. Dis. 1999;179(Suppl 1):S188–S191. doi: 10.1086/514283. PubMed DOI

Blanco P, Palucka AK, Pascual V, Banchereau J. Dendritic cells and cytokines in human inflammatory and autoimmune diseases. Cytokine Growth Factor Rev. 2008;19:41–52. doi: 10.1016/j.cytogfr.2007.10.004. PubMed DOI PMC

Bosio CM, et al. Ebola and Marburg viruses replicate in monocyte-derived dendritic cells without inducing the production of cytokines and full maturation. J. Infect. Dis. 2003;188:1630–1638. doi: 10.1086/379199. PubMed DOI

De Madrid AT, Porterfield JS. A simple micro-culture method for the study of group B arboviruses. Bull. World Health Organ. 1969;40:113–121. PubMed PMC

Schindelin J, et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods. 2012;9:676–682. doi: 10.1038/nmeth.2019. PubMed DOI PMC

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–408. doi: 10.1006/meth.2001.1262. PubMed DOI

Kiely JM, Luscinskas FW, Gimbrone MA., Jr. Leukocyte-endothelial monolayer adhesion assay (static conditions) Methods Mol. Biol. 1999;96:131–136. PubMed

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