#Serological #Evidence of #Yersiniosis, #TBE, #WNV, #Hepatitis E, #CCHF, Lyme #Borreliosis, and #Brucellosis in Febrile Patients Presenting at Diverse Hospitals in #Kenya (Vector Borne Zoo Dis., abstract)

[Source: Vector-Borne and Zoonotic Diseases, full page: (LINK). Abstract, edited.]

Serological Evidence of Yersiniosis, Tick-Borne Encephalitis, West Nile, Hepatitis E, Crimean-Congo Hemorrhagic Fever, Lyme Borreliosis, and Brucellosis in Febrile Patients Presenting at Diverse Hospitals in Kenya

Josphat Nyataya, Moureen Maraka, Allan Lemtudo, Clement Masakhwe, Beth Mutai, Kariuki Njaanake, Benson B. Estambale, Nancy Nyakoe, Joram Siangla, and John Njenga Waitumbi

Published Online: 13 Jan 2020 / DOI: https://doi.org/10.1089/vbz.2019.2484

 

Abstract

Data on pathogen prevalence is crucial for informing exposure and disease risk. We evaluated serological evidence of tick-borne encephalitis (TBE), West Nile (WN), Hepatitis E virus (HEV), Crimean-Congo Hemorrhagic Fever (CCHF), Yersiniosis, Lyme Disease (LD), and brucellosis in 1033 patients presenting with acute febrile illness at 9 health care facilities from diverse ecological zones of Kenya: arid and semiarid (Garissa District Hospital, Lodwar District Hospital, Marigat District Hospital, Gilgil District Hospital), Lake Victoria basin (Kisumu District Hospital, Alupe District Hospital, Kombewa Sub-County Hospital), Kisii highland (Kisii District Hospital), and coastal (Malindi District Hospital). Epidemiological information of the patients such as geography, age, gender, and keeping animals were analyzed as potential risk factors. Of the 1033 samples, 619 (59.9%) were seropositive to at least one pathogen by IgM (current exposure), IgG/IgM (recent exposure), and IgG (past exposure). Collective seroprevalence for current, recent, and past to the pathogens was 9.4%, 5.1%, and 21.1% for LD; 3.6%, 0.5%, and 12.4% for WN; 0.9%, 0.5%, and 16.9% for HEV; 5.8%, 1.3%, and 3.9% for brucellosis; 5.7%, 0.2%, and 2.3% for yersiniosis; 1.7%, 0%, and 6.2% for TBE; and 0.4%, 0%, and 1.9% for CCHF. Brucellosis risk was higher in patients recruited at Garissa District Hospital (odds ratio [OR] = 3.41), HEV (OR = 2.45) and CCHF (OR = 5.46) in Lodwar District Hospital, LD in Alupe District Hospital (OR = 5.73), Kombewa Sub-district hospital (OR = 8.17), and Malindi District hospital (OR = 3.3). Exposure to LD was highest in the younger age group, whereas yersiniosis did not vary with age. Age was a significant risk for WN, brucellosis, CCHF, TBE, and HEV and in those aged >14 years there was an increased risk to WN (OR = 2.30, p < 0.0001), brucellosis (OR = 1.84, p = 0.005), CCHF (OR = 4.35, p = 0.001), TBE (OR = 2.78, p < 0.0001), and HEV (OR = 1.94, p = 0.0001). We conclude that LD is pervasive and constitutes a significant health burden to the study population, whereas yersiniosis and CCHF are not significant threats. Going forward, community-based studies will be needed to capture the true seroprevalence rates and the associated risk factors.

Keywords: Arbovirus; WNV; CCHF; Borreliosis; TBE; Brucellosis; Seroprevalence; Kenya.

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An E460D #substitution in the #NS5 protein of #TBE virus confers #resistance to the #inhibitor #Galidesivir (BCX4430) and also attenuates the virus for mice (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

An E460D substitution in the NS5 protein of tick-borne encephalitis virus confers resistance to the inhibitor Galidesivir (BCX4430) and also attenuates the virus for mice

Ludek Eyer, Antoine Nougairède, Marie Uhlířová, Jean-Sélim Driouich, Darina Zouharová, James J. Valdés, Jan Haviernik, Ernest A. Gould, Erik De Clercq, Xavier de Lamballerie, Daniel Ruzek

DOI: 10.1128/JVI.00367-19

 

ABSTRACT

The adenosine analogue Galidesivir (BCX4430), a broad-spectrum RNA virus inhibitor, has entered a Phase 1 clinical safety and pharmacokinetics study in healthy subjects and is under clinical development for treatment of Ebola virus infection. Moreover, Galidesivir also inhibits the reproduction of tick-borne encephalitis virus (TBEV) and numerous other medically important flaviviruses. Until now, studies of this antiviral agent have not yielded resistant viruses. Here, we demonstrate that an E460D substitution, in the active site of TBEV RNA-dependent-RNA-polymerase (RdRp), confers resistance to Galidesivir in cell culture. Galidesivir-resistant TBEV exhibited no cross-resistance to structurally different antiviral nucleoside analogues, such as 7-deaza-2′-C-methyladenosine, 2′-C-methyladenosine and 4′-azido-aracytidine. Although, the E460D substitution led only to a subtle decrease in viral fitness in cell culture, Galidesivir-resistant TBEV was highly attenuated in vivo, with 100% survival rate and no clinical signs observed in infected mice. Furthermore, no virus was detected in serum, spleen or brain of mice inoculated with the Galidesivir-resistant TBEV. Our results contribute to understanding the molecular basis of Galidesivir antiviral activity, flavivirus resistance to nucleoside inhibitors and the potential contribution of viral RdRp to flavivirus neurovirulence.

 

IMPORTANCE

Tick-borne encephalitis virus (TBEV) is a pathogen that causes severe human neuroinfections in Europe and Asia and for which there is currently no specific therapy. We have previously found that Galidesivir (BCX4430), a broad-spectrum RNA virus inhibitor, which is under clinical development for treatment of Ebola virus infection, has a strong antiviral effect against TBEV. For any antiviral drug, it is important to generate drug-resistant mutants to understand how the drug works. Here, we produced TBEV mutants resistant to Galidesivir and found that the resistance is caused by a single amino acid substitution in an active site of the viral RNA-dependent RNA polymerase, an enzyme which is crucial for replication of viral RNA genome. Although, this substitution led only to a subtle decrease in viral fitness in cell culture, Galidesivir-resistant TBEV was highly attenuated in a mouse model. Our results contribute to understanding the molecular basis of Galidesivir antiviral activity.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antivirals; Drugs Resistance; Galidesivir; Flavivirus; Tick-Borne Encephalitis Virus.

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#Molecular basis of a protective/neutralizing #monoclonal #antibody targeting envelope proteins of both #tick-borne #encephalitis virus and louping ill virus (J Virol., abstract)

[Source: Journal of Virology, full page: (LINK). Abstract, edited.]

Molecular basis of a protective/neutralizing monoclonal antibody targeting envelope proteins of both tick-borne encephalitis virus and louping ill virus

Xu Yang, Jianxun Qi, Ruchao Peng, Lianpan Dai, Ernest A. Gould, George F. Gao, Po Tien

DOI: 10.1128/JVI.02132-18

 

ABSTRACT

Tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) are members of the tick-borne flaviviruses (TBFVs) in the family Flaviviridae, which cause encephalomeningitis and encephalitis in humans and other animals. Although vaccines against TBEV and LIV are available, infection rates are rising due to the low vaccination coverage. To date, no specific therapeutics have been licensed. Several neutralizing monoclonal antibodies (MAbs) show promising effectiveness in the control of TBFVs, but the underlying molecular mechanisms are yet to be characterized. Here, we determined the crystal structures of LIV envelope protein (E) and report the comparative structural analysis of a TBFV broadly neutralizing murine MAb (MAb 4.2) in complex with either LIV or TBEV E proteins. The structures reveal that MAb 4.2 binds to the lateral ridge of Domain III (EDIII) of LIV-E or TBEV-E, an epitope also reported for other potently neutralizing MAbs against mosquito-borne flaviviruses (MBFVs), but adopts a unique binding orientation. Further structural analysis suggested that MAb 4.2 may neutralize flavivirus infection by preventing the structural rearrangement required for membrane fusion during virus entry. These findings extend our understanding of the vulnerability of TBFVs and other flaviviruses (including MBFVs) and provide an avenue for antibody-based TBFVs antiviral development.

 

Importance

Understanding the mechanism of antibody neutralization/protection against a virus is crucial for antiviral counter-measures development. Tick-borne encephalitis virus (TBEV) and louping ill virus (LIV) are tick-borne flaviviruses (TBFVs) in the family Flaviviridae. They cause encephalomeningitis and encephalitis in humans and other animals. Although vaccines for both viruses are available, infection rates are rising due to the low vaccination coverage. In this study, we solved the crystal structures of LIV envelope protein (E) and a broadly-neutralizing/protective TBFV MAb, MAb 4.2, in complex with E from either TBEV or LIV. Key structural features shared by TBFV E proteins were analyzed. Structures of E-antibody complexes show that MAb 4.2 targets the lateral ridge of both TBEV and LIV E proteins, a vulnerable site in flaviviruses for other potent neutralizing MAbs. Thus, this site represents a promising target for TBFV antiviral development. Further, these structures provide important information for understanding TBFV antigenicity.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Flavivirus; Tick-borne encephalitis virus; Louping ill virus; Monoclonal antibodies.

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#Serological Evidence of #Tick-Borne #Encephalitis and #WNV #Infections Among #Children with #Arthritis in #Turkey (Vector Borne Zoo Dis., abstract)

[Source: Vector Borne and Zoonotic Diseases, full page: (LINK). Abstract, edited.]

Serological Evidence of Tick-Borne Encephalitis and West Nile Virus Infections Among Children with Arthritis in Turkey

Huseyin Yilmaz, Kenan Barut, Asiye Karakullukcu, Ozgur Kasapcopur, Bekir Kocazeybek, Eda Altan Tarakci, Utku Y. Cizmecigil, Aysun Yilmaz, Zahide Bilgin, Meltem Ulutas Esatgil, Christine Klaus, Juergen A. Richt, and Nuri Turan

Published Online: 28 Jan 2019 / DOI: https://doi.org/10.1089/vbz.2018.2349

 

Abstract

Tick-borne encephalitis virus (TBEV) and West Nile virus (WNV) are mainly transmitted by arthropod vectors to vertebrate hosts including humans, resulting in fever and neurological signs. The aim of this study was to investigate the presence of antibodies to TBEV and WNV, and TBEV-RNA and WNV-RNA in Turkish children with fever and/or arthritis. For this purpose, 110 sera and buffy-coat samples were collected; sera were analyzed by indirect enzyme-linked immunosorbent assay for the presence of IgM and IgG antibodies to TBEV and WNV, and buffy-coat-derived white blood cells were analyzed by quantitative real-time RT-PCR for TBEV-RNA and WNV-RNA. IgM antibodies to TBEV were detected in five children between the ages of 3 and 7 years; no IgG antibodies to TBEV were detected. IgG antibodies to WNV were detected in two children and IgM antibodies to WNV were detected in six children, between the ages of 3 and 7 years. One of the children had IgM antibodies to WNV and to TBEV. Children who had antibodies to TBEV and WNV had fever and/or arthritis but no obvious neurological signs. Molecular diagnostic approaches revealed that neither TBEV-RNA nor WNV-RNA was present in any of the buffy-coat samples, not even in children with IgM-specific antibodies. Our serological results indicate that children in Turkey are exposed to TBEV and WNV.

Keywords: Arbovirus; Tick-borne encephalitis; WNV; Seroprevalence; Arthritis; Turkey.

—–

A #Serosurvey of #Flavivirus #Infection in #Horses and #Birds in #Slovakia (Vector Borne Zoo Dis., abstract)

[Source: Vector Borne and Zoonotic Diseases, full page: (LINK). Abstract, edited.]

Vector-Borne and Zoonotic Diseases

A Serosurvey of Flavivirus Infection in Horses and Birds in Slovakia

To cite this article: Csank Tomáš, Drzewnioková Petra, Korytár Ľuboš, Major Peter, Gyuranecz Miklós, Pistl Juraj, and Bakonyi Tamás. Vector-Borne and Zoonotic Diseases. February 2018, ahead of print. https://doi.org/10.1089/vbz.2017.2216

Online Ahead of Print: February 13, 2018

Author information: Tomáš Csank,1 Petra Drzewnioková,1 Ľuboš Korytár,2 Peter Major,3 Miklós Gyuranecz,4 Juraj Pistl,1 and Tamás Bakonyi5,6

1 Department of Microbiology and Immunology, University of Veterinary Medicine and Pharmacy (UVMP) in Košice, Košice, Slovakia. 2 Department of Environment, Veterinary Legislation and Economy, University of Veterinary Medicine and Pharmacy (UVMP) in Košice, Košice, Slovakia. 3 Department of Clinic for Birds and Exotic Animals, University of Veterinary Medicine and Pharmacy (UVMP) in Košice, Košice, Slovakia. 4 Institute for Veterinary Medical Research, MTA Centre for Agricultural Research, Hungarian Academy of Sciences, Budapest, Hungary. 5 Department of Microbiology and Infectious Diseases, University of Veterinary Medicine, Budapest, Hungary. 6 Viral Zoonoses, Emerging and Vector-Borne Infections Group, Institute of Virology, University of Veterinary Medicine, Vienna, Vienna, Austria.

Address correspondence to: Tomáš Csank, PhD, Department of Microbiology and Immunology, University of Veterinary Medicine and Pharmacy (UVMP) in Košice, Komenského 73, Košice 04181, Slovakia, E-mail: tomas.csank@uvlf.sk

 

ABSTRACT

In central Europe, at least three flaviviruses circulate among vectors and vertebrate hosts. West Nile virus (WNV) and Usutu virus (USUV) are mosquito-borne viruses maintained in the nature by enzootic cycle between mosquitoes and birds. Tick-borne encephalitis virus (TBEV) is a flavivirus causing annual human cases in Slovakia. The aim of this study is the prevalence assessment of flavivirus infections in horses (n = 145) and birds (n = 109) by enzyme-linked immunosorbent assay (ELISA) and confirmation by neutralization test (VNT). WNV antibodies have been detected in 11.7% of tested horses and 11.9% of tested birds and confirmed in 6.9% of horse and 9.2% of bird samples. None of the WNV seropositive or dubious horses had WNV IgM (ELISA), and none of the tested horses had USUV neutralizing antibodies. Autochthonous WNV infections have been confirmed in 16.7% of horses without international travelling history. Most of them were from western Slovakia with known endemic WNV transmission. An autochthonous WNV infection in a horse from highland area of Kremnické vrchy (central Slovakia) with unknown data of WNV circulation and without travelling history was detected. TBEV antibody was detected in 6.2% of horses and in 3.4% has been confirmed. In two horses, WNV and TBEV infection could not be distinguished. Confirmed WNV seropositive were eight raptors showing nonspecific signs or suffering from trauma, one white stork, and one house sparrow. The sparrow was caught in a locality in eastern Slovakia, where WNV RNA had been previously detected in sparrows. USUV neutralizing antibodies were present in pooled sample from four Eurasian great tits. Because of insufficient volume, TBEV VNT was not carried out in birds. Results further prove the endemicity of WNV and other vector-borne flaviviruses in natural and accidental hosts in Slovakia, giving better insight in flavivirus epidemiology in European countries in general.

Keywords: Slovakia; Flavivirus; WNV; Usutu Virus; TBEV; Horses; Wild birds.

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#Viperin restricts #Zika virus and #TBE virus #replication by targeting NS3 for proteasomal degradation (J Virol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Virol. 2018 Jan 10. pii: JVI.02054-17. doi: 10.1128/JVI.02054-17. [Epub ahead of print]

Viperin restricts Zika virus and tick-borne encephalitis virus replication by targeting NS3 for proteasomal degradation.

Panayiotou C1, Lindqvist R1, Kurhade C1, Vonderstein K1, Pasto J1, Edlund K1, Upadhyay AS1, Överby AK2.

Author information: 1 Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden. Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden. 2 Department of Clinical Microbiology, Virology, Umeå University, Umeå, Sweden. Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden. anna.overby@umu.se.

 

Abstract

Flaviviruses are arthropod-borne viruses that constitute a major global health problem, with millions of human infections annually. Their pathogenesis ranges from mild illness to severe manifestations such as hemorrhagic fever and fatal encephalitis. Type I interferons (IFNs) are induced in response to viral infection, and stimulate the expression of interferon-stimulated genes (ISGs), including that encoding viperin (virus-inhibitory protein, endoplasmic reticulum-associated, IFN-inducible), which shows antiviral activity against a broad spectrum of viruses including several flaviviruses. Here we describe a novel antiviral mechanism exerted by viperin against two prominent flaviviruses, tick-borne encephalitis virus (TBEV) and Zika virus (ZIKV). Viperin was found to interact and co-localize with the structural proteins pre-membrane (prM) and envelope (E) of TBEV, as well as the non-structural (NS) proteins NS2A, NS2B, and NS3. Interestingly, viperin expression reduced the NS3 protein level, and the stability of the other interacting viral proteins, but only in the presence of NS3. We also found that although viperin interacted with NS3 of mosquito-borne flaviviruses (ZIKV, Japanese encephalitis virus, and yellow fever virus), only ZIKV was sensitive to the antiviral effect of viperin. This sensitivity correlated with viperin’s ability to induce proteasome-dependent degradation of NS3. ZIKV and TBEV replication was rescued completely when NS3 was overexpressed, suggesting that the viral NS3 is the specific target of viperin. In summary, we present here a novel antiviral mechanism of viperin that is selective for specific viruses in the genus Flavivirus, affording the possibility of new drug targets that can be used for therapeutic intervention.

 

Importance

Flaviviruses are a group of enveloped RNA viruses that cause severe diseases in humans and animals worldwide, but no antiviral treatment is yet available. Viperin, a host protein produced in response to infection, effectively restricts the replication of several flaviviruses but the exact molecular mechanisms have not been elucidated. Here we have identified a novel mechanism exerted by viperin to inhibit the replication of two flaviviruses; tick-borne encephalitis virus (TBEV) and Zika virus (ZIKV). Viperin induced selective degradation via the proteasome of TBEV and ZIKV non-structural 3 (NS3) protein, which is involved in several steps of the viral life cycle. Furthermore, viperin also reduced the stability of several other viral proteins in a NS3-dependent manner, suggesting a central role of NS3 in viperin’s anti-flaviviral activity. Taken together, our work shows important similarities and differences among the members of the genus Flavivirus, and could lead to the possibility of therapeutic intervention.

PMID: 29321318 DOI: 10.1128/JVI.02054-17

Keywords: Flavivirus; Zika Virus; Viperin.

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Unrecognized Subclinical #Infection with #Tick-Borne #Encephalitis Virus, #Japan (@CDC_EIDjournal, abstract)

[Source: US Centers for Disease Control and Prevention (CDC), Emerging Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Volume 23, Number 10—October 2017 / Research Letter

Unrecognized Subclinical Infection with Tick-Borne Encephalitis Virus, Japan

Kentaro Yoshii, Reiji Kojima, and Hiroshi Nishiura

Author affiliations: Hokkaido University, Sapporo, Japan (K. Yoshii); Japan Self-Defense Forces Sapporo Hospital, Sapporo (R. Kojima); University of Yamanashi, Yamanashi, Japan (R. Kojima); Hokkaido University, Sapporo (H. Nishiura)

 

Abstract

During early 2017, we conducted a seroepidemiologic investigation for tick-borne encephalitis virus among 291 Japan Self-Defense Forces members in Hokkaido. Two (0.7%) tested positive. Neither had clinically apparent symptoms after removing ticks.

Keywords: Tick-Borne Encephalitis; Japan.

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