#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 #infection with #dengue and #Zika viruses in #horses on French #Pacific Islands (PLoS Negl Trop Dis., abstract)

[Source: PLoS Neglected Tropical Diseases, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Serological evidence of infection with dengue and Zika viruses in horses on French Pacific Islands

Cécile Beck , Isabelle Leparc-Goffart, Denise Desoutter, Estelle Debergé, Hervé Bichet, Steeve Lowenski, Marine Dumarest, Gaelle Gonzalez, Camille Migné, Jessica Vanhomwegen, Stéphan Zientara, Benoit Durand , Sylvie Lecollinet

Published: February 7, 2019 / DOI: https://doi.org/10.1371/journal.pntd.0007162 / This is an uncorrected proof.

 

Abstract

New Caledonia and French Polynesia are areas in which arboviruses circulate extensively. A large serological survey among horses from New Caledonia and French Polynesia was carried out to investigate the seroprevalence of flaviviruses in the horse population. Here, 293 equine sera samples were screened for flaviviruses using a competitive enzyme-linked immunosorbent assay (cELISA). The positive sera were then confirmed using a flavivirus-specific microsphere immunoassay (MIA) and seroneutralization tests. This serosurvey showed that 16.6% (27/163) and 30.8% (40/130) of horses were positive for cELISA tests in New Caledonia and French Polynesia, respectively, but the MIA technique, targeting only flaviviruses causing neuro-invasive infections in humans and horses (i.e. West Nile virus [WNV], Japanese encephalitis virus [JEV] and tick-borne encephalitis virus [TBEV]), showed negative results for more than 85% (57/67) of the cELISA-positive animals. Seroneutralization tests with the main flaviviruses circulating in the South Pacific revealed that 6.1% (10/163; confidence interval [95% CI] 3.0%-11.0%) of sera in New Caledonia and 7.7% (10/130; 95% CI 3.8%-13.7%) in French Polynesia were positive for dengue virus serotype 1 (DENV1) and 4.3% (7/163; 95% CI 1.7%-8.6%) in New Caledonia and 15.4% (20/130, 95% CI 9.7%-22.8%) in French Polynesia were found positive for Zika virus (ZIKV). Seroprevalence of the JEV and WNV flaviviruses on the 293 samples from both island groups were comparatively much lower (less than 2%). This seroprevalence study in the horse population shows that horses can be infected with dengue and Zika viruses and that these infections lead to seroconversions in horses. The consequences of these infections in horses and their role in ZIKV and DENV epidemiological cycles are two issues that deserve further investigation.

 

Author summary

New Caledonia and French Polynesia, located in the South Pacific, are facing circulation of dengue virus (DENV) for a long time and emergence of Zika virus (ZIKV) since 2013. A large serosurvey among horses’ population from these two islands was carried out to investigate the seroprevalence of the main flaviviruses circulating in the South Pacific. We find out that 6 to 7% of equine sera tested were positive for DENV serotype 1 in the two islands and 4% and 15% were positive for ZIKV in New Caledonia and French Polynesia respectively. Our study highlighted serological evidence of DENV serotype 1 and ZIKV infections of horses leading to meaningful seroconversion. Seroprevalence of other mosquito-borne flaviviruses (i.e. Japanese encephalitis and West-Nile viruses) were comparatively much lower (less than 2%) in New Caledonia and French Polynesia groups suggesting the absence of past active circulation of these viruses in both islands. This finding emphasized the need to investigate the consequences of such infections in the horse population and to determine the role of domestic animals in ZIKV and DENV epidemiological cycles.

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Citation: Beck C, Leparc-Goffart I, Desoutter D, Debergé E, Bichet H, Lowenski S, et al. (2019) Serological evidence of infection with dengue and Zika viruses in horses on French Pacific Islands. PLoS Negl Trop Dis 13(2): e0007162. https://doi.org/10.1371/journal.pntd.0007162

Editor: David W.C. Beasley, University of Texas Medical Branch, UNITED STATES

Received: July 24, 2018; Accepted: January 15, 2019; Published: February 7, 2019

Copyright: © 2019 Beck et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Flavivirus; Zika Virus; Dengue Fever; Horses; New Caledonia.

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CCR2 plays a protective role in #Rocio virus induced #encephalitis by promoting #macrophage infiltration into the #brain (J Infect Dis., abstract)

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

CCR2 plays a protective role in Rocio virus induced encephalitis by promoting macrophage infiltration into the brain

Alberto A Amarilla, Nilton Nascimento Santos-Junior, Mario Luis Figueiredo, Joao Paulo Mesquita, Luiz Marcilio, Jorge Fumagalli, David F Colón, Veronica Lippi, Helda Liz Alfonso, Djalma S Lima-Junior, Amanda C Trabuco, Richard L Spinieli, Amanda C Desidera, Christie R A Leite-Panissi, Flávio Lauretti, Silvia Elena Sánchez Mendoza, Cleide Lúcia Araújo, Silva Eduardo Magalhaes Rego, Leonardo J Galvao-Lima, Gabriel S Bassi, Sandra L B Penharvel Martíns, Wilson Gomez Manrique, José Carlos Alves-Filho, Fernando Q Cunha Nias, Y G Peng, Naphak Modhiran, Yin Xiang Setoh, Alexander A Khromykh, Luiz T M Figueiredo, Victor H Aquino Quintana

The Journal of Infectious Diseases, jiz029, https://doi.org/10.1093/infdis/jiz029

Published: 04 February 2019

 

Abstract

Rocio virus (ROCV) is a highly neuropathogenic mosquito-transmitted flavivirus responsible for an unprecedented outbreak of human encephalitis during 1975-1976 in Sao Paulo State, Brazil. Previous studies have shown an increased number of inflammatory macrophages into the central nervous system (CNS) of ROCV-infected mice, implying a role for macrophages in the pathogenesis of ROCV. Here, we showed that ROCV infection results in increased expression of C-C chemokine ligand 2 (CCL2) in the blood and in infiltration of macrophages into the brain. Moreover, we showed using C-C chemokine receptor 2 (CCR2) knockout mice that CCR2 expression was essential for macrophage infiltration in the brains during ROCV infection and that the lack of CCR2 resulted in increased disease severity and mortality. Thus, our findings show the protective role of CCR2-mediated infiltration of macrophages in the brain during ROCV infection.

ROCV, encephalitis, CCL2, macrophages, pathogenesis

Issue Section: Major Article

This content is only available as a PDF.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Flavivirus; Rocio Virus; Encephalitis; Animal models.

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#Yellowfever virus is susceptible to #sofosbuvir both in vitro and in vivo (PLoS Negl Trop Dis., abstract)

[Source: PLoS Neglected Tropical Diseases, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Yellow fever virus is susceptible to sofosbuvir both in vitroand in vivo

Caroline S. de Freitas , Luiza M. Higa , Carolina Q. Sacramento, André C. Ferreira, Patrícia A. Reis, Rodrigo Delvecchio, Fabio L. Monteiro, Giselle Barbosa-Lima, Harrison James Westgarth, Yasmine Rangel Vieira, Mayara Mattos, Natasha Rocha, Lucas Villas Bôas Hoelz,  [ … ], Thiago Moreno L. Souza

Published: January 30, 2019 / DOI: https://doi.org/10.1371/journal.pntd.0007072 / This is an uncorrected proof.

 

Abstract

Yellow fever virus (YFV) is a member of the Flaviviridae family. In Brazil, yellow fever (YF) cases have increased dramatically in sylvatic areas neighboring urban zones in the last few years. Because of the high lethality rates associated with infection and absence of any antiviral treatments, it is essential to identify therapeutic options to respond to YFV outbreaks. Repurposing of clinically approved drugs represents the fastest alternative to discover antivirals for public health emergencies. Other Flaviviruses, such as Zika (ZIKV) and dengue (DENV) viruses, are susceptible to sofosbuvir, a clinically approved drug against hepatitis C virus (HCV). Our data showed that sofosbuvir docks onto YFV RNA polymerase using conserved amino acid residues for nucleotide binding. This drug inhibited the replication of both vaccine and wild-type strains of YFV on human hepatoma cells, with EC50 values around 5 μM. Sofosbuvir protected YFV-infected neonatal Swiss mice and adult type I interferon receptor knockout mice (A129-/-) from mortality and weight loss. Because of its safety profile in humans and significant antiviral effects in vitro and in mice, Sofosbuvir may represent a novel therapeutic option for the treatment of YF.

Key-words: Yellow fever virus; Yellow fever, antiviral; sofosbuvir

 

Author summary

Yellow fever virus is transmitted by mosquitoes and its infection may be asymptomatic or lead to a wide clinical spectrum ranging from a mild febrile illness to a potentially lethal viral hemorrhagic fever characterized by liver damage. Although a yellow fever vaccine is available, low coverage allows 80,000–200,000 cases and 30,000–60,000 deaths annually worldwide. There are no specific therapy and treatment relies on supportive care, reinforcing an urgent need for antiviral repourposing. Here, we showed that sofosbuvir, clinically approved against hepatitis C, inhibits yellow fever virus replication in liver cell lines and animal models. In vitro, sofosbuvir inhibits viral RNA replication, decreases the number of infected cells and the production of infectious virus particles. These data is particularly relevante since the liver is the main target of yellow fever infection. Sofosbuvir also protected infected animals from mortality, weight loss and liver injury, especially prophylatically. Our pre-clinical results supports a second use of sofosbuvir against yellow fever.

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Citation: de Freitas CS, Higa LM, Sacramento CQ, Ferreira AC, Reis PA, Delvecchio R, et al. (2019) Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo. PLoS Negl Trop Dis 13(1): e0007072. https://doi.org/10.1371/journal.pntd.0007072

Editor: Samuel V. Scarpino, Northeastern University, UNITED STATES

Received: March 25, 2018; Accepted: December 12, 2018; Published: January 30, 2019

Copyright: © 2019 de Freitas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files.

Funding: The financial support was provided by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ – http://www.faperj.br/ – Grant Number E-26/201.573/2014) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq – http://cnpq.br/ – Grant Numbers 306389/2014-2 and 425636/2016-0). TMLS received the funds. This work has received financial support from the National Institute of Science and Technology in Dengue (INCT dengue), a scheme funded by the Brazilian National Science Council (CNPq, Brazil) and Minas Gerais Foundation for Science (FAPEMIG, Brazil). Funding was also provided by National Council for Scientific and Technological Development (CNPq), Ministry of Science, Technology, Information and Communications (no. 465313/2014-0); Ministry of Education/CAPES (no. 465313/2014-0); Research Foundation of the State of Rio de Janeiro/FAPERJ (no. 465313/2014-0) and Oswaldo Cruz Foundation/FIOCRUZ to National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Keywords: Yellow Fever; Flavivirus; Antivirals; Sofosbuvir; Animal models.

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Dissecting #Flavivirus #Biology in #Salivary Gland Cultures from Fed and Unfed #Ixodes scapularis (Black-Legged #Tick) (mBio, abstract)

[Source: mBio, full page: (LINK). Abstract, edited.]

Dissecting Flavivirus Biology in Salivary Gland Cultures from Fed and Unfed Ixodes scapularis (Black-Legged Tick)

Jeffrey M. Grabowski, Olof R. Nilsson, Elizabeth R. Fischer, Dan Long, Danielle K. Offerdahl, Yoonseong Park, Dana P. Scott, Marshall E. Bloom

Thomas E. Morrison, Editor

DOI: 10.1128/mBio.02628-18

 

ABSTRACT

The Ixodes scapularis tick transmits a number of pathogens, including tick-borne flaviviruses (TBFVs). In the United States, confirmed human infections with the Powassan virus (POWV) TBFV have a fatality rate of ∼10% and are increasing in incidence. Tick salivary glands (SGs) serve as an organ barrier to TBFV transmission, and little is known regarding the location of TBFV infection in SGs from fed ticks. Previous studies showed I. scapularis vanin (VNN) involved with TBFV infection of I. scapularis ISE6 embryonic cells, suggesting a potential role for this gene. The overall goal of this study was to use SG cultures to compare data on TBFV biology in SGs from fully engorged, replete (fed) ticks and from unfed ticks. TBFV multiplication was higher in SGs from fed ticks than in those from unfed ticks. Virus-like particles were observed only in granular acini of SGs from unfed ticks. The location of TBFV infection of SGs from fed ticks was observed in cells lining lobular ducts and trachea but not observed in acini. Transcript knockdown of VNN decreased POWV multiplication in infected SG cultures from both fed and unfed ticks. This work was the first to identify localization of TBFV multiplication in SG cultures from a fed tick and a tick transcript important for POWV multiplication in the tick SG, an organ critical for TBFV transmission. This research exemplifies the use of SG cultures in deciphering TBFV biology in the tick and as a translational tool for screening and identifying potential tick genes as potential countermeasure targets.

 

IMPORTANCE

Tick-borne flaviviruses (TBFVs) are responsible for more than 15,000 human disease cases each year, and Powassan virus lineage 2 (POWV-L2) deer tick virus has been a reemerging threat in North America over the past 20 years. Rapid transmission of TBFVs in particular emphasizes the importance of preventing tick bites, the difficulty in developing countermeasures to prevent transmission, and the importance of understanding TBFV infection in tick salivary glands (SGs). Tick blood feeding is responsible for phenomenal physiological changes and is associated with changes in TBFV multiplication within the tick and in SGs. Using SG cultures from Ixodes scapularis female ticks, the primary aims of this study were to identify cellular localization of virus-like particles in acini of infected SGs from fed and unfed ticks, localization of TBFV infection in infected SGs from fed ticks, and a tick transcript (with associated metabolic function) involved in POWV-L2 infection in SG cultures.

Keywords: Arbovirus; Flavivirus; Powassan virus; Ticks.

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#Viral #Infections of the #CNS in #Africa (Brain Res Bull., abstract)

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

Brain Res Bull. 2019 Jan 15. pii: S0361-9230(18)30341-1. doi: 10.1016/j.brainresbull.2018.12.019. [Epub ahead of print]

Viral Infections of the Central Nervous System in Africa.

Kakooza-Mwesige A1, Tshala-Katumbay D2, Juliano SL3.

Author information: 1 Department of Paediatrics & Child Health, Makerere University College of Health Sciences and Mulago Hospital, Kampala, Uganda; Astrid Lindgren Children’s Hospital, Neuropediatric Research Unit, Karolinska Institutet, Sweden. Electronic address: akakooza246@gmail.com. 2 Department of Neurology and School of Public Health, Oregon Health & Science University, Portland, OR, USA; Department of Neurology, University of Kinshasa, Democratic Republic of the Congo; Institut National de Recherches Biomedicales, University of Kinshasa, Democratic Republic of the Congo. Electronic address: tshalad@ohsu.edu. 3 Neuroscience, USUHS, Bethesda, MD, 20814, USA. Electronic address: sharon.juliano@usuhs.edu.

 

Abstract

Viral infections are a major cause of human central nervous system infection, and may be associated with significant mortality, and long-term sequelae. In Africa, the lack of effective therapies, limited diagnostic and human resource facilities are especially in dire need. Most viruses that affect the central nervous system are opportunistic or accidental pathogens. Some of these viruses were initially considered harmless, however they have now evolved to penetrate the nervous system efficiently and exploit neuronal cell biology thus resulting in severe illness. A number of potentially lethal neurotropic viruses have been discovered in Africa and over the course of time shown their ability to spread wider afield involving other continents leaving a devastating impact in their trail. In this review we discuss key viruses involved in central nervous system disease and of major public health concern with respect to Africa. These arise from the families of Flaviviridae, Filoviridae, Retroviridae, Bunyaviridae, Rhabdoviridae and Herpesviridae. In terms of the number of cases affected by these viruses, HIV (Retroviridae) tops the list for morbidity, mortality and long term disability, while the Rift Valley Fever virus (Bunyaviridae) is at the bottom of the list. The most deadly are the Ebola and Marburg viruses (Filoviridae). This review describes their epidemiology and key neurological manifestations as regards the central nervous system such as meningoencephalitis and Guillain-Barré syndrome. The potential pathogenic mechanisms adopted by these viruses are debated and research perspectives suggested.

Copyright © 2019. Published by Elsevier Inc.

KEYWORDS: CNS viral infections; Ebola; HIV; Herpes; Rabies; Zika

PMID: 30658129 DOI: 10.1016/j.brainresbull.2018.12.019

Keywords: Emerging Diseases; Neurology; Flavivirus; Filovirus; Rhabdovirus; Herpesvirus; HIV/AIDS; Bunyavirus; Retrovirus.

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Expanding #Usutu virus #circulation in #Italy: detection in the Lazio region, central Italy, 2017 to 2018 (Euro Surveill., abstract)

[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

Expanding Usutu virus circulation in Italy: detection in the Lazio region, central Italy, 2017 to 2018

Fabrizio Carletti1, Francesca Colavita1, Francesca Rovida2, Elena Percivalle2, Fausto Baldanti2,3, Ida Ricci4, Claudio De Liberato4, Francesca Rosone4, Francesco Messina1, Eleonora Lalle1, Licia Bordi1, Francesco Vairo5, Maria Rosaria Capobianchi1, Giuseppe Ippolito6, Giuseppina Cappiello7, Alberto Spanò7, Silvia Meschi1, Concetta Castilletti1

Affiliations: 1 Laboratory of Virology, National Institute for Infectious Diseases ‘Lazzaro Spallanzani’ IRCCS, Rome, Italy; 2 Molecular Virology Unit, Microbiology and Virology Department, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 3 Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Italy; 4 Istituto Zooprofilattico Sperimentale delle regioni Lazio e Toscana, Rome, Italy; 5 Regional Service for Surveillance and Control of Infectious Diseases (SERESMI)-Lazio Region, National Institute for Infectious Diseases ‘Lazzaro Spallanzani’ IRCCS, Rome, Italy; 6 Scientific Direction, National Institute for Infectious Diseases ‘Lazzaro Spallanzani’ IRCCS, Rome, Italy; 7 Unit of Microbiology, Sandro Pertini Hospital, Rome, Italy

Correspondence: Silvia Meschisilvia.meschiinmi.it

Citation style for this article: Carletti Fabrizio, Colavita Francesca, Rovida Francesca, Percivalle Elena, Baldanti Fausto, Ricci Ida, De Liberato Claudio, Rosone Francesca, Messina Francesco, Lalle Eleonora, Bordi Licia, Vairo Francesco, Capobianchi Maria Rosaria, Ippolito Giuseppe, Cappiello Giuseppina, Spanò Alberto, Meschi Silvia, Castilletti Concetta. Expanding Usutu virus circulation in Italy: detection in the Lazio region, central Italy, 2017 to 2018. Euro Surveill. 2019;24(3):pii=1800649. https://doi.org/10.2807/1560-7917.ES.2019.24.3.1800649

Received: 03 Dec 2018;   Accepted: 16 Jan 2019

 

Abstract

Blood donation screening for West Nile virus (WNV) was mandatory in the Lazio region in 2017 and 2018 (June-November) according to the national surveillance plan. In these years, all five donations reactive in WNV nucleic acid amplification tests harboured instead Usutu virus (USUV). Clade ‘Europe 2’ was identified in four blood donations and a 2018 mosquito pool. The cocirculation of WNV and USUV in Lazio warrants increased laboratory support and awareness of possible virus misidentification.

©  This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords: Arbovirus; Usutu Virus; WNV; Italy.

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