Tick-borne viruses: A review from the perspective of therapeutic approaches

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TTBDIS-321; No. of Pages 9

Ticks and Tick-borne Diseases xxx (2014) xxx–xxx

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Review Article

Tick-borne viruses: A review from the perspective of therapeutic approaches Rafidah Lani a , Ehsan Moghaddam a , Amin Haghani b , Li-Yen Chang a , Sazaly AbuBakar a , Keivan Zandi a,∗ a Tropical Infectious Disease Research and Education Centre (TIDREC), Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia b Department of Environmental and Occupational Health, Faculty of Medicine and Health Sciences, University Putra Malaysia, Malaysia

a r t i c l e

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Article history: Received 29 August 2013 Received in revised form 7 March 2014 Accepted 1 April 2014 Available online xxx Keywords: Tick-borne disease Arbovirus Therapy Antiviral

a b s t r a c t Several important human diseases worldwide are caused by tick-borne viruses. These diseases have become important public health concerns in recent years. The tick-borne viruses that cause diseases in humans mainly belong to 3 families: Bunyaviridae, Flaviviridae, and Reoviridae. In this review, we focus on therapeutic approaches for several of the more important tick-borne viruses from these 3 families. These viruses are Crimean-Congo hemorrhagic fever virus (CCHF) and the newly discovered tick-borne phleboviruses, known as thrombocytopenia syndromevirus (SFTSV), Heartland virus and Bhanja virus from the family Bunyaviridae, tick-borne encephalitis virus (TBEV), Powassan virus (POWV), Louping-ill virus (LIV), Omsk hemorrhagic fever virus (OHFV), Kyasanur Forest disease virus (KFDV), and Alkhurma hemorrhagic fever virus (AHFV) from the Flaviviridae family. To date, there is no effective antiviral drug available against most of these tick-borne viruses. Although there is common usage of antiviral drugs such as ribavirin for CCHF treatment in some countries, there are concerns that ribavirin may not be as effective as once thought against CCHF. Herein, we discuss also the availability of vaccines for the control of these viral infections. The lack of treatment and prevention approaches for these viruses is highlighted, and we hope that this review may increase public health awareness with regard to the threat posed by this group of viruses. © 2014 Elsevier GmbH. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Family Bunyaviridae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Crimean-Congo hemorrhagic fever virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Issues concerning the treatment and prevention of CCHF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Severe fever with thrombocytopenia syndrome virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment outlook of tick-borne phleboviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Family Flaviviridae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tick-borne flaviviruses with encephalitis manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tick-borne encephalitis virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Powassan virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Louping-ill virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tick-borne flaviviruses with hemorrhagic manifestation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Omsk hemorrhagic fever virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kyasanur Forest disease virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Family Reoviridae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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∗ Corresponding author. Fax: +60 379676674. E-mail address: [email protected] (K. Zandi). http://dx.doi.org/10.1016/j.ttbdis.2014.04.001 1877-959X/© 2014 Elsevier GmbH. All rights reserved.

Please cite this article in press as: Lani, R., et al., Tick-borne viruses: A review from the perspective of therapeutic approaches. Ticks Tick-borne Dis. (2014), http://dx.doi.org/10.1016/j.ttbdis.2014.04.001

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Colorado tick fever virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment outlook for CTFV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction Tick-borne viruses are a group of viruses with significant worldwide importance in public health and as such a global concern. Currently, there is no effective therapeutic agent or vaccine for most of these viruses. Novel viral mutants and different variants can emerge and may potentially become a public health threat. These new emerging viruses could also pose a biosecurity threat. The aim of this review is to increase the public awareness of this group of viruses, particularly with regard to the possible treatment approaches and antiviral drugs for the management, control, and prevention of the diseases caused by these viruses. Generally, the therapeutic strategies comprise of (i) vaccination; (ii) administration of high-titer antibodies; and (iii) treatment with antiviral drugs. In this review, we have focused on tick-borne viruses that are of public health importance and the antiviral drug perspective for the treatment of the diseases caused by them. Family Bunyaviridae Crimean-Congo hemorrhagic fever virus Crimean-Congo hemorrhagic fever virus (CCHFV; genus: Nairovirus; family: Bunyaviridae) was first identified in 1944 in the Crimean Peninsula (Chumakov et al., 1963; Mourya et al., 2012), and it was then isolated from a patient in Kisangani, Congo, in 1956 (Simpson et al., 1967; Mourya et al., 2012). This virus, which is maintained in nature by ixodid species (Labuda and Nuttall, 2004) and is transmitted by Hyalomma ticks (Tekin et al., 2010), has been associated in a series of outbreaks with a large geographical distribution across Europe, Middle East, Asia, and Africa (Hoogstraal, 1979; Whitehouse, 2004; Flick and Whitehouse, 2005; Papa et al., 2010; Tekin et al., 2010; Ergonul, 2012). Besides transmission of the virus by ixodid ticks, CCHFV can be transmitted by contact with tissues and excreta or secreta of infected animals or humans (Keshtkar-Jahromi et al., 2011; Ergonul, 2008; Whitehouse, 2004). Early signs of the disease typically include fever, hypotension, conjunctivitis, and cutaneous flushing or skin rash. Later, patients may have signs of progressive hemorrhagic diathesis, similar to petechiae, and mucous membrane and conjunctival hemorrhage hematuria, hematemesis, and melena. Disseminated intravascular coagulation (DIC) and circulatory shock may ensue (Ergonul, 2012). The mortality rate of CCHF is between 9% and 50% (Ergonul, 2008). Issues concerning the treatment and prevention of CCHF There is currently no effective vaccine available for CCHF, although several vaccine candidates have been developed and evaluated. One example of a candidate vaccine for CCHF is the inactivated mouse brain vaccine, which was used on a small scale in the former Soviet Union and Bulgaria on several hundred human volunteers (Tkachenko et al., 1971; Vasilenko, 1973). Despite the vaccine being able to induce high detectable antibody levels, no sufficient clinical trials were performed as there were concerns about using mouse-brain vaccines, which have the potential to cause autoimmune responses. Additionally, there is a lack of commercial value for the vaccine as CCHF is a disease confined to poor-resource countries.

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More recently, a DNA vaccine containing the CCHF genome M segment was developed, and it was demonstrated that it induces neutralizing antibodies in mice, as well as antibodies that immunoprecipitate with the M segment expression products (Spik et al., 2006; Keshtkar-Jahromi et al., 2011). However, the protective effect of the vaccine was not evaluated. Currently, management of CCHF is based on general supportive measures and monitoring of the patient’s hematologic and coagulation status, with replacement of cells and factors as needed (Ergonul, 2008). To date the only drug that is placed on the WHO essential medicines list to be used against CCHFV infection is ribavirin (Ergonul, 2006); however, there are many contradictions with regard to the efficacy of this drug for CCHF disease. Ribavirin inhibits the growth of CCHFV in vitro and in experimentally infected mice (Watts et al., 1989; Tignor and Hanham, 1993). There is evidence about the effectiveness of this drug in patients following oral and intravenous administration (Mardani et al., 2003; Elaldi et al., 2009). However, in one randomized controlled trial published on this topic, there was no significant positive effect in the clinical or laboratory parameters after administration of ribavirin in CCHF patients (Koksal et al., 2010). In a meta-analysis of 21 unique studies including one randomized controlled trial of ribavirin to investigate the effect of ribavirin in CCHF patients, it was noted that the current data available are insufficient to understand the efficacy of the drug (Soares-Weiser et al., 2010). For example, studies in which ribavirin was combined with cycloferon, which is an interferon inducer, either in the form of solution or tablets, shortened the period of the fever in CCHF patients, minimized the intoxication syndrome, promoted earlier resolution of hemorrhagic eruption, and lowered the frequency of complications, which improved the disease prognosis (Cherenov et al., 2012; Romantsov et al., 2012). Administration of corticosteroids together with ribavirin was also reported to be useful, particularly during early stages of the disease–however, this experience was limited to an observational study of only 6 patients (Jabbari et al., 2006). Currently, ribavirin is used in most endemic countries and ethical issues about using a randomized trial have been raised (Arda et al., 2012). Researchers should therefore consider how ribavirin therapy might be further evaluated without violating ethical guidelines. Given the high fatality rate associated with CCHF, well-designed multi-center and random-controlled trials are urgently needed to provide evidence-based data about the efficacy of ribavirin (Maltezou and Papa, 2011). Besides ribavirin, there are some other studies to find effective antiviral compounds against CCHFV, including the in vitro inhibitory properties of exogenous nitric oxide (NO) on CCHFV replication (Simon et al., 2006). Type-I interferon (IFN) has significant antiviral activity against many hemorrhagic fever viruses in vitro, and in animal models, Karlberg et al. (2010) in an in vitro study showed significant antiviral activity of a natural IFN-␣ produced in human leukocytes (multiferon) compared to 2 recombinant IFN-␣ preparations (roferon A and intron A) against CCHFV. However, there are data suggesting that CCHFV possesses mechanisms to defeat the IFNinduced defense mechanisms by delaying IFN secretion for 48 h post infection (Andersson et al., 2008). In one study using a small interfering RNAs (siRNAs) approach, it was shown that the IFNinduced MxA GTPase is a major factor mediating the antiviral effect against CCHFV, and the IFN-␣ inhibits the growth of CCHFV in

Please cite this article in press as: Lani, R., et al., Tick-borne viruses: A review from the perspective of therapeutic approaches. Ticks Tick-borne Dis. (2014), http://dx.doi.org/10.1016/j.ttbdis.2014.04.001

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human endothelial and hepatoma cells (Andersson et al., 2006). In addition, IFN-stimulated genes (ISGs) seem to be sufficient for significant CCHFV growth inhibition (Andersson et al., 2006). Proteins such as ISG20, P56, RNA-specific adenosine deaminase 1, promyelocytic leukemia protein, and guanylate-binding protein 1 have also been demonstrated to have antiviral activities against CCHFV (Ergonul, 2008). Besides the above-mentioned strategies, there was an early recognition of the possible benefits of treatment using serum prepared from the blood of recovered CCHF patients or ␥-globulin obtained from immunized horses (Hoogstraal, 1979). Bulgarian scientists reported the fast recovery of 7 severely ill patients treated via passive simultaneous transfer of 2 different specific immunoglobulin preparations, “CCHF-bulin” (for intramuscular use) and “CCHF-venin” (for intravenous use), prepared from the plasma of CCHF survivor donors boosted with one dose of CCHF vaccine (Vasilenko et al., 1990). Prompt administration of CCHFV hyper-immunoglobulin has been demonstrated to be effective and a new treatment approach for high-risk CCHF patients (Kubar et al., 2011). In a recent study, combination of intravenous immunoglobulin (IVIG), high-dose methylprednisolone (HDMP), and fresh frozen plasma (FFP) seemed to be effective in patients with CCHF associated with reactive hemophagocytic lymphohistiocytosis (HLH) (Erduran et al., 2013). Specifically, the suppression of macrophage activation and treatment of HLH was achieved using HDMP. The DIC was treated using FFP, and IVIG was for suppression of macrophage and cytokine storm development in CCHF associated with reactive HLH patients. However, as HLH is a hemotologic disorder that may occur in association with infection by other microorganisms or in association with diseases such as lymphoma or autoimmune diseases, the therapeutic effect from the combination of IVIG, HDMP, and FFP may not be specific for CCHF, but for HLH. Severe fever with thrombocytopenia syndrome virus Severe fever with thrombocytopenia syndrome virus (SFTSV) also known as Huaiyangshan virus is a new member of the phlebovirus genus from the Bunyaviridae family. This virus was reported for the first time in the vicinity of Huaiyangshan, China (Jin et al., 2012). Later, infections due to SFTSV were reported from 11 Chinese provinces (Lam et al., 2013) with a significant mortality rate of up to 30% (Hofmann et al., 2013). The virus is transmitted by ticks, and the viral genomic RNA has been detected mostly in Haemaphysalis longicornis ticks from endemic regions and Rhipicephalus microplus in non-endemic regions (Zhang et al., 2012a; Jiang et al., 2012). However, there is evidence of human-to-human transmission through contact with infected blood samples (Liu et al., 2012). The clinical manifestation of the disease consists of 3 stages: fever stage, multiple organ dysfunction stage, and convalescent stage (Gai et al., 2012). The first stage persists for approximately 7 days with clinical signs of sudden onset of fever, headache, gastrointestinal symptoms, thrombocytopenia and leukocytopenia and lymphadenopathy (Gai et al., 2012; Zhang et al., 2012b). Then, 7–13 days after disease onset, multiple organ dysfunction will occur with elevation of serum AST, CK, CK-MB, and LDH, and subsequently progresses to hemorrhagic manifestations, central nervous system manifestations, DIC, and multiple organ failure (MOF) (Gai et al., 2012). In some cases, pronounced coagulation disturbances have been reported (Zhang et al., 2012b). In patients who recover, the clinical symptoms and abnormal laboratory parameters gradually return to their normal status (Gai et al., 2012). It seems that the fatal outcome is associated with high viral RNA load during disease progression, and it suggests the role of active virus in determining the clinical outcome of the disease (Gai et al., 2012; Zhang et al., 2012b). Recently, a new virus named Heartland virus was isolated from 2 severely febrile patients in Missouri, USA (McMullan et al., 2012). This virus is classified as a distinct member of the Phlebovirus

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genus, and it is closely related to SFTSV. Heartland virus is a tickborne virus, and there are many more tick-borne viruses with unassigned genera. For example, Bhanja virus, which was previously unassigned to a genus, has recently been found to be more closely related to the novel emerging SFTSV and Heartland virus using phylogenetic and serological analyses (Matsuno et al., 2013). These tick-borne phleboviruses are becoming a global concern due to the insufficient information about the pathogenesis, epidemiology, and many other aspects of these viruses, and also the lack of therapeutic and vaccination approaches to control the spread of the disease.

Treatment outlook of tick-borne phleboviruses The current clinical approaches for treatment of these viruses are on the basis of general supportive measures. It is essential to monitor the hematologic and coagulation status of patients. Intravenous transfusion of FFP, whole blood, platelet cells, albumin, or granulocyte colony-stimulating factor should be conducted as needed. In some severe cases, intravenous ribavirin was administered; however, no clinical studies have been able to confirm the efficacy of this antiviral drug on phleboviruses (Gai et al., 2012). Recently, there has been some development in characterizing molecular aspects of SFTSV infection to find new approaches for prevention and treatment of this virus. For instance, in one study, the entry of SFTSV to the host cells has been elucidated, which is the initial insight into cell tropism, receptor usage and proteolytic activation of SFTSV (Hofmann et al., 2013). Further, the crystal structure of the SFTSV’s viral nucleocapsid protein has been determined (Jiao et al., 2013). From the protein structure, it was demonstrated that a mutant of SFTSV-N with triple mutations would result in an inhibitory effect on the transcription and replication of the viral RNA. It was also determined that the drug suramin which is commonly used in the treatment of trypanosomiasis and helminthiasis, has an inhibitory effect on SFTSV replication in Vero cells. Accordingly, these recent findings can be considered as insights for drug and vaccine development against these novel phleboviruses and will help to prevent its potential as a public health threat.

Family Flaviviridae Tick-borne flaviviruses with encephalitis manifestations Tick-borne encephalitis virus Tick-borne encephalitis virus (TBEV) is a member of the Flavivirus genus. TBEV is a neurotropic virus endemic in central, eastern, and northern Europe, and north-eastern Asia (Gritsun et al., 2003b; Heinz et al., 2007; Toporkova et al., 2008; Süss et al., 2008; Lu et al., 2008; Takashima et al., 1997). Russia is reported as being the country with the highest incidence with 3721 clinical cases during 1990–2009 (Süss, 2011). The principal vectors for this virus are Ixodes ricinus for the European subtype (Gritsun et al., 2003b) and Ixodes persulcatus for the Siberian and the Far-Eastern subtypes (Süss, 2003). In the life cycle of TBEV, the virus is mainly maintained in nature by transmission between ixodid ticks, wild mammalian hosts and, in some cases, migrating birds (Gray, 1991; Süss, 2003; Charrel et al., 2004; Mansfield et al., 2009; Waldenström et al., 2007). Infection with this virus is usually initiated by a bite from an infected tick, while the other infection route is due to consumption of raw, unpasteurized milk and dairy products (Greˇsíková et al., 1975; Dumpis et al., 1999). Typically, the symptoms of patients with TBE have a biphasic pattern starting with influenza-like symptoms such as fatigue, headache, pain in neck, high fever, and vomiting. In 20–30% of the patients, there will be an asymptomatic period of 2–10 days, followed by the second phase where there is neurological involvement (meningitis, encephalitis, myelitis, and radiculitis)

Please cite this article in press as: Lani, R., et al., Tick-borne viruses: A review from the perspective of therapeutic approaches. Ticks Tick-borne Dis. (2014), http://dx.doi.org/10.1016/j.ttbdis.2014.04.001

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(Andzhaparidze et al., 1978; Monath and Heinz, 1996; Gritsun et al., 2003a; Süss et al., 2007). There has been an upward rise of clinical cases related to TBEV infection, and this increase is likely due to urbanization and increased human activities like agriculture in the wild (Gritsun et al., 2003b). Other factors that had increasing effects on TBE prevalence can be exemplified by increase of ticks population due to global warming, moving of ticks to higher altitudes, and emergence of new TBE foci (Randolph et al., 2000; Lindgren et al., 2000; Lindgren and Gustafson, 2001; Bröker and Gniel, 2003). The prevention of TBE can be achieved by avoidance of exposure to the bite of an infected tick and by not drinking non-pasteurized dairy products (Dumpis et al., 1999). An effective alternative for TBE prevention is vaccination (Kunz et al., 1980; Kunz, 2003). To date, there are at least 4 formaldehyde-inactivated vaccines available against TBEV infection: the Austrian FSME-IMMUN, German Encepur Adult and Children, and 2 Russian vaccines manufactured in Moscow and Tomsk (EnceVir and TBE vaccine Moscow) (Levkovich et al., 1960; Bock et al., 1990; Harabacz et al., 1992; Hayasaka et al., 2001; Barrett et al., 2003, 2004). Following vaccination, there is efficient crossprotection against different TBEV strains with a reduced, but still protective, neutralization capacity against more distantly related viruses such as Omsk hemorrhagic fever virus (Orlinger et al., 2011). This was clearly demonstrated by quantitatively comparing the cross-protection profiles of vaccines, FSME-IMMUN (derived from European subtype), EnceVir and IPVE (both derived from Far Eastern subtype), and there was no significant difference on the degree of protection (Fritz et al., 2012). However, it also showed that TBE vaccine Moscow and Encepur had a high immunogenicity compared to EnceVir and FSME-IMMUN (Leonova and Pavlenko, 2009). As a result, more studies are required to determine and evaluate the vaccine-induced cross-protection against different TBEV strains. It is worth mentioning that the vaccination coverage differs significantly between countries with TBE endemicity. In Austria, 88% of the population showed immunity against TBEV due to wide vaccination (Heinz et al., 2007). In contrast, neighboring countries such as Germany and the Czech Republic have only 13% and 11% vaccination coverage, respectively (Heinz et al., 2007). This would then increase the risk of acquiring TBE with the recent rise in tourism (Dumpis et al., 1999). This can be illustrated by many TBE reports in travelers to Europe (McNair and Brown, 1991; Aendekerk et al., 1996; Kessels et al., 1999; Bröker and Gniel, 2003) and more recently by the first reported case of imported TBE in Australia, where the patient traveled through Russia on a 6-week ˚ zek, 2013). In addition to the prevention trip (Chaudhuri and Ruˇ of TBE, an effective treatment and post-exposure management approach is highly needed. In addition to aforementioned inactivated vaccines, several attempts have been done to develop live attenuated vaccines on the basis of Langat virus (LGTV), which is a member of the tickborne encephalitis virus (TBEV) antigenic complex (Il’enko et al., 1968; Dubov, 1969; Price et al., 1970; Mayer, 1973; Timofeev and Karganova, 2003; Pripuzova et al., 2009). However, vaccineassociated severe complications in some patients (Dubov, 1969; Smorodintsev and Dubov, 1986) and delayed progressive subacute sclerosing encephalitis through in vivo studies (Zlotnik et al., 1973; Zlotnik and Grant, 1976; Pogodina et al., 1981) have resulted in attempts to develop more attenuated virus vaccines. This can be illustrated by new types of live attenuated vaccines that use mutagenesis of the viral genome or chimerization of 2 different viruses (Mandl et al., 1998; Pletnev et al., 2001; Lai and Monath, 2003; Kofler et al., 2004). Pletnev and Men (1998) have produced a chimeric virus with the prM and E genes encoding structural proteins of LGTV strain TP21 and remaining part of the genome from dengue virus type 4. The attenuation efficacy of the chimera LGT/DEN4 against virulent strains of TBEV has been shown in

mice, monkeys, and humans in past years (Pletnev and Men, 1998; Pletnev et al., 2000, 2001; Rumyantsev et al., 2006; Wright et al., 2008; Pripuzova et al., 2009). However, to make a decision about vaccine strain safety, it is required to do more evaluation for the possibility of long-term persistence of attenuated viruses in the recipients and other complications (Pripuzova et al., 2009). More recently, a replication-defective flavivirus mutant platform, RepliVax was used in the construction of RepliVax-TBE variants containing the prM-E genes of TBEV (Rumyantsev et al., 2013). It was demonstrated in mice and non-human primates that the RepliVax-TBEV variants were highly attenuated, immunogenic, and protective, and have potential as a single-dose TBEV vaccine. Treatment outlook for TBE. Currently, there is no approved antiviral drug available for TBE. Therefore, the treatment of TBE patients is supportive and symptomatic (Kaiser, 2012; Mansfield et al., 2009). Administration of corticosteroids has been only supported by few studies like a progressive case from Lithuania (Mickiene et al., 2002) and treatment of a group of TBE patients in Germany (Duniewicz and Kulková, 1982). In Russia, specific immunoglobulins have been used against TBE with more than 60% efficacy in the first 96 h post exposure (Kunz et al., 1981; Kreil and Eibl, 1997; Dumpis et al., 1999). However, this medicine was withdrawn completely from the market in Europe, as there was a hypothesis about the antibody-dependent enhancement of infection in some cases (Arras et al., 1996; Waldvogel et al., 1996). For example, specific prophylactic post-exposure immunoglobulins may have caused severe encephalitis and negative effects on the course of the disease in some age group less than 7 years old in Europe (Kluger et al., 1995; Waldvogel et al., 1996). On the other hand, there are many factors that may affect the treatment using immunoglobulins, which is worth more evaluation. This can be illustrated by a significant correlation of the efficacy of immunoglobulins with calculating adequate doses (Vereta et al., 1994) or HLA phenotype ˚ zek et al. of the patients (Chernitsyna et al., 1992). Recently, Ruˇ (2013) have discussed whether early administration of high dose IVIG therapy may have a positive therapeutic effect on severe cases of TBE. Accordingly, obtaining immunoglobulins from blood donors vaccinated against TBE may be a good strategy in TBE treatment. Further study is required to evaluate the possible benefits of this therapeutic approach. Another approach that has shown promising results in the treatment of TBE trials is using antioxidants such as cytoflavin, emoxypine (mexidol), and panavir (Abramenko, 2011; Kon’kovaReˇidman and Ratnikova, 2012; Skripchenko and Egorova, 2011; Udintseva et al., 2012; Litvin et al., 2009). In a recent study, Achazi et al. (2012) demonstrated the in vitro inhibitory effect of siRNAs on TBEV replication. RNAi has been demonstrated to be a useful technique for inhibiting the replication of many different viruses including the human immunodeficiency virus (HIV), hepatitis viruses, dengue virus, West Nile virus, Japanese encephalitis virus, yellow fever virus, and human respiratory syncytial virus (Achazi et al., 2012). Besides the aforementioned approaches, other potent antiviral agents include pancreatic ribonuclease (RNAse) (Glukhov et al., 1976), complementary and non-complementary oligonucleotides (Frolova et al., 1994), and lincomycin (Votiakov et al., 1992). Additionally, combinations of thymalin (immunomodulator polypeptides) and leukinferon (a complex preparation containing alpha-interferon and cytokines of the first phase of immune response such as interleukins 1, 6, and 12, and tumor necrosis factor to activate the phagocytic process) with human leukocytic IFN (Krylova and Leonova, 2001) may be effective as a treatment for TBE. Recently, Osolodkin et al. (2013) by constructing homology models of envelope glycoproteins of tick-transmitted flaviviruses, have proposed 17 compounds with significant in vitro inhibitory

Please cite this article in press as: Lani, R., et al., Tick-borne viruses: A review from the perspective of therapeutic approaches. Ticks Tick-borne Dis. (2014), http://dx.doi.org/10.1016/j.ttbdis.2014.04.001

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effects on TBEV, Powassan virus (POWV), or Omsk hemorrhagic fever virus (OHFV). Among these compounds, the ones belonging to the series of 1,4-dihydropyridines, had inhibitory effects against TBEV or OHFV, and others from pyridothiadiazines, have a stronger inhibitory effect against TBEV compared to POWV. In summary, further investigations through in vitro, in vivo studies and clinical trials are required to evaluate the therapeutic efficacy of the above-mentioned approaches on TBE patients in the limitation for the usage of these compounds for treatment purposes. Powassan virus Powassan virus (POWV) belongs to the genus Flavivirus and was first isolated from the CNS of a 5-year-old boy who suffered from encephalitis in 1958 (Mclean and Donohue, 1959). The principal vector for this virus is Ixodes cookei, which is found mainly in Canada and the northeastern United States (Birge and Sonnesyn, 2012; Mclean et al., 1967). This virus was found in South Dakota, western United States, western Canada, and Siberia (Lvov et al., 1975; Gritsun et al., 2003a). Additionally, human infection has been documented in the northern United States and Russia (Ebel and Kramer, 2004). Patients infected by this virus present with encephalitis and neurological signs after an incubation period of 1–4 weeks (Birge and Sonnesyn, 2012). The main pathological finding in POWV infection is lymphocytic infiltration of perivascular neuronal tissues with a predilection for gray matter (Gholam et al., 1999), which then leads to long-term neurological sequelae and death in at least 10% of the cases (Hinten et al., 2008; Ebel and Kramer, 2004). Severe encephalitis with a high incidence of neurological sequelae and a mortality rate of up to 60% has been reported in Canada and the United States (Gritsun et al., 2003a). Louping-ill virus Louping-ill virus (LIV) from the Flavivirus genus was isolated for the first time from sheep brains in England and Scotland (Hubálek and Rudolf, 2012). There are significant antigenic and genomic similarities between LIV and TBEV (Hubálek and Rudolf, 2012). Most of the LIV infections in humans are due to occupational exposure in people who had direct contact with animals (Lawson et al., 1949; Charrel et al., 2004; Dobler, 2010) or through the consumption of raw goat or sheep milk (Reid et al., 1984; Reid and Pow, 1985; Hubálek and Rudolf, 2012). The clinical manifestations of the disease are similar to the western European subtype of TBEV (Charrel et al., 2004; Hubálek and Rudolf, 2012). Antigenic and genetic similarity of this virus to TBEV has suggested that LIV is one of the subtypes of TBEV (Hubálek et al., 1995; Grard et al., 2007; Dobler, 2010). However, this virus rarely infects humans (Grard et al., 2007). Treatment outlook for POWV and LIV. Due to the lack of antiviral agents against these viruses, the general management of these viral diseases is based on supportive and symptomatic therapy. Diagnosis and management of simultaneous complications such as secondary bacterial infections, aspiration pneumonia, respiratory failure, cardiac abnormalities, and electrolyte imbalance are other aspects to be considered for the treatment (Ferrari et al., 2009). Concerning specific antiviral agents, there are a few studies on antivirals that directly target POWV and LIV. Examples are given by studies on antivirals like d-[1,2,4] triazole (ETAR) (McDowell et al., 2010) and siRNA (Maffioli et al., 2012), which have an inhibitory effect on LGTV and other flaviviruses; however, no clinical trial has been done to evaluate their therapeutic efficacy. Recently, it has been shown that some compounds belonging to the series pyridothiadiazines have inhibitory effects against POWV (Osolodkin et al., 2013). According to the recent case reports with POWV in the northern United States (Dobler, 2010; Raval et al., 2012), there

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is an urgent need to do further research to find the safe and effective antiviral agents against POWV as it is becoming a serious public health threat. Tick-borne flaviviruses with hemorrhagic manifestation Omsk hemorrhagic fever virus Omsk hemorrhagic fever virus (OHFV) is a flavivirus that was first isolated from a patient with fever and hemorrhage in the Omsk district, Siberia in 1947 (Dobler, 2010). The virus was also isolated from arthropods, particularly ticks of the species Dermacentor reticulatus and vertebrates such as muskrats (Charrel et al., 2004). The Centers for Disease Control and Prevention (CDC) has named several other hosts for this virus. The natural foci of OHFV are in Omsk, Novosibirsk, Tyumen, and Kurgan with a range of fatality rates between 0.5% and 3.0% (Charrel et al., 2004). The transmission routes of this virus are tick bites (Charrel et al., 2004), contact with feces or urine of infected or dead muskrats, contact with viremic blood of infected hosts, and aerosol transmission (Dobler, 2010). The clinical manifestations of OHF include fever, headache, myalgia, cough, and sometimes the appearance of petechial rash or bruises. In the second phase of the infection, meningeal signs with neurological system involvement are noted (Charrel et al., 2004; ˚ zek et al., 2010). Chronic forms of OHF have not been reported in Ruˇ ˚ zek et al., 2010). The hemorrhagic humans (Charrel et al., 2004; Ruˇ manifestation is actually due to vascular and circulatory capillary damage (Charrel et al., 2004). To date, there is no licensed vaccine available against OHFV, although there is some evidence that ˚ zek et al., 2010; TBEV vaccines have the ability to cross-protect (Ruˇ Orlinger et al., 2011; Pripuzova et al., 2013). Kyasanur Forest disease virus Kyasanur Forest disease virus (KFDV) was isolated after an outbreak of severe disease in monkeys in Kyasanur Forest and people living near the forest in Karnataka state of India in 1957 (Kasabi et al., 2013; Holbrook, 2012; Pavri, 1989). Transmission of KFDV is mainly through the bites of infected ticks from the genus Haemaphysalis, particularly Hemaphysalis spinigera. The known natural hosts are Blanford rat (Rattus blanfordi), the striped forest squirrel (Funambulus tristriatus tristriatus), and the house shrew (Suncus murinus) (Dobler, 2010). The annual incidence of KFD in India is estimated to be 400–500 cases with seasonal outbreaks during January to June (Holbrook, 2012; Kasabi et al., 2013). The clinical manifestation of KFD is similar to OHF (Bossi et al., 2004). Since 1990, a formalin-inactivated KFDV vaccine derived from infected cell cultures has been produced and used in India (Dandawate et al., 1994; Holbrook et al., 2005). However, due to insufficient efficacy of the current vaccine protocol, an increasing number of KFD cases were detected in Karnataka state of the Indian subcontinent from 1999 to 2012 (Pattnaik, 2006; Holbrook et al., 2005). There is another genetic variant of KFDV that caused outbreaks in 1994 in Saudi Arabia, and the virus is named Alkhurma hemorrhagic fever virus (AHFV). It has a mortality rate of 25%, and there is a 1.3% seroprevalence in hemorrhagic patients in Saudi Arabia (Charrel and de Lamballerie, 2003; Memish et al., 2011). Treatment outlook for OHFV, KFDV, and AHFV. These diseases are mostly self-limiting. Strict bed-rest and supportive therapy are important for the management of these patients (Mazbich and Netsky, 1952). Administration of aspirin and other non-steroidal anti-inflammatory drugs with potential side effects should be ˚ zek et al., 2010). Despite the potential use of these avoided (Ruˇ viruses as biological weapons, according to the list from the CDC, there are only a few studies aiming to develop antiviral agents against OHFV. Some of the antiviral drugs available are virazol (ribavirin), a broad-spectrum antiviral nucleoside, and realdiron, a

Please cite this article in press as: Lani, R., et al., Tick-borne viruses: A review from the perspective of therapeutic approaches. Ticks Tick-borne Dis. (2014), http://dx.doi.org/10.1016/j.ttbdis.2014.04.001

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recombinant human interferon alfa-2b, which binds to cell surface receptors to modulate downstream intracellular signal transduction pathways. Another antiviral agent is interferon inducers, for example larifan and rifastin, which have inhibitory effects against the virus replication (Loginova et al., 2002). Nevertheless, no experimental clinical trials have been done to confirm the effectiveness of these drugs. The compounds belonging to 1,4-dihydropyridines have also shown significant inhibitory effects against OHFV and TBEV in homology models (Osolodkin et al., 2013). However, further in vitro and in vivo studies are necessary to evaluate their efficacy and safety. Family Reoviridae

further study is indispensable to find a potent antiviral agent or vaccine for a better control of these viruses. Conclusion According to the aforementioned discussion, it can be concluded that tick-borne viruses are important viruses with many obscure aspects. They are zoonotic agents that pose a serious threat to public health. Therefore, finding and establishing efficient therapeutic strategies is crucial due to the lack of availability of approved antiviral drugs and licensed vaccines. We hope this review will improve the public perception of this menacing viral group and will lead to new insights for future investigations toward finding effective treatment strategies for these viral diseases.

Colorado tick fever virus Acknowledgement Colorado tick fever virus (CTFV) is a virus of the genus Coltivirus. It was isolated from infected human blood in 1944 (Cimolai et al., 1988). The mountain wood tick, Dermacentor andersoni, is the vector of CTFV, and the prevalence of the disease is directly dependent on the seasonal activity and geographical distribution of the ticks (Meagher and Decker, 2012; Rust, 2012; Cimolai et al., 1988). As a result, CTF is mainly prevalent from May to July, and it is mostly localized in the mountainous regions of the western United States and Canada (Meagher and Decker, 2012; Rust, 2012; Cimolai et al., 1988). After West Nile virus, CTFV is the second most important arboviral infection with 200–400 case reports per year in the northern United States (Romero and Simonsen, 2008; Meagher and Decker, 2012). Transmission routes for this virus include bites of infected ticks, contact with infected animal blood or tissues, and person-to-person transmission via blood transfusion (Emmons, 1988; Cimolai et al., 1988). After an incubation period of 3–5 days, an acuteingited febrile illness is presented (Meagher and Decker, 2012). The clinical symptoms comprise fever, chills, malaise, lymphadenopathy, headache, conjunctivitis, photophobia, nausea, vomiting, asthenia, myalgia, weakness, and, in some cases, development of meningismus (Rust, 2012). Macular rash has also been seen in about 10% of the cases (Cimolai et al., 1988). “Saddleback” course, which is a recurrence of fever, may occur in some cases (Rust, 2012). Treatment outlook for CTFV Due to the sporadic and self-limiting nature of these viral diseases, management is only with supportive care and avoidance of medications that compromise platelet functions, such as aspirin or non-steroidal anti-inflammatory drugs. Currently, there is no antiviral drug or vaccine available for CTFV. However, there are a few studies that focused on specific antiviral drugs for this disease. In 1981, the efficacy of 4 ribonucleic acid virus inhibitors including ribavirin, 3-deazaguanine, 3-deazauridine, and 9-(S)(2,3-dihydroxypropyl) adenine were evaluated in vivo and in vitro against CTFV (Smee et al., 1981). Findings demonstrated that ribavirin and 3-deazaguanine markedly inhibited CTFV replication in MA-104 cells. In addition, the therapeutic effect of ribavirin triacetate in CTFV-infected mice was reported. In another study, a nucleoside analog, 3 -fluoro-3 deoxyadenosine (3 F3 dAdo) was shown to have inhibitory potency against CTFV replication in Vero cells (Smee et al., 1992). On the other hand, ribavirin was less active against CTFV in this study, and this finding was not consistent with the results from the previous study (Smee et al., 1992). Accordingly, the aforementioned studies have demonstrated the availability of some antiviral candidates for CTFV with some contradictions regarding the efficacy of ribavirin; as a consequence, owing to insufficient data on drugs and vaccine development,

We thank University of Malaya for University Malaya Research Grants #RG383-11HTM and #RP013-2012. References Abramenko, IuV., 2011. The assessment of the clinical efficacy, vasoactive and metabolic effects of mexidol in elderly patients with discirculatory encephalopathy. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova 111, 35–41. Achazi, K., Patel, P., Paliwal, R., 2012. RNA interference inhibits replication of tickborne encephalitis virus in vitro. Antiviral Res. 93, 94–100. Aendekerk, R.P., Schrivers, A.N., Koehler, P.J., 1996. Tick-borne encephalitis complicated by a polio-like syndrome following a holiday in central Europe. Clin. Neurol. Neurosurg. 98, 262–264. Andersson, I., Karlberg, H., Mousavi-Jazi, M., Martínez-Sobrido, L., Weber, F., Mirazimi, A., 2008. Crimean-Congo hemorrhagic fever virus delays activation of the innate immune response. J. Med. Virol. 80, 1397–1404. Andersson, I., Lundkvist, A., Haller, O., Mirazimi, A., 2006. Type I interferon inhibits Crimean-Congo hemorrhagic fever virus in human target. J. Med. Virol. 78, 216–222. Andzhaparidze, O.G., Rozina, E.E., Bogomolova, N.N., Boriskin, Y.S., 1978. Morphological characteristics of the infection of animals with tick-borne encephalitis virus persisting for a long time in cell cultures. Acta Virol. 22, 218–224. Arda, B., Aciduman, A., Johnston, J.C., 2012. A randomized controlled trial of ribavirin in Crimean-Congo hemorrhagic fever, ethical considerations. J. Med. Ethics 38, 117–120. Arras, C., Fescharek, R., Gregersen, J.P., 1996. Do specific hyperimmunoglobulins aggravate clinical course of tick-borne encephalitis? Lancet 347, 698–699. Barrett, P.N., Schober-Bendixen, S., Ehrlich, H.J., 2003. History of TBE vaccines. Vaccine 21, 41–49. Barrett, P.N., Dorner, F., Ehrlich, H., Plotkin, S.A., 2004. Tick-borne encephalitis virus vaccine. In: Plotkin, S.A., Orenstein, W.A. (Eds.), Vaccines. Saunders/Elsevier, New York, p. 38. Birge, J., Sonnesyn, S., 2012. Powassan virus encephalitis, Minnesota, USA. Emerg. Infect. Dis. 18, 1669–1671. Bossi, P., Tegnell, A., Baka, A., Van Loock, F., Hendriks, J., Werner, A., Maidhof, H., Gouvras, G., 2004. Bichat guidelines for clinical management of hemorrhagic fever viruses and bioterrorism-related hemorrhagic fever viruses. Euro. Surveill. 9, E11–E12. Bock, H.L., Klockmann, U., Jungst, C., Schindel-Kunzel, F., Theobald, K., Zerban, R., 1990. A new vaccine against tick-borne encephalitis: initial trial in man including a dose–response study. Vaccine 8, 22–24. Bröker, M., Gniel, D., 2003. New foci of tick-borne encephalitis virus in Europe: consequences for travellers from abroad. Travel Med. Infect. Dis. 1, 181–183. Charrel, R.N., Attoui, H., Butenko, A.M., Clegg, J.C., Deubel, V., Frolova, T.V., Gould, E.A., Gritsun, T.S., Heinz, F.X., Labuda, M., Lashkevich, V.A., Loktev, V., Lundkvist, A., Lvov, D.V., Mandl, C.W., Niedrig, M., Papa, A., Petrov, V.S., Plyusnin, A., Randolph, S., Süss, J., Zlobin, V., de Lamballerie, X., 2004. Tick-borne virus diseases of human interest in Europe. Clin. Microbiol. Infect. 10, 1040–1055. Charrel, R.N., de Lamballerie, X., 2003. The Alkhurma virus (family Flaviviridae, genus Flavivirus), an emerging pathogen responsible for hemorrhage fever in the Middle East. Med. Trop. 63, 296–299. ˚ zek, D., 2013. First documented case of imported tick-borne Chaudhuri, A., Ruˇ encephalitis in Australia. Intern. Med. J. 43, 93–96. Cherenov, I.V., Galimzianov, K.M., Sologub, T.V., Romantsov, M.G., Lokteva, O.M., Kovalenko, A.L., 2012. Efficacy of antiviral agents in the treatment of Crimean hemorrhagic fever. Klin. Med. (Mosk.) 90, 59–62. Chernitsyna, L.O., Konenkov, V.I., Ierusalimskii, A.P., 1992. Evaluation of the effectiveness of various methods of the treatment of tick-borne encephalitis in the acute period. Zh. Nevropatol. Psikhiatr. Im. S. S. Korsakova 92, 50–53. Chumakov, M.P., Karpovich, L.G., Sarmanova, E.S., Sergeeza, G.I., Bychkova, M.V., Tapupere, V.O., Libikova, E.O., Maier, V., Rzhegachek, R., Kozhukhm, O., Ernek, E., 1963. Isolation of a virus from the tick Ixodes persulcatus in western Siberia

Please cite this article in press as: Lani, R., et al., Tick-borne viruses: A review from the perspective of therapeutic approaches. Ticks Tick-borne Dis. (2014), http://dx.doi.org/10.1016/j.ttbdis.2014.04.001

G Model TTBDIS-321; No. of Pages 9

ARTICLE IN PRESS R. Lani et al. / Ticks and Tick-borne Diseases xxx (2014) xxx–xxx

and from patients which differs from the pathogen of tick encephalitis. Vopr. Virusol. 8, 98–99. Cimolai, N., Anand, C.M., Gish, G.J., Calisher, C.H., Fishbein, D.B., 1988. Human Colorado tick fever in southern Alberta. CMAJ 139, 45–46. Dandawate, C.N., Desai, G.B., Achar, T.R., Banerjee, K., 1994. Field evaluation of formalin-inactivated Kyasanur Forest disease virus tissue culture vaccine in three districts of Karnataka state. Indian J. Med. Res. 99, 152–158. Dobler, G., 2010. Zoonotic tick-borne flaviviruses. Vet. Microbiol. 140, 221–228. Dubov, A., 1969. Live Vaccine Against Tick-borne Encephalitis. Tyumen Scientific Research Institute of Regional Infectious Pathology, pp. 161. Dumpis, U., Crook, D., Oksi, J., 1999. Tick-borne encephalitis. Clin. Infect. Dis. 28, 882–890. Duniewicz, M., Kulková, H., 1982. Corticoids in the therapy of tick- and other type of viral meningoencephalitis. Münch. Med. Wochenschr. 124, 69–70. Ebel, G.D., Kramer, L.D., 2004. Short report, duration of tick attachment required for transmission of Powassan virus by deer ticks. Am. J. Trop. Med. Hyg. 71, 268–271. Elaldi, N., Bodur, H., Ascioglu, S., Celikbas, A., Ozkurt, Z., Vahaboglu, H., Leblebicioglu, H., Yilmaz, N., Engin, A., Sencan, M., Aydin, K., Dokmetas, I., Cevik, M.A., Dokuzoguz, B., Tasyaran, M.A., Ozturk, R., Bakir, M., Uzun, R., 2009. Efficacy of oral ribavirin treatment in Crimean-Congo hemorrhagic fever, a quasi-experimental study from Turkey. J. Infect. 58, 238–244. Emmons, R.W., 1988. Ecology of Colorado tick fever. Annu. Rev. Microbiol. 42, 49–64. Erduran, E., Bahadir, A., Palanci, N., Gedik, Y., 2013. The treatment of CrimeanCongo hemorrhagic fever with high-dose methylprednisolone, intravenous immunoglobulin, and fresh frozen plasma. J. Pediatr. Hematol. Oncol. 35, e19–e24. Ergonul, O., 2006. Crimean-Congo hemorrhagic fever. Lancet Infect. Dis. 6, 203–214. Ergonul, O., 2008. Treatment of Crimean-Congo hemorrhagic fever. Antiviral Res. 78, 125–131. Ergonul, O., 2012. Crimean-Congo hemorrhagic fever virus, new outbreaks, new discoveries. Curr. Opin. Virol. 2, 215–220. Ferrari, S., Toniolo, A., Monaco, S., Luciani, F., Cainelli, F., Baj, A., Temesgen, Z., Vento, S., 2009. Viral encephalitis, etiology, clinical features, diagnosis and management. Open Infect. Dis. J. 3, 1–12. Flick, R., Whitehouse, C.A., 2005. Crimean-Congo hemorrhagic fever virus. Curr. Mol. Med. 5, 753–760. Fritz, R., Orlinger, K.K., Hofmeister, Y., Janecki, K., Traweger, A., Perez-Burgos, L., Barrett, P.N., Kreil, T.R., 2012. Quantitative comparison of the cross-protection induced by tick-borne encephalitis virus vaccines based on European and Far Eastern virus subtypes. Vaccine 30, 1165–1169. Frolova, T.V., Nomokonova, N.Iu., Roikhel, V.M., 1994. Antiviral effect of various oligonucleotide derivatives, complementary to tick-borne encephalitis virus RNA. Vopr. Virusol. 39, 232–235. Gai, Z.T., Zhang, Y., Liang, M.F., Jin, C., Zhang, S., Zhu, C.B., Li, C., Li, X.Y., Zhang, Q.F., Bian, P.F., Zhang, L.H., Wang, B., Zhou, N., Liu, J.X., Song, X.G., Xu, A., Bi, Z.Q., Chen, S.J., Li, D.X., 2012. Clinical progress and risk factors for death in severe fever with thrombocytopenia syndrome patients. J. Infect. Dis. 206, 1095–1102. Gholam, B.I., Puksa, S., Provias, J.P., 1999. Powassan encephalitis, a case report with neuropathology and literature review. CMAJ 161, 1419–1422. Glukhov, B.N., Jerusalimsky, A.P., Canter, V.M., Salganik, R.I., 1976. Ribonuclease treatment of tick-borne encephalitis. Arch. Neurol. 33, 598–603. Grard, G., Moureau, G., Charrel, R.N., Lemasson, J.J., Gonzalez, J.P., Gallian, P., Gritsun, T.S., Holmes, E.C., Gould, E.A., de Lamballerie, X., 2007. Genetic characterization of tick-borne flaviviruses, new insights into evolution, pathogenetic determinants and taxonomy. Virology 361, 80–92. Gray, J.S., 1991. The development and seasonal activity of the tick Ixodes ricinus: a vector of Lyme borreliosis. Rev. Med. Vet. Entomol. 79, 323–333. Greˇsíková, M., Sekeyova, M., Stupalova, S., Neˇcas, S., 1975. Sheep milk-borne epidemic of tick-borne encephalitis in Slovakia. Intervirology 5, 57–61. Gritsun, T.S., Nuttall, P.A., Gould, E.A., 2003a. Tick-borne flaviviruses. Adv. Virus Res. 61, 317–371. Gritsun, T.S., Frolova, T.V., Zhankov, A.I., Armesto, M., Turner, S.L., Frolova, M.P., Pogodina, V.V., Lashkevich, V.A., Gould, E.A., 2003b. Characterization of a Siberian virus isolated from a patient with progressive chronic tick-borne encephalitis. J. Virol. 77, 25–36. Harabacz, I., Bock, H., Jungst, C., Klockmann, U., Praus, M., Weber, R., 1992. A randomized phase II study of a new tick-borne encephalitis vaccine using three different doses and two immunization regimens. Vaccine 10, 145–150. Hayasaka, D., Goto, A., Yoshii, K., Mizutani, T., Kariwa, H., Takashima, I., 2001. Evaluation of European tick-borne encephalitis virus vaccine against recent Siberian and far-eastern subtype strains. Vaccine 19, 4774–4779. Heinz, F.X., Holzmann, H., Essl, A., Kundi, M., 2007. Field effectiveness of vaccination against tick-borne encephalitis. Vaccine 25, 7559–7567. Hofmann, H., Li, X., Zhang, X., Liu, W., Kühl, A., Kaup, F., Soldan, S.S., GonzálezScarano, F., Weber, F., He, Y., Pöhlmann, S., 2013. Severe fever with thrombocytopenia virus glycoproteins are targeted by neutralizing antibodies and can use DC-SIGN as a receptor for pH-dependent entry into human and animal cell lines. J. Virol. 87, 4384–4394. Hinten, S.R., Beckett, G.A., Gensheimer, K.F., Pritchard, E., Courtney, T.M., Sears, S.D., Woytowicz, J.M., Preston, D.G., Smith, R.P., Rand, P.W., Lacombe, E.H., Holman, M.S., Lubelczyk, C.B., Kelso, P.T., Beelen, A.P., Stobierski, M.G., Sotir, M.J., Wong, S., Ebel, G., Kosoy, O., Piesman, J., Campbell, G.L., Marfin, A.A., 2008. Increased recognition of Powassan encephalitis in the United States, 1999–2005. Vector Borne Zoonotic Dis. 8, 733–740. Hoogstraal, H., 1979. The epidemiology of tick-borne Crimean-Congo hemorrhagic fever in Asia, Europe, and Africa. J. Med. Entomol. 15, 307–417.

7

Holbrook, M.R., 2012. Kyasanur Forest disease. Antiviral Res. 96, 353–362. Holbrook, M.R., Aronson, J.F., Campbell, G.A., Jones, S., Feldmann, H., Barrett, A.D., 2005. An animal model for the tickborne flavivirus–Omsk hemorrhagic fever virus. J. Infect. Dis. 191, 100–108. Hubálek, Z., Rudolf, I., 2012. Tick-borne viruses in Europe. Parasitol. Res. 111, 9–36. Hubálek, Z., Pow, I., Reid, H.W., Hussain, M.H., 1995. Antigenic similarity of central European encephalitis and louping-ill viruses. Acta Virol. 39, 251–256. Il’enko, V.I., Smorodintsev, A.A., Prozorova, I.N., Platonov, V.G., 1968. Experience in the study of a live vaccine made from the TP-21 strain of Malayan Langat virus. Bull. World Health Organ. 39, 425–431. Jabbari, A., Besharat, S., Abbasi, A., Moradi, A., Kalavi, K., 2006. Crimean-Congo hemorrhagic fever: case series from a medical center in Golestan province. Northeast of Iran (2004). Indian J. Med. Sci. 60, 327–329. Jiang, X.L., Wang, X.J., Li, J.D., Ding, S.J., Zhang, Q.F., Qu, J., Zhang, S., Li, C., Wu, W., Jiang, M., Liang, M.F., Bi, Z.Q., Li, D.X., 2012. Isolation, identification and characterization of SFTS bunyavirus from ticks collected on the surface of domestic animals. Bing. Du. Xue. Bao. 28, 252–257. Jiao, L., Ouyang, S., Liang, M., Niu, F., Shaw, N., Wu, W., Ding, W., Jin, C., Peng, Y., Zhu, Y., Zhang, F., Wang, T., Li, C., Zuo, X., Luan, C.H., Li, D., Liu, Z.J., 2013. Structure of severe fever with thrombocytopenia syndrome virus nucleocapsid protein in complex with suramin reveals therapeutic potential. J. Virol. 87, 6829–6839. Jin, C., Liang, M., Ning, J., Gu, W., Jiang, H., Wu, W., Zhang, F., Li, C., Zhang, Q., Zhu, H., Chen, T., Han, Y., Zhang, W., Zhang, S., Wang, Q., Sun, L., Liu, Q., Li, J., Wang, T., Wei, Q., Wang, S., Deng, Y., Qin, C., Li, D., 2012. Pathogenesis of emerging severe fever with thrombocytopenia syndrome virus in C57/BL6 mouse model. Proc. Natl. Acad. Sci. U.S.A. 109, 10053–10058. Kaiser, R., 2012. Tick-borne encephalitis, clinical findings and prognosis in adults. Wien. Med. Wochenschr. 162, 239–243. Karlberg, H., Lindegren, G., Mirazimi, A., 2010. Comparison of antiviral activity of recombinant and natural interferons against Crimean-Congo hemorrhagic fever virus. Open Virol. J. 22, 38–41. Kasabi, G.S., Murhekar, M.V., Sandhya, V.K., Raghunandan, R., Kiran, S.K., Channabasappa, G.H., Mehendale, S.M., 2013. Coverage and effectiveness of Kyasanur Forest disease (KFD) vaccine in Karnataka, South India, 2005–10. PLoS Negl. Trop. Dis. 7, e2025. Keshtkar-Jahromi, M., Kuhn, J.H., Christova, I., Bradfute, S.B., Jahrling, P.B., Bavari, S., 2011. Crimean-Congo hemorrhagic fever, current and future prospects of vaccines and therapies. Antiviral Res. 90, 85–92. Kessels, B.L., van Dijl, R., van Keulen, P.H., Verburg, G.P., 1999. Tick encephalitis after a vacation in southern Germany. Ned. Tijdschr. Geneeskd. 143, 1784–1786. Kluger, G., Schottler, A., Waldvogel, K., Nadal, D., Hinrichs, W., Wundisch, G.F., 1995. Tick-borne encephalitis despite specific immunoglobulin prophylaxis. Lancet 346, 1502. Kofler, R.M., Heinz, F.X., Mandl, C.W., 2004. A novel principle of attenuation for the development of new generation live flavivirus vaccines. Arch. Virol. 18, 191–200. Koksal, I., Yilmaz, G., Aksoy, F., Aydin, H., Yavuz, I., Iskender, S., Akcay, K., Erensoy, S., Caylan, R., Aydin, K., 2010. The efficacy of ribavirin in the treatment of CrimeanCongo hemorrhagic fever in Eastern Black Sea region in Turkey. J. Clin. Virol. 47, 65–68. Kon’kova-Reˇidman, A.B., Ratnikova, L.I., 2012. Neuroimmune aspects of the pathogenesis and nitric oxide negative effects modifying the pathogenetic treatment of tick-borne infections. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova 112, 40–45. Kreil, T.R., Eibl, M.M., 1997. Pre- and postexposure protection by passive immunoglobulin but no enhancement of infection with a flavivirus in a mouse model. J. Virol. 71, 2921–2927. Krylova, N.V., Leonova, G.N., 2001. Comparative in vitro study of the effectiveness of various immunomodulating substances in tick-borne encephalitis. Vopr. Virusol. 46, 25–28. Kubar, A., Haciomeroglu, M., Ozkul, A., Bagriacik, U., Akinci, E., Sener, K., Bodur, H., 2011. Prompt administration of Crimean-Congo hemorrhagic fever (CCHF) virus hyperimmunoglobulin in patients diagnosed with CCHF and viral load monitorization by reverse transcriptase-PCR. Jpn. J. Infect. Dis. 64, 439–443. Kunz, C., Hofmann, H., Heinz, F.X., Dippe, H., 1980. Efficacy of vaccination against tick-borne encephalitis. Wien. Klin. Wochenschr. 92, 809–813. Kunz, C., Hofmann, H., Kundi, M., Mayer, K., 1981. Zur Wirksamkeit von FSMEImmunoglobulin. Wien. Med. Wochenschr. 21, 665–668. Kunz, C., 2003. TBE vaccination and the Austrian experience. Vaccine 21, 50–55. Labuda, M., Nuttall, P.A., 2004. Tick-borne viruses. Parasitology 129, S221–S245. Lai, C.J., Monath, T.P., 2003. Chimeric flaviviruses: novel vaccines against dengue fever, tick-borne encephalitis, and Japanese encephalitis. Adv. Virus Res. 61, 469–509. Lam, T.T., Liu, W., Bowden, T.A., Cui, N., Zhuang, L., Liu, K., Zhang, Y.Y., Cao, W.C., Pybus, O.G., 2013. Evolutionary and molecular analysis of the emergent severe fever with thrombocytopenia syndrome virus. Epidemics 5, 1–10. Lawson, J.H., Manderson, W.G., Hurst, E.W., 1949. Louping-ill meningo-encephalitis: a further case and a serological survey. Lancet 2, 696–699. Leonova, G.N., Pavlenko, E.V., 2009. Characterization of neutralizing antibodies to Far Eastern of tick-borne encephalitis virus subtype and the antibody avidity for four tick-borne encephalitis vaccines in human. Vaccine 27, 2899–2904. Levkovich, E.N., Zasukhina, G.D., Chumakov, M.P., Lashkevich, V.A., Gagarina, A.V., 1960. Cultural vaccine against tick-borne encephalitis. Vopr. Virusol. 2, 233–236. Lindgren, E., Tälleklint, L., Polfeldt, T., 2000. Impact of climatic change on the northern latitude limit and population density of the disease-transmitting European tick Ixodes ricinus. Environ. Health Perspect. 108, 119–123. Lindgren, E., Gustafson, R., 2001. Tick-borne encephalitis in Sweden and climate change. Lancet 358, 16–18.

Please cite this article in press as: Lani, R., et al., Tick-borne viruses: A review from the perspective of therapeutic approaches. Ticks Tick-borne Dis. (2014), http://dx.doi.org/10.1016/j.ttbdis.2014.04.001

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ARTICLE IN PRESS R. Lani et al. / Ticks and Tick-borne Diseases xxx (2014) xxx–xxx

Litvin, A.A., Ratnikova, L.I., Deriabin, P.G., 2009. Preclinical and clinical studies of the efficacy of Panavir in therapy for tick-borne encephalitis. Vopr. Virusol. 54, 26–32. Liu, Y., Li, Q., Hu, W., Wu, J., Wang, Y., Mei, L., Walker, D.H., Ren, J., Wang, Y., Yu, X.J., 2012. Person-to-person transmission of severe fever with thrombocytopenia syndrome virus. Vector Borne Zoonotic Dis. 12, 156–160. Loginova, S.Ia., Efanova, T.N., Koval’chuk, A.V., Faldina, V.N., Androshchuk, I.A., Pistsov, M.N., Borisevich, S.V., Kopylova, N.K., Pashchenko, Iu.I., Khamitov, P.A., Maksimov, V.A., Vasil’ev, N.T., 2002. Effectiveness of virazol, realdiron and interferon inductors in experimental Omsk hemorrhagic fever. Vopr. Virusol. 47, 27–30. Lu, Z., Bröker, M., Liang, G., 2008. Tick-borne encephalitis in mainland China. Vector Borne Zoonotic Dis. 8, 713–720. Lvov, D.K., Timopheeva, A.A., Smirnov, V.A., Gromashevsky, V.L., Sidorova, G.A., Nikiforov, L.P., Sazonov, A.A., Andreev, A.P., Skvortzova, T.M., Beresina, L.K., Aristova, V.A., 1975. Ecology of tick-borne viruses in colonies of birds in the USSR. Med. Biol. 53, 325–330. Maffioli, C., Grandgirard, D., Leib, S.L., Engler, O., 2012. SiRNA inhibits replication of Langat virus, a member of the tick-borne encephalitis virus complex in organotypic rat brain slices. PLoS ONE 7, e44703. Maltezou, H.C., Papa, A., 2011. Crimean-Congo hemorrhagic fever, epidemiological trends and controversies in treatment. BMC Med. 9, 131. Mandl, C.W., Holzmann, H., Meixner, T., Rauscher, S., Stadler, P.F., Allison, S.L., Heinz, F.X., 1998. Spontaneous and engineered deletions in the 30 noncoding region of tick-borne encephalitis virus: construction of highly attenuated mutants of a flavivirus. J. Virol. 72, 2132–2140. Mansfield, K.L., Johnson, N., Phipps, L.P., Stephenson, J.R., Fooks, A.R., Solomon, T., 2009. Tick-borne encephalitis virus – a review of an emerging zoonosis. J. Gen. Virol. 90, 1781–1794. Mardani, M., Keshtkar Jahromi, M., Holakouie Naieni, K., Zeinali, M., 2003. The efficacy of oral ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran. Clin. Infect. Dis. 36, 1613–1618. Matsuno, K., Weisend, C., Travassos da Rosa, A.P., Anzick, S.L., Dahlstrom, E., Porcella, S.F., Dorward, D.W., Yu, X.J., Tesh, R.B., Ebihara, H., 2013. Characterization of the Bhanja serogroup viruses (Bunyaviridae), a novel species of the genus Phlebovirus and its relationship with other emerging tick-borne phleboviruses. J. Virol. 87, 3719–3728. Mayer, V., 1973. Humoral antibody response in volunteers given the live, highly attenuated “14” clone derived from Langat E5 virus. Acta Virol. 17, 367. Mazbich, I.B., Netsky, G.I., 1952. Three years of study of Omsk hemorrhagic fever (1946–1948). Trud. Omsk Inst. Epidemiol. Microbiol. Gigien. 1, 51–67. McDowell, M., Gonzales, S.R., Kumarapperuma, S.C., Jeselnik, M., Arterburn, J.B., Hanley, K.A., 2010. A novel nucleoside analog, 1-␤-D-ribofuranosyl-3-ethynyl[1,2,4] triazole (ETAR), exhibits efficacy against a broad range of flaviviruses in vitro. Antiviral Res. 87, 78–80. Mclean, D.M., Donohue, W.L., 1959. Powassan virus, isolation of virus from a fatal case of encephalitis. Can. Med. Assoc. J. 80, 708–711. Mclean, D.M., Cobb, C., Gooderham, S.E., Smart, C.A., Wilson, A.G., Wilson, W.E., 1967. Powassan virus, persistence of virus activity during 1966. Can. Med. Assoc. J. 9, 660–664. McMullan, L.K., Folk, S.M., Kelly, A.J., MacNeil, A., Goldsmith, C.S., Metcalfe, M.G., ˜ C.G., Zaki, S.R., Rollin, P.E., Nicholson, W.L., Nichol, S.T., Batten, B.C., Albarino, 2012. A new phlebovirus associated with severe febrile illness in Missouri. N. Engl. J. Med. 367, 834–841. McNair, A.N., Brown, J.L., 1991. Tick-borne encephalitis complicated by monoplegia and sensorineural deafness. J. Infect. 22, 81–86. Meagher, K.E., Decker, C.F., 2012. Other tick-borne illnesses, tularemia, Colorado tick fever, tick paralysis. Dis. Mon. 58, 370–376. Memish, Z.A., Albarrak, A., Almazroa, M.A., Al-Omar, I., Alhakeem, R., Assiri, A., Fagbo, S., MacNeil, A., Rollin, P.E., Abdullah, N., Stephens, G., 2011. Seroprevalence of Alkhurma and other hemorrhagic fever viruses, Saudi Arabia. Emerg. Infect. Dis. 17, 2316–2318. Mickiene, A., Laiskonis, A., Günther, G., Vene, S., Lundkvist, A., Lindquist, L., 2002. Tick-borne encephalitis in an area of high endemicity in Lithuania, disease severity and long-term prognosis. Clin. Infect. Dis. 35, 650–658. Monath, T.P., Heinz, F.X., 1996. Flaviviruses. In: Fields Virology, 3rd ed., pp. 961–1034. Mourya, D.T., Yadav, P.D., Shete, A.M., Gurav, Y.K., Raut, C.G., Jadi, R.S., Pawar, S.D., Nichol, S.T., Mishra, A.C., 2012. Detection, isolation and confirmation of CrimeanCongo hemorrhagic fever virus in human, ticks and animals in Ahmadabad, India, 2010–2011. PLoS Negl. Trop. Dis. 6, e1653. Orlinger, K.K., Hofmeister, Y., Fritz, R., Holzer, G.W., Falkner, F.G., Unger, B., LoewBaselli, A., Poellabauer, E.M., Ehrlich, H.J., Barrett, P.N., Kreil, T.R., 2011. A tick-borne encephalitis virus vaccine based on the European prototype strain induces broadly reactive cross-neutralizing antibodies in humans. J. Infect. Dis. 203, 1556–1564. Osolodkin, D.I., Kozlovskaya, L.I., Dueva, E.V., Dotsenko, V.V., Rogova, Y.V., Frolov, K.A., Krivokolysko, S.G., Romanova, E.G., Morozov, A.S., Karganova, G.G., 2013. Inhibitors of tick-borne flavivirus reproduction from structure-based virtual screening. ACS Med. Chem. Lett. 4, 869–874. Papa, A., Dalla, V., Papadimitriou, E., Kartalis, G.N., Antoniadis, A., 2010. Emergence of Crimean-Congo hemorrhagic fever in Greece. Clin. Microbiol. Infect. 16, 843–847. Pattnaik, P., 2006. Kyasanur forest disease, an epidemiological view in India. Rev. Med. Virol. 16, 151–165.

Pavri, K., 1989. Clinical, clinicopathologic, and hematologic features of Kyasanur Forest disease. Rev. Infect. Dis. 11, S854–S859. Pletnev, A.G., Men, R., 1998. Attenuation of the Langat tick-borne flavivirus by chimerization with mosquito-borne flavivirus dengue type 4. Proc. Natl. Acad. Sci. U.S.A. 95, 1746–1751. Pletnev, A.G., Karganova, G.G., Dzhivanyan, T.I., Lashkevich, V.A., Bray, M., 2000. Chimeric Langat/Dengue viruses protect mice from heterologous challenge with the highly virulent strains of tick-borne encephalitis virus. Virology 274, 26–31. Pletnev, A.G., Bray, M., Hanley, K.A., Speicher, J., Elkins, R., 2001. Tick-borne Langat/mosquito-borne dengue flavivirus chimera, a candidate to live attenuated vaccine for protection against disease caused by members of the tick-borne encephalitis virus complex: evaluation in rhesus monkeys and in mosquitoes. J. Virol. 75, 8259–8267. Pogodina, V.V., Frolova, M.P., Malenko, G.V., Fokina, G.I., Levina, L.S., Mamonenko, L.L., Koreshkova, G.V., Ralf, N.M., 1981. Persistence of tick-borne encephalitis virus in monkeys. I. Features of experimental infection. Acta Virol. 25, 337–343. Price, W.H., Thind, I.S., Teasdall, R., O’Leary, W., 1970. Vaccination of human volunteers against Russian Spring-Summer (RSS) virus complex with attenuated Langat E5 virus. Bull. World Health Organ. 42, 82–94. Pripuzova, N.S., Tereshkina, N.V., Gmyl, L.V., Dzhivanyan, T.I., Rumyantsev, A.A., Romanova, L.I., Karganova, G.G., 2009. Safety evaluation of chimeric Langat/Dengue 4 flavivirus, a live vaccine candidate against tick-borne encephalitis. J. Med. Virol. 81, 1777–1785. Pripuzova, N.S., Gmyl, L.V., Romanova, L.Iu., Tereshkina, N.V., Rogova, Y.V., Terekhina, L.L., Kozlovskaya, L.I., Vorovitch, M.F., Grishina, K.G., Timofeev, A.V., Karganova, G.G., 2013. Exploring of primate models of tick-borne flaviviruses infection for evaluation of vaccines and drugs efficacy. PLoS ONE 8, e61094. Randolph, S.E., Green, R.M., Peacey, M.F., Rogers, D.J., 2000. Seasonal synchrony: the key to tick-borne encephalitis foci identified by satellite data. Parasitology 121, 15–23. Raval, M., Singhal, M., Guerrero, D., Alonto, A., 2012. Powassan virus infection, case series and literature review from a single institution. BMC Res. Notes 5, 594. Reid, H.W., Pow, I., 1985. Excretion of louping-ill virus in ewes’ milk. Vet. Rec. 117, 470. Reid, H.W., Buxton, D., Pow, I., Finlayson, J., 1984. Transmission of louping-ill virus in goat milk. Vet. Rec. 114, 163–165. Romantsov, M.G., Galimzianov, Kh.M., Lokteva, O.M., Kovalenko, A.L., Stepanov, A.V., 2012. Experimental and clinicolaboratory evaluation of complex therapy efficacy in arboviral infections. Antibiot. Khimioter. 57, 12–22. Romero, J.R., Simonsen, K.A., 2008. Powassan encephalitis and Colorado tick fever. Infect. Dis. Clin. North Am. 22, 545–559. Rumyantsev, A.A., Chanock, R.M., Murphy, B.R., Pletnev, A.G., 2006. Comparison of live and inactivated tick-borne encephalitis virus vaccines for safety, immunogenicity and efficacy in rhesus monkeys. Vaccine 24, 133–143. Rumyantsev, A.A., Goncalvez, A.P., Giel-Moloney, M., Catalan, J., Liu, Y., Gao, Q.S., Almond, J., Kleanthous, H., Pugachev, K.V., 2013. Single-dose vaccine against tick-borne encephalitis. Proc. Natl. Acad. Sci. U.S.A. 110, 13103–13108. Rust, R.S., 2012. Human arboviral encephalitis. Semin. Pediatr. Neurol. 19, 130–151. ˚ zek, D., Yakimenko, V.V., Karan, L.S., Tkachev, S.E., 2010. Omsk hemorrhagic fever. Ruˇ Lancet 376, 2104–2113. ˚ zek, D., Dobler, G., Niller, H.H., 2013. early intervention with high dose intravenous Ruˇ immunoglobulin pose a potentially successful treatment for severe cases of tickborne encephalitis? BMC Infect. Dis. 13, 306. Simon, M., Falk, K.I., Lundkvist, A., Mirazimi, A., 2006. Exogenous nitric oxide inhibits Crimean Congo hemorrhagic fever virus. Virus Res. 120, 184–190. Simpson, D.I., Knight, E.M., Courtois, G., Williams, M.C., Weinbren, M.P., Kibukamusoke, J.W., 1967. Congo virus, a hitherto undescribed virus occurring in Africa. I. Human isolations – clinical notes. East Afr. Med. J. 44, 86–92. Skripchenko, N.V., Egorova, E.S., 2011. Cytoflavin in the complex treatment of neuroinfections in children. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova 111, 28–31. Smee, D.F., Sidwell, R.W., Clark, S.M., Barnett, B.B., Spendlove, R.S., 1981. Inhibition of bluetongue and Colorado tick fever orbiviruses by selected antiviral substances. Antimicrob. Agents Chemother. 20, 533–538. Smee, D.F., Morris, J.L., Barnard, D.L., Van Aerschot, A., 1992. Selective inhibition of arthropod-borne and arenaviruses in vitro by 3 -fluoro-3 -deoxyadenosine. Antiviral Res. 18, 151–162. Smorodintsev, A.A., Dubov, A.V., 1986. Tick-borne encephalitis and its prevention. Leningrad-Medicina, 231. Soares-Weiser, K., Thomas, S., Thomson, G., Garner, P., 2010. Ribavirin for CrimeanCongo hemorrhagic fever, systematic review and meta-analysis. BMC Infect. Dis. 10, 207. Spik, K., Shurtleff, A., McElroy, A.K., Guttieri, M.C., Hooper, J.W., SchmalJohn, C., 2006. Immunogenicity of combination DNA vaccines for Rift Valley fever virus, tickborne encephalitis virus, Hantaan virus, and Crimean Congo hemorrhagic fever virus. Vaccine 24, 4657–4666. Süss, J., 2003. Epidemiology and ecology of TBE relevant to the production of effective vaccines. Vaccine 1, 19–35. Süss, J., Gelpi, E., Klaus, C., Bagon, A., Liebler-Tenorio, E.M., Budka, H., Stark, B., Müller, W., Hotzel, H., 2007. Tickborne encephalitis in a naturally exposed monkey (Macaca sylvanus). Emerg. Infect. Dis. 13, 905–907. Süss, J., Dobler, G., Zöller, G., Essbauer, S., Pfeffer, M., Klaus, C., Liebler-Tenorio, E.M., Gelpi, E., Stark, B., Hotzel, H., 2008. Genetic characterization of a tickborne encephalitis virus isolated from the brain of a naturally exposed monkey (Macaca sylvanus). Int. J. Med. Microbiol. 298, 295–300. Süss, J., 2011. Tick-borne encephalitis 2010, epidemiology, risk areas, and virus strains in Europe and Asia – an overview. Ticks Tick Borne Dis. 2, 2–15.

Please cite this article in press as: Lani, R., et al., Tick-borne viruses: A review from the perspective of therapeutic approaches. Ticks Tick-borne Dis. (2014), http://dx.doi.org/10.1016/j.ttbdis.2014.04.001

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Takashima, I., Morita, K., Chiba, M., Hayasaka, D., Sato, T., Tekezawa, C., Igarashi, A., Kariwa, H., Yoshimatsu, K., 1997. A case of tick-borne encephalitis in Japan and isolation of the virus. J. Clin. Microbiol. 35, 1943–1947. Tekin, S., Barut, S., Bursali, A., Gul Aydogan, G., Yuce, O., Demir, F., Yildirim, B., 2010. Seroprevalence of Crimean-Congo hemorrhagic fever (CCHF) in risk groups in Tokat Province of Turkey. African J. Microb. Res. 4, 214–217. Tignor, G.H., Hanham, C.A., 1993. Ribavirin efficacy in an in vivo model of Crimean-Congo hemorrhagic fever virus (CCHF) infection. Antiviral Res. 22, 309–325. Timofeev, A.V., Karganova, G.G., 2003. Tick-borne Encephalitis Vaccine: From Past to Future. Pronto Prints, Moscow, pp. 44. Tkachenko, Y.A., Butenko, A.M., Badalov, M.Y., 1971. Investigation of immunogenic activity of killed brain vaccine against Crimean hemorrhagic fever viral hemorrhagic fevers. In: Chumakov, M.P. (Ed.), Viral Hemorrhagic Fevers – Crimean Hemorrhagic Fever, Omsk Hemorrhagic Fever, Hemorrhagic Fever with Renal Syndrome, vol. XIX. Trudy Instituta Poliomielita i Virusnykh Entsefalitov, USSR Academy of Medical Sciences, Moscow, USSR, pp. 119–129. Toporkova, M.G., Aleshin, S.E., Ozherelkov, S.V., Nadezhdina, M.V., Stephenson, J.R., Timofeev, A.V., 2008. Serum levels of interleukin 6 in recently hospitalized tickborne encephalitis patients correlate with age, but not with disease outcome. Clin. Exp. Immunol. 152, 517–521. Udintseva, I.N., Bartfel’t, N.N., Zhukova, N.G., Poponina, A.M., 2012. Mexidol in the complex treatment of patients in the acute period of tick-borne encephalitis. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova 112, 34–38. Vasilenko, S.M., 1973. Results of the investigation on etiology, epidemiology features and the specific prophylaxis of Crimean hemorrhagic fever (CHF) in Bulgaria. In: Papaevangelou, G.J. (Ed.), Ninth International Congress on Tropical Medicine and Malaria. October 14–21, Athens, Greece, pp. 32–33. Vasilenko, S.M., Vassilev, T.L., Bozadjiev, L.G., Bineva, I.L., Kazarov, G.Z., 1990. Specific intravenous immunoglobulin for Crimean-Congo hemorrhagic fever. Lancet 335, 791–792. Vereta, L.A., Zakharycheva, T.A., Aleksandrov, V.I., Skupchenko, V.V., Nikolaeva, S.P., 1994. The relationship of the therapeutic efficacy of immunoglobulin against tick-borne encephalitis to the specific activity of the preparation and the times of its administration. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova 94, 68–70.

9

Votiakov, V.I., Mishaeva, N.P., Protas, I.I., Ierusalimskii, A.P., Shutov, A.A., Kovalenko, V.N., Kichkil’deev, N.K., Samo˘ılova, T.I., Drakina, S.A., Zgirovskaia, A.A., 1992. The efficacy of lincomycin in tick-borne encephalitis. Klin. Med. (Mosk.) 70, 65–67. Waldenström, J., Lundkvist, A., Falk, K.I., Garpmo, U., Bergström, S., Lindegren, G., Sjöstedt, A., Mejlon, H., Fransson, T., Haemig, P.D., Olsen, B., 2007. Migrating birds and tickborne encephalitis virus. Emerg. Infect. Dis. 13, 1215–1218. Waldvogel, K., Bossart, W., Huisman, T., Boltshauser, E., Nadal, D., 1996. Severe tick-borne encephalitis following passive immunisation. Eur. J. Pediatr. 155, 775–779. Watts, D.M., Ussery, M.A., Nash, D., Peters, C.J., 1989. Inhibition of Crimean-Congo hemorrhagic fever viral infectivity yields in vitro by ribavirin. Am. J. Trop. Med. Hyg. 41, 581–585. Whitehouse, C.A., 2004. Crimean-Congo hemorrhagic fever. Antiviral Res. 64, 145–160. Wright, P.F., Ankrah, S., Henderson, S.E., Durbin, A.P., Speicher, J., Whitehead, S.S., Murphy, B.R., Pletnev, A.G., 2008. Evaluation of the Langat/dengue 4 chimeric virus as a live attenuated tick-borne encephalitis vaccine for safety and immunogenicity in healthy adult volunteers. Vaccine 26, 882–890. Zhang, Y.Z., Zhou, D.J., Qin, X.C., Tian, J.H., Xiong, Y., Wang, J.B., Chen, X.P., Gao, D.Y., He, Y.W., Jin, D., Sun, Q., Guo, W.P., Wang, W., Yu, B., Li, J., Dai, Y.A., Li, W., Peng, J.S., Zhang, G.B., Zhang, S., Chen, X.M., Wang, Y., Li, M.H., Lu, X., Ye, C., de Jong, M.D., Xu, J., 2012a. The ecology, genetic diversity, and phylogeny of Huaiyangshan virus in China. J. Virol. 86, 2864–2868. Zhang, Y.Z., He, Y.W., Dai, Y.A., Xiong, Y., Zheng, H., Zhou, D.J., Li, J., Sun, Q., Luo, X.L., Cheng, Y.L., Qin, X.C., Tian, J.H., Chen, X.P., Yu, B., Jin, D., Guo, W.P., Li, W., Wang, W., Peng, J.S., Zhang, G.B., Zhang, S., Chen, X.M., Wang, Y., Li, M.H., Li, Z., Lu, S., Ye, C., de Jong, M.D., Xu, J., 2012b. Hemorrhagic fever caused by a novel Bunyavirus in China, pathogenesis and correlates of fatal outcome. Clin. Infect. Dis. 54, 527–533. Zlotnik, I., Grant, D.P., Carter, G.B., Batter-Yatton, D., 1973. Subacute sclerosing encephalitis in adult hamsters infected with Langat virus. Br. J. Exp. Pathol. 54, 29–39. Zlotnik, I., Grant, D.P., 1976. Further observations on subacute sclerosing encephalitis in adult hamsters: the effects of intranasal infections with Langat virus, measles virus and SSPE-measles virus. Br. J. Exp. Pathol. 57, 49–66.

Please cite this article in press as: Lani, R., et al., Tick-borne viruses: A review from the perspective of therapeutic approaches. Ticks Tick-borne Dis. (2014), http://dx.doi.org/10.1016/j.ttbdis.2014.04.001