Lethal #mutagenesis of #RVF virus induced by #favipiravir (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Lethal mutagenesis of Rift Valley fever virus induced by favipiravir

Belén Borrego, Ana I. de Ávila, Esteban Domingo, Alejandro Brun

DOI: 10.1128/AAC.00669-19

 

ABSTRACT

Rift Valley fever virus (RVFV) is an emerging, mosquito-borne, zoonotic pathogen with recurrent outbreaks paying a considerable toll of human deaths in many African countries, for which no effective treatment is available. In cell culture studies and with laboratory animal models, the nucleoside analogue favipiravir (T-705) has demonstrated great potential for the treatment of several seasonal, chronic and emerging RNA virus infections of humans, suggesting applicability to control some viral outbreaks. Treatment with favipiravir was shown to reduce the infectivity of Rift Valley fever virus both in cell cultures and in experimental animal models, but the mechanism of this protective effect is not understood. In this work we show that favipiravir at concentrations well below the toxicity threshold estimated for cells is able to extinguish RVFV from infected cell cultures. Nucleotide sequence analysis has documented RVFV mutagenesis associated with virus extinction, with a significant increase in G to A and C to U transition frequencies, and a decrease of specific infectivity, hallmarks of lethal mutagenesis.

Copyright © 2019 Borrego et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Antivirals; Favipiravir; Arbovirus; Rift Valley fever.

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The influence of raw #milk #exposures on #RVF virus #transmission (PLoS Negl Trop Dis., abstract)

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

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

The influence of raw milk exposures on Rift Valley fever virus transmission

Elysse N. Grossi-Soyster , Justin Lee, Charles H. King, A. Desiree LaBeaud

Published: March 20, 2019 / DOI: https://doi.org/10.1371/journal.pntd.0007258 / This is an uncorrected proof.

 

Abstract

Rift Valley fever virus (RVFV) is a zoonotic phlebovirus that can be transmitted to humans or livestock by mosquitoes or through direct contact with contaminated bodily fluids and tissues. Exposure to bodily fluids and tissues varies by types of behaviors engaged for occupational tasks, homestead responsibilities, or use in dietary or therapeutic capacities. While previous studies have included milk exposures in their analyses, their primary focus on livestock exposures has been on animal handling, breeding, and slaughter. We analyzed data from multiple field surveys in Kenya with the aim of associating RVFV infection to raw milk exposures from common animal species. Of those with evidence of prior RVFV infection by serology (n = 267), 77.2% engaged in milking livestock compared to 32.0% for 3,956 co-local seronegative individuals (p < 0.001), and 86.5% of seropositive individuals consumed raw milk compared to 33.4% seronegative individuals (p < 0.001). Individuals who milked and also consumed raw milk had greater odds of RVFV exposure than individuals whose only contact to raw milk was through milking. Increased risks were associated with exposure to milk sourced from cows (p < 0.001), sheep (p < 0.001), and goats (p < 0.001), but not camels (p = 0.98 for consuming, p = 0.21 for milking). Our data suggest that exposure to raw milk may contribute to a significant number of cases of RVFV, especially during outbreaks and in endemic areas, and that some animal species may be associated with a higher risk for RVFV exposure. Livestock trade is regulated to limit RVFV spread from endemic areas, yet further interventions designed to fully understand the risk of RVFV exposure from raw milk are imperative.

 

Author summary

Part of the transmission cycle for Rift Valley fever virus (RVFV) is related to direct human interaction with animals as part of everyday activities, including consumption of animal products for nutritional or therapeutic benefits. Although the vector-borne transmission of RVFV by mosquito populations is well understood, less is known about how human contact with animal tissues and fluids yields direct (non-vector-borne) RVFV transmission. This study describes the risks of RVFV transmission contributed by exposure to raw milk. It analyzed humans’ milk-related activities and their cumulative risk of RVFV infection, as determined by community-based behavioral and serological surveys in four villages in Kenya. Our data suggest that likelihood of exposure is increased both by actively milking live animals and by direct consumption of raw milk. The risk of RVFV exposure varied among the species of animals kept as livestock and utilized for milk production. Further investigations are necessary to fully characterize the dynamics of RVFV in milk. A better understanding of the role of milk in RVFV transmission will contribute to the public health management of RVFV outbreaks and interepidemic infections.

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Citation: Grossi-Soyster EN, Lee J, King CH, LaBeaud AD (2019) The influence of raw milk exposures on Rift Valley fever virus transmission. PLoS Negl Trop Dis 13(3): e0007258. https://doi.org/10.1371/journal.pntd.0007258

Editor: Abdallah M. Samy, Faculty of Science, Ain Shams University (ASU), EGYPT

Received: November 30, 2018; Accepted: February 23, 2019; Published: March 20, 2019

Copyright: © 2019 Grossi-Soyster 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: Data is available in a repository hosted by, and can be accessed by the following link: https://purl.stanford.edu/cd405gd1933

Funding: the author(s) received no specific funding for this work.

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

Keywords: Rift Valley Fever; Food Safety.

——

#RVF Virus and #YellowFever Virus in #Urine: A Potential #Source of #Infection (Virol Sin., summary)

[Source: Virologica Sinica, full page: (LINK). Summary, edited.]

Rift Valley Fever Virus and Yellow Fever Virus in Urine: A Potential Source of Infection

Authors: Meng Li, Beibei Wang, Liqiang Li, Gary Wong, Yingxia Liu, Jinmin Ma, Jiandong Li, Hongzhou Lu, Mifang Liang, Ang Li, Xiuqing Zhang, Yuhai Bi, Hui Zeng

Letter / First Online: 19 March 2019

___

Dear Editor,

In recent years, the incidence of human infections caused by emerging or re-emerging pathogens has rapidly increased. Diseases that were once regional now have the ability to spread globally in a short amount of time and pose a wider threat to public health (Weaver et al.2018). Yellow fever virus (YFV, family Flaviviridae, genus Flavivirus) is a mosquito-borne flavivirus that causes yellow fever in humans and has been endemic in Africa and Latin America for many years (Domingo et al. 2018). The most recent large-scale outbreak of YFV occurred in Brazil in which the mortality rate as of February 28, 2018 is 32.78% (WHO 2018). Rift Valley fever virus (RVFV, family Bunyaviridae, genus Phlebovirus) is another mosquito-borne virus and primarily circulates in Africa and the Middle East, and in recent years in Europe (Mansfield et al. 2015). During the initial stage of infection, most patients infected with YFV or RVFV present nonspecific symptoms such as fever, headache, and…

(…)

____

Meng Li, Beibei Wang and Liqiang Li have contributed equally to this work.

Electronic supplementary material

The online version of this article ( https://doi.org/10.1007/s12250-019-00096-2) contains supplementary material, which is available to authorized users.

 

Notes

Acknowledgements

This work is supported by grants from the National Science and Technology Major Project of China (2016ZX10004222 and 2016YFC1200800), Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29010102), Sanming Project of Medicine in Shenzhen (SZSM201412003), Shenzhen Municipal Government of China (JCYJ20160427151920801) and Beijing Municipal Science & Technology Commission (Z161100000116049), and the National Natural Science Foundation of China (NSFC) International Cooperation and Exchange Program (816110193). Y.B. is supported by the NSFC Outstanding Young Scholars (31822055) and Youth Innovation Promotion Association of Chinese Academy of Sciences (CAS) (2017122).

 

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Animal and Human Rights Statement

Informed consent was obtained from all patients for the collection and use of all clinical specimens. This article does not contain any studies with animal subjects performed by any of the authors.

Keywords: Flavivirus; Phlebovirus; Yellow Fever; Rift Valley Fever.

——

#Insecticide #resistance genes affect #Culex quinquefasciatus #vector competence for #WNV (Proc Roy Soc B., abstract)

[Source: Proceedings of the Royal Society Biological Sciences, full page: (LINK). Abstract, edited.]

Insecticide resistance genes affect Culex quinquefasciatus vector competence for West Nile virus

Célestine M. Atyame, Haoues Alout, Laurence Mousson, Marie Vazeille, Mawlouth Diallo, Mylène Weill and Anna-Bella Failloux

Published: 16 January 2019 / DOI: https://doi.org/10.1098/rspb.2018.2273

 

Abstract

Insecticide resistance has been reported to impact the interactions between mosquitoes and the pathogens they transmit. However, the effect on vector competence for arboviruses still remained to be investigated. We examined the influence of two insecticide resistance mechanisms on vector competence of the mosquito Culex quinquefasciatus for two arboviruses, Rift Valley Fever virus (RVFV) and West Nile virus (WNV). Three Cx. quinquefasciatus lines sharing a common genetic background were used: two insecticide-resistant lines, one homozygous for amplification of the Ester2locus (SA2), the other homozygous for the acetylcholinesterase ace-1 G119S mutation (SR) and the insecticide-susceptible reference line Slab. Statistical analyses revealed no significant effect of insecticide-resistant mechanisms on vector competence for RVFV. However, both insecticide resistance mechanisms significantly influenced the outcome of WNV infections by increasing the dissemination of WNV in the mosquito body, therefore leading to an increase in transmission efficiency by resistant mosquitoes. These results showed that insecticide resistance mechanisms enhanced vector competence for WNV and may have a significant impact on transmission dynamics of arboviruses. Our findings highlight the importance of understanding the impacts of insecticide resistance on the vectorial capacity parameters to assess the overall consequence on transmission.

Keywords: Arbovirus; Rift Valley Fever virus; West Nile Virus; Mosquitoes; Insecticides; Culex quinquefasciatus.

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Systematic #literature #review of #RiftValley fever virus #seroprevalence in #livestock, #wildlife and #humans in #Africa from 1968 to 2016 (PLoS Negl Trop Dis., abstract)

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

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Systematic literature review of Rift Valley fever virus seroprevalence in livestock, wildlife and humans in Africa from 1968 to 2016

Madeleine H. A. Clark , George M. Warimwe, Antonello Di Nardo, Nicholas A. Lyons, Simon Gubbins

Published: July 23, 2018 / DOI: https://doi.org/10.1371/journal.pntd.0006627 / This is an uncorrected proof.

 

Abstract

Background

Rift Valley fever virus (RVFV) is a zoonotic arbovirus that causes severe disease in livestock and humans. The virus has caused recurrent outbreaks in Africa and the Arabian Peninsula since its discovery in 1931. This review sought to evaluate RVFV seroprevalence across the African continent in livestock, wildlife and humans in order to understand the spatio-temporal distribution of RVFV seroprevalence and to identify knowledge gaps and areas requiring further research. Risk factors associated with seropositivity were identified and study designs evaluated to understand the validity of their results.

Methodology

The Preferred Reporting of Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to produce a protocol to systematically search for RVFV seroprevalence studies in PubMed and Web of Science databases. The Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement guided the evaluation of study design and analyses.

Principal findings

A total of 174 RVFV seroprevalence studies in 126 articles fulfilled the inclusion criteria. RVFV seroprevalence was recorded in 31 African countries from 1968 to 2016 and varied by time, species and country. RVFV seroprevalence articles including either livestock and humans or livestock and wildlife seroprevalence records were limited in number (8/126). No articles considered wildlife, livestock and human seroprevalence concurrently, nor wildlife and humans alone. Many studies did not account for study design bias or the sensitivity and specificity of diagnostic tests.

Conclusions

Future research should focus on conducting seroprevalence studies at the wildlife, livestock and human interface to better understand the nature of cross-species transmission of RVFV. Reporting should be more transparent and biases accounted for in future seroprevalence research to understand the true burden of disease on the African continent.

 

Author summary

Rift Valley fever virus (RVFV) is a vector-borne virus that infects wildlife and livestock, and can subsequently spread to humans. Due to the nature of the disease it has the potential to cause substantial economic and public health impacts. Rift Valley Fever (RVF) has been identified in Africa and the Arabian Peninsula, but has the potential to spread more widely. This systematic review assessed the distribution of RVF in livestock and humans in Africa by collating all the relevant studies we could find, extracting the data and critically evaluating them. Understanding when and where RVF has occurred in Africa and why some animals and humans get disease helps target control strategies and, in particular, those that reduce spread from livestock to humans. Furthermore, by evaluating past studies we can ensure that future ones are more robust and reproducible, so they can help us better understand the disease.

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Citation: Clark MHA, Warimwe GM, Di Nardo A, Lyons NA, Gubbins S (2018) Systematic literature review of Rift Valley fever virus seroprevalence in livestock, wildlife and humans in Africa from 1968 to 2016. PLoS Negl Trop Dis 12(7): e0006627. https://doi.org/10.1371/journal.pntd.0006627

Editor: Christopher M. Barker, University of California, Davis, UNITED STATES

Received: October 9, 2017; Accepted: June 22, 2018; Published: July 23, 2018

Copyright: © 2018 Clark 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: MHAC is supported by a Pirbright Institute studentship with funding from Biotechnology and Biological Sciences Research Council (BBSRC; bbsrc.ac.uk) and the Department of Health (https://www.gov.uk/government/organisations/department-of-health; GHR Project:16/107/03 – Advanced development of a safe and effective Rift Valley Fever vaccine for livestock). This project is independent research funded by the Department of Health and funded from an ODA budget. The views expressed in this publication are those of the author(s) and not necessarily those of the Department of Health. NAL is supported by the Biotechnology and Biological Sciences Research Council (grant code: BBS/E/I/00007036). GMW is supported by an Oak Foundation fellowship (http://oakfnd.org/). SG is supported by the Biotechnology and Biological Sciences Research Council (grant codes: BBS/E/I/00007033 and BBS/E/I/00007036). ADN is supported by the United Kingdom Department for Environment Food and Rural Affairs (Defra; http://www.defra.gov.uk) grant code: SE2943. 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: RVF; Human; Livestock; Wildlife; Seroprevalence; Africa Region.

——

Novel #activities of safe-in-human broad-spectrum #antiviral agents (Antiviral Res., abstract)

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

Antiviral Res. 2018 Apr 23. pii: S0166-3542(18)30098-6. doi: 10.1016/j.antiviral.2018.04.016. [Epub ahead of print]

Novel activities of safe-in-human broad-spectrum antiviral agents.

Ianevski A1, Zusinaite E2, Kuivanen S3, Strand M4, Lysvand H5, Teppor M6, Kakkola L7, Paavilainen H8, Laajala M9, Kallio-Kokko H10, Valkonen M11, Kantele A12, Telling K13, Lutsar I14, Letjuka P15, Metelitsa N16, Oksenych V17, Bjørås M18, Nordbø SA19, Dumpis U20, Vitkauskiene A21, Öhrmalm C22, Bondeson K23, Bergqvist A24, Aittokallio T25, Cox RJ26, Evander M27, Hukkanen V28, Marjomaki V29, Julkunen I30, Vapalahti O31, Tenson T32, Merits A33, Kainov D34.

Author information: 1 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7028, Norway. Electronic address: aleksandr.ianevski@helsinki.fi. 2 Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: eva.zusinaite@gmail.com. 3 Department of Virology, University of Helsinki, Helsinki 00014, Finland. Electronic address: suvi.kuivanen@helsinki.fi. 4 Department of Clinical Microbiology, Umeå University, Umeå 90185, Sweden. Electronic address: marten.strand@umu.se. 5 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway. Electronic address: hilde.lysvand@ntnu.no. 6 Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: mona.teppor@gmail.com. 7 Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: laura.kakkola@utu.fi. 8 Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: hojpaa@utu.fi. 9 Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä 40500, Finland. Electronic address: mira.a.laajala@jyu.fi. 10 Department of Virology and Immunology, University of Helsinki, Helsinki University Hospital, Helsinki 00014, Finland. Electronic address: hannimari.kallio-kokko@hus.fi. 11 Helsinki University Hospital, Helsinki 00014, Finland. Electronic address: miia.valkonen@hus.fi. 12 Helsinki University Hospital, Helsinki 00014, Finland. Electronic address: anu.kantele@helsinki.fi. 13 Institute of Medical Microbiology, University of Tartu, Tartu 50411, Estonia. Electronic address: kaidi.telling@ut.ee. 14 Institute of Medical Microbiology, University of Tartu, Tartu 50411, Estonia. Electronic address: irja.lutsar@ut.ee. 15 Narva Haigla, Narva 20104, Estonia. Electronic address: ellipellip@mail.ru. 16 Narva Haigla, Narva 20104, Estonia. Electronic address: nmetelitsa@gmail.com. 17 St. Olavs Hospital, Trondheim University Hospital, Clinic of Medicine, Trondheim 7006, Norway. Electronic address: valentyn.oksenych@ntnu.no. 18 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway. Electronic address: magnar.bjoras@ntnu.no. 19 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7491, Norway; Department of Medical Microbiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim 7006, Norway. Electronic address: svein.a.nordbo@ntnu.no. 20 Pauls Stradins Clinical University Hospital, Riga 1002, Latvia. Electronic address: uga.dumpis@gmail.com. 21 Department of Laboratory Medicine, Lithuanian University of Health Science, Kaunas 44307, Lithuania. Electronic address: astra.vitkauskiene@kaunoklinikos.lt. 22 Department of Medical Sciences, Uppsala University, Uppsala 75309, Sweden. Electronic address: christina.ohrmalm@akademiska.se. 23 Department of Medical Sciences, Uppsala University, Uppsala 75309, Sweden. Electronic address: kare.bondeson@akademiska.se. 24 Department of Medical Sciences, Uppsala University, Uppsala 75309, Sweden. Electronic address: anders.bergqvist@akademiska.se.  25 Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki 00290, Finland; Department of Mathematics and Statistics, University of Turku, Turku 20014, Finland. Electronic address: tero.aittokallio@fimm.fi. 26 Influenza Centre, Department of Clinical Science, University of Bergen, Bergen 5021, Norway. Electronic address: rebecca.cox@uib.no. 27 Department of Clinical Microbiology, Umeå University, Umeå 90185, Sweden. Electronic address: magnus.evander@umu.se. 28 Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: veijo.hukkanen@utu.fi. 29 Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä 40500, Finland. Electronic address: varpu.s.marjomaki@jyu.fi. 30 Institute of Biomedicine, University of Turku, Turku 20520, Finland. Electronic address: ilkka.julkunen@utu.fi. 31 Department of Virology, University of Helsinki and Helsinki University Hospital, Helsinki 00014, Finland; Department of Veterinary Biosciences, University of Helsinki, Helsinki 00014, Finland. Electronic address: olli.vapalahti@helsinki.fi. 32 Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: tanel.tenson@ut.ee. 33 Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: andres.merits@ut.ee. 34 Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim 7028, Norway; Institute of Technology, University of Tartu, Tartu 50090, Estonia. Electronic address: denikaino@gmail.com.

 

Abstract

According to the WHO, there is an urgent need for better control of viral diseases. Re-positioning existing safe-in-human antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. We tested 55 of these compounds against eight different RNA and DNA viruses. We found novel activities for dalbavancin against echovirus 1, ezetimibe against human immunodeficiency virus 1 and Zika virus, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against Rift valley fever virus. Thus, the spectrum of antiviral activities of existing antiviral agents could be expanded towards other viral diseases.

PMID: 29698664 DOI: 10.1016/j.antiviral.2018.04.016

Keywords: Emerging Diseases; Zika Virus; RVF; HIV; Echovirus 1; Antivirals; Dalbavancin; Ezetimibe; Azacitidine; Cyclosporine; Minocycline; Oritavancin; Ritonavir.

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A #RVF virus Gn ectodomain-based #DNA #vaccine induces a partial protection not improved by APC targeting (npj Vaccines, abstract)

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

A Rift Valley fever virus Gn ectodomain-based DNA vaccine induces a partial protection not improved by APC targeting

Tiphany Chrun, Sandra Lacôte, Céline Urien, Luc Jouneau, Céline Barc, Edwige Bouguyon, Vanessa Contreras, Audrey Ferrier-Rembert, Christophe N. Peyrefitte, Nuria Busquets, Enric Vidal, Joan Pujols, Philippe Marianneau & Isabelle Schwartz-Cornil

npj Vaccines, volume 3, Article number: 14 (2018) / doi:10.1038/s41541-018-0052-x

Received: 04 October 2017 – Revised: 26 February 2018 – Accepted: 28 March 2018 – Published online: 20 April 2018

 

Abstract

Rift Valley fever virus, a phlebovirus endemic in Africa, causes serious diseases in ruminants and humans. Due to the high probability of new outbreaks and spread to other continents where competent vectors are present, vaccine development is an urgent priority as no licensed vaccines are available outside areas of endemicity. In this study, we evaluated in sheep the protective immunity induced by DNA vaccines encoding the extracellular portion of the Gn antigen which was either or not targeted to antigen-presenting cells. The DNA encoding untargeted antigen was the most potent at inducing IgG responses, although not neutralizing, and conferred a significant clinical and virological protection upon infectious challenge, superior to DNA vaccines encoding the targeted antigen. A statistical analysis of the challenge parameters supported that the anti-eGn IgG, rather than the T-cell response, was instrumental in protection. Altogether, this work shows that a DNA vaccine encoding the extracellular portion of the Gn antigen confers substantial—although incomplete—protective immunity in sheep, a natural host with high preclinical relevance, and provides some insights into key immune correlates useful for further vaccine improvements against the Rift Valley fever virus.

Keywords: RVF; Vaccines; Animal Models.

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Transmission of #RVF virus from #European-breed #lambs to #Culex pipiens #mosquitoes (PLoS Negl Trop Dis., abstract)

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

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Transmission of Rift Valley fever virus from European-breed lambs to Culex pipiens mosquitoes

Rianka P. M. Vloet, Chantal B. F. Vogels, Constantianus J. M. Koenraadt, Gorben P. Pijlman, Martin Eiden, Jose L. Gonzales, Lucien J. M. van Keulen, Paul J. Wichgers Schreur, Jeroen Kortekaas

Published: December 27, 2017 / DOI: https://doi.org/10.1371/journal.pntd.0006145 / This is an uncorrected proof.

 

Abstract

Background

Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus of the genus Phlebovirus that is highly pathogenic to ruminants and humans. The disease is currently confined to Africa and the Arabian Peninsula, but globalization and climate change may facilitate introductions of the virus into currently unaffected areas via infected animals or mosquitoes. The consequences of such an introduction will depend on environmental factors, the availability of susceptible ruminants and the capacity of local mosquitoes to transmit the virus. We have previously demonstrated that lambs native to the Netherlands are highly susceptible to RVFV and we here report the vector competence of Culex (Cx.) pipiens, the most abundant and widespread mosquito species in the country. Vector competence was first determined after artificial blood feeding of laboratory-reared mosquitoes using the attenuated Clone 13 strain. Subsequently, experiments with wild-type RVFV and mosquitoes hatched from field-collected eggs were performed. Finally, the transmission of RVFV from viremic lambs to mosquitoes was studied.

Principal findings

Artificial feeding experiments using Clone 13 demonstrated that indigenous, laboratory-reared Cx. pipiens mosquitoes are susceptible to RVFV and that the virus can be transmitted via their saliva. Experiments with wild-type RVFV and mosquitoes hatched from field-collected eggs confirmed the vector competence of Cx. pipiens mosquitoes from the Netherlands. To subsequently investigate transmission of the virus under more natural conditions, mosquitoes were allowed to feed on RVFV-infected lambs during the viremic period. We found that RVFV is efficiently transmitted from lambs to mosquitoes, although transmission was restricted to peak viremia. Interestingly, in the mosquito-exposed skin samples, replication of RVFV was detected in previously unrecognized target cells.

Significance

We here report the vector competence of Cx. pipiens mosquitoes from the Netherlands for RVFV. Both laboratory-reared mosquitoes and well as those hatched from field-collected eggs were found to be competent vectors. Moreover, RVFV was transmitted efficiently from indigenous lambs to mosquitoes, although the duration of host infectivity was found to be shorter than previously assumed. Interestingly, analysis of mosquito-exposed skin samples revealed previously unidentified target cells of the virus. Our findings underscore the value of including natural target species in vector competence experiments.

 

Author summary

The consequences of first introductions of mosquito-borne viruses into previously unaffected areas depend on environmental factors, the availability of susceptible hosts and local vector populations. We have previously demonstrated that sheep breeds native to the Netherlands are highly susceptible to Rift Valley fever virus (RVFV), a mosquito-borne virus that causes severe outbreaks among domesticated ruminants and humans in Africa and the Arabian Peninsula. To gain further insight into the risk of a future RVFV introduction into the Netherlands, we have now investigated the vector competence of Cx. pipiens, the most abundant mosquito species in the country. Vector competence was first determined after artificial blood feeding and subsequently after feeding on viremic lambs. The results from artificial feeding experiments suggested that indigenous Cx. pipiens mosquitoes are competent vectors. The vector competence of Cx. pipiens was confirmed after feeding on viremic lambs. Transmission from lambs to mosquitoes was found to be very efficient, although largely confined to peak viremia. The localized inflammatory response resulting from mosquito bites was associated with enhanced virus replication in the skin.

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Citation: Vloet RPM, Vogels CBF, Koenraadt CJM, Pijlman GP, Eiden M, Gonzales JL, et al. (2017) Transmission of Rift Valley fever virus from European-breed lambs to Culex pipiens mosquitoes. PLoS Negl Trop Dis 11(12): e0006145. https://doi.org/10.1371/journal.pntd.0006145

Editor: Michael J. Turell, INDEPENDENT RESEARCHER, UNITED STATES

Received: April 10, 2017; Accepted: December 1, 2017; Published: December 27, 2017

Copyright: © 2017 Vloet 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: This study was supported by EU grant FP7-613996 Vmerge (http://www.vmergedata.com) and projects WOT- 01-003-074 and KB-21-006-020, financed by the Dutch Ministry of Economic Affairs. 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: Rift Valley Fever; Culex Pipiens; Mosquitoes; Livestock.

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#Wolbachia effects on #RVF virus #infection in #Culex tarsalis #mosquitoes (PLoS Negl Trop Dis., abstract)

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

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Wolbachia effects on Rift Valley fever virus infection in Culex tarsalis mosquitoes

Brittany L. Dodson , Elizabeth S. Andrews , Michael J. Turell, Jason L. Rasgon

Published: October 30, 2017 / DOI: https://doi.org/10.1371/journal.pntd.0006050 / This is an uncorrected proof.

 

Abstract

Innovative tools are needed to alleviate the burden of mosquito-borne diseases, and strategies that target the pathogen are being considered. A possible tactic is the use of Wolbachia, a maternally inherited, endosymbiotic bacterium that can (but does not always) suppress diverse pathogens when introduced to naive mosquito species. We investigated effects of somatic Wolbachia (strain wAlbB) infection on Rift Valley fever virus (RVFV) in Culex tarsalismosquitoes. When compared to Wolbachia-uninfected mosquitoes, there was no significant effect of Wolbachia infection on RVFV infection, dissemination, or transmission frequencies, nor on viral body or saliva titers. Within Wolbachia-infected mosquitoes, there was a modest negative correlation between RVFV body titers and Wolbachia density, suggesting that Wolbachia may slightly suppress RVFV in a density-dependent manner in this mosquito species. These results are contrary to previous work in the same mosquito species, showing Wolbachia-induced enhancement of West Nile virus infection rates. Taken together, these results highlight the importance of exploring the breadth of pathogen modulations induced by Wolbachia.

 

Author summary

An integrated vector management program utilizes several practices, including pesticide application and source reduction, to reduce mosquito populations. However, mosquitoes are developing resistance to some of these methods and new control approaches are needed. A novel technique involves the bacterium Wolbachia that lives naturally in many insects. Wolbachia can be transferred to uninfected mosquitoes and can block pathogen transmission to humans, although in some circumstances pathogen enhancement has been observed. Additionally, Wolbachia is maternally inherited, allowing it to spread quickly through uninfected field populations of mosquitoes. We studied the impacts of Wolbachia on Rift Valley fever virus (RVFV) in the naturally uninfected mosquito, Culex tarsalis. Wolbachia had no effect on the frequencies at which Culex tarsalis became infected with or transmitted RVFV. However, when we analyzed the relationship between Wolbachia densities and RVFV titers, we determined that high densities of Wolbachia were associated with no virus infection or low levels of virus, suggesting that Wolbachia might suppress RVFV at high densities. These results contrast with our previous study that showed Wolbachia enhances West Nile virus infection in Culex tarsalis. Together, these studies highlight the importance of studying Wolbachia effects on a variety of pathogens so that control methods that use Wolbachia are not impeded by unintended or off-target effects.

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Citation: Dodson BL, Andrews ES, Turell MJ, Rasgon JL (2017) Wolbachia effects on Rift Valley fever virus infection in Culex tarsalis mosquitoes. PLoS Negl Trop Dis11(10): e0006050. https://doi.org/10.1371/journal.pntd.0006050

Editor: Rhoel Ramos Dinglasan, University of Florida, UNITED STATES

Received: May 19, 2017; Accepted: October 18, 2017; Published: October 30, 2017

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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

Funding: This study was funded by NIH grants R01AI116636 and R21AI128918 to JLR. 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: Mosquitoes; Culex spp.; RVF.

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Structures of #phlebovirus #glycoprotein Gn and identification of a neutralizing #antibody epitope (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Structures of phlebovirus glycoprotein Gn and identification of a neutralizing antibody epitope

Yan Wu a,b,1, Yaohua Zhu c,d,1, Feng Gao e,1,2, Yongjun Jiao f,1, Babayemi O. Oladejo a, Yan Chai a, Yuhai Bi a,b,g, Shan Lu h, Mengqiu Dong h, Chang Zhang a, Guangmei Huang a, Gary Wong a, Na Lii, Yanfang Zhang a, Yan Li a, Wen-hai Feng c,d, Yi Shi a,b,g, Mifang Liang j, Rongguang Zhang i, Jianxun Qi a, and George F. Gao a,b,g,i,j,k,2

Author Affiliations: a Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; b Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People’s Hospital, Shenzhen 518112, China; c State Key Laboratory of Agrobiotechnology, Beijing 100193, China; d Department of Microbiology and Immunology, College of Biological Sciences, China Agricultural University, Beijing 100193, China; e Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; f Institute of Pathogenic Microbiology, Jiangsu Provincial Center for Disease Prevention and Control, Key Laboratory of Enteric Pathogenic Microbiology, Ministry Health, Nanjing 210009, China; g Center for Influenza Research and Early-Warning, Chinese Academy of Sciences, Beijing 100101, China; h National Institute of Biological Sciences, Beijing 102206, China; i National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201210, China; j National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China; k Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China

Edited by Stephen C. Harrison, Children’s Hospital Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, and approved July 25, 2017 (received for review March 30, 2017)

 

Significance

Bunyaviruses are emerging zoonotic pathogens of public-health concern. Lack of structures for proteins on the viral membrane (“envelope”) surface limits understanding of entry. We describe atomic-level structures for the globular “head” of the envelope protein, glycoprotein N (Gn), from two members, severe fever with thrombocytopenia syndrome virus (SFTSV) and Rift Valley fever virus (RVFV), of Phleboviruses genus in the bunyavirus family, and a structure of the SFTSV Gn bound with a neutralizing antibody Fab. The results show the folded Gn structure and define virus-specific neutralizing-antibody binding sites. Biochemical assays suggest that dimerization, mediated by conserved cysteines in the region (“stem”) connecting the Gn head with the transmembrane domain, is a general feature of bunyavirus envelope proteins and that the dimer is probably the olimeric form on the viral surface.

 

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) and Rift Valley fever virus (RVFV) are two arthropod-borne phleboviruses in the Bunyaviridae family, which cause severe illness in humans and animals. Glycoprotein N (Gn) is one of the envelope proteins on the virus surface and is a major antigenic component. Despite its importance for virus entry and fusion, the molecular features of the phleboviruse Gn were unknown. Here, we present the crystal structures of the Gn head domain from both SFTSV and RVFV, which display a similar compact triangular shape overall, while the three subdomains (domains I, II, and III) making up the Gn head display different arrangements. Ten cysteines in the Gn stem region are conserved among phleboviruses, four of which are responsible for Gn dimerization, as revealed in this study, and they are highly conserved for all members in Bunyaviridae. Therefore, we propose an anchoring mode on the viral surface. The complex structure of the SFTSV Gn head and human neutralizing antibody MAb 4–5 reveals that helices α6 in subdomain III is the key component for neutralization. Importantly, the structure indicates that domain III is an ideal region recognized by specific neutralizing antibodies, while domain II is probably recognized by broadly neutralizing antibodies. Collectively, Gn is a desirable vaccine target, and our data provide a molecular basis for the rational design of vaccines against the diseases caused by phleboviruses and a model for bunyavirus Gn embedding on the viral surface.

bunyavirus – SFTSV – glycoprotein – neutralizing antibody – RVFV

 

Footnotes

1 Y.W., Y. Zhu, F.G., and Y.J. contributed equally to this work.

2 To whom correspondence may be addressed. Email: gaofeng@genetics.ac.cn or gaof@im.ac.cn.

Keywords: Phlebovirus; Bunyavirus; SFTS; RVF.

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