#Sequential #Infection of #Aedes aegypti #Mosquitoes with #Chikungunya Virus and #Zika Virus Enhances Early Zika Virus Transmission (Insects, abstract)

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

Insects. 2018 Dec 1;9(4). pii: E177. doi: 10.3390/insects9040177.

Sequential Infection of Aedes aegypti Mosquitoes with Chikungunya Virus and Zika Virus Enhances Early Zika Virus Transmission.

Magalhaes T1, Robison A2, Young MC3, Black WC 4th4, Foy BD5, Ebel GD6, Rückert C7.

Author information: 1 Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. Tereza.Magalhaes@colostate.edu. 2 Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. lexir5394@gmail.com. 3 Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. emceeyoung@gmail.com. 4 Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. William.Black@colostate.edu. 5 Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. Brian.Foy@colostate.edu. 6 Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. Gregory.Ebel@colostate.edu. 7 Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA. Claudia.Rueckert@Colostate.edu.

 

Abstract

In urban settings, chikungunya, Zika, and dengue viruses are transmitted by Aedes aegypti mosquitoes. Since these viruses co-circulate in several regions, coinfection in humans and vectors may occur, and human coinfections have been frequently reported. Yet, little is known about the molecular aspects of virus interactions within hosts and how they contribute to arbovirus transmission dynamics. We have previously shown that Aedes aegypti exposed to chikungunya and Zika viruses in the same blood meal can become coinfected and transmit both viruses simultaneously. However, mosquitoes may also become coinfected by multiple, sequential feeds on single infected hosts. Therefore, we tested whether sequential infection with chikungunya and Zika viruses impacts mosquito vector competence. We exposed Ae. aegypti mosquitoes first to one virus and 7 days later to the other virus and compared infection, dissemination, and transmission rates between sequentially and single infected groups. We found that coinfection rates were high after sequential exposure and that mosquitoes were able to co-transmit both viruses. Surprisingly, chikungunya virus coinfection enhanced Zika virus transmission 7 days after the second blood meal. Our data demonstrate heterologous arbovirus synergism within mosquitoes, by unknown mechanisms, leading to enhancement of transmission under certain conditions.

KEYWORDS: Zika; arboviruses; chikungunya; coinfection; mosquitoes; sequential infection

PMID: 30513725 DOI: 10.3390/insects9040177

Keywords: Arbovirus; Chikungunya fever; Zika Virus; Dengue fever; Mosquitoes; Aedes spp.; Aedes aegypti.

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Epidemiological #Evidence for #Lineage-specific Differences in the #Risk of Inapparent #Chikungunya Virus #Infection (J Virol., abstract)

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

Epidemiological Evidence for Lineage-specific Differences in the Risk of Inapparent Chikungunya Virus Infection

Fausto Bustos Carrillo, Damaris Collado, Nery Sanchez, Sergio Ojeda, Brenda Lopez Mercado, Raquel Burger-Calderon, Lionel Gresh, Aubree Gordon, Angel Balmaseda, Guillermina Kuan,Eva Harris

DOI: 10.1128/JVI.01622-18

 

ABSTRACT

In late 2013, chikungunya virus (CHIKV) was introduced into the Americas, leading to widespread epidemics. A large epidemic caused by the Asian chikungunya virus (CHIKV) lineage occurred in Managua, Nicaragua, in 2015. Literature reviews commonly state that the proportion of inapparent CHIKV infections ranges from 3 to 28%. This study estimates the symptomatic-to-asymptomatic ratio of CHIKV infections and identifies risk factors of infection. In October-November 2015, 60 symptomatic CHIKV-infected children were enrolled as index cases and prospectively followed, alongside 236 household contacts, in an index cluster study. Samples were collected upon enrollment and on days 14 or 35 and tested by rRT-PCR, IgM-ELISA, and Inhibition ELISA to detect pre- and post-enrollment CHIKV infections. Of 236 household contacts, 55 (23%) had experienced previous or very recent infections, 41 (17%) had active infections at enrollment, and 21 (9%) experienced incident infections. Vehicle ownership (multivariate-adjusted risk ratio (aRR): 1.58) increased the risk of CHIKV infection whereas ≥4 municipal trash collections/week (aRR: 0.38) and having an external water faucet (aRR: 0.52) protected against CHIKV infection. Among 63 active and incident infections, 31 (49%, 95% CI: 36%, 62%) were asymptomatic, yielding a symptomatic-to-asymptomatic ratio of 1:0.97 (95% CI: 1:0.56, 1:1.60). Although our estimate is outside the 3-28% range reported previously, Bayesian and simulation analyses, informed by a systematic literature search, suggested that the proportion of inapparent CHIKV infections is lineage-dependent and that more inapparent infections are associated with the Asian lineage than the ECSA lineage. Overall, these data substantially improve knowledge regarding chikungunya epidemics.

 

Importance

Chikungunya virus (CHIKV) is an understudied threat to human health. During the 2015 chikungunya epidemic in Managua, Nicaragua, we estimated the ratio of symptomatic-to-asymptomatic CHIKV infections, which is important for understanding transmission dynamics and public health impact. This index cluster study identified persons at risk of infection and followed them, enabling capture of asymptomatic infections. We estimated that 31 (49%) of 63 at-risk participants had asymptomatic CHIKV infections, which is significantly outside the 3-28% range reported in literature reviews. However, recent seroprevalence studies, including two large pediatric cohort studies in the same setting, had also found percentages of inapparent infections outside the 3-28% range. Bayesian and simulation analyses, informed by a systematic literature search, revealed that the percentage of inapparent infections in epidemic settings varies by the phylogenetic lineage of CHIKV. Our study quantifies and provides the first epidemiological evidence that chikungunya epidemic characteristics are strongly influenced by CHIKV lineage.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Chikungunya Fever; Seroprevalence; Nicaragua.

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Beyond members of the #Flaviviridae family, #sofosbuvir also inhibits #chikungunya virus #replication (Antimicrob Agents Chemother., abstract)

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

Beyond members of the Flaviviridae family, sofosbuvir also inhibits chikungunya virus replication

André C. Ferreira, Patrícia A. Reis, Caroline S. de Freitas, Carolina Q. Sacramento, Lucas Villas Bôas Hoelz, Mônica M. Bastos, Mayara Mattos, Natasha Rocha,Isaclaudia Gomes de Azevedo Quintanilha, Carolina da Silva Gouveia Pedrosa, Leticia Rocha Quintino Souza, Erick Correia Loiola, Pablo Trindade, Yasmine Rangel Vieira,Giselle Barbosa-Lima, Hugo C. de Castro Faria Neto, Nubia Boechat, Stevens K. Rehen, Karin Brüning, Fernando A. Bozza, Patrícia T. Bozza, Thiago Moreno L. Souza

DOI: 10.1128/AAC.01389-18

 

ABSTRACT

Chikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector, Aedes mosquitos, has failed. As there is no vaccine or specific treatment for CHIKV, patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. CHIKV RNA polymerase is similar to the orthologue enzyme of other positive-sense RNA viruses, such as members of the Flaviviridae family. Among the Flaviviridae, not only is hepatitis C virus RNA polymerase susceptible to sofosbuvir, a clinically approved nucleotide analogue, but so is dengue, Zika, and yellow fever virus replication. Here, we found that sofosbuvir was three times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell–derived astrocytes was less susceptible to sofosbuvir compared to the hepatoma cells, sofosbuvir nevertheless impaired virus production and cell death in a multiplicity of infection–dependent manner. Sofosbuvir also exhibited antiviral activity in vivo by preventing CHIKV-induced paw edema in adult mice at a dose of 20 mg/kg/day, and prevented mortality in a neonate mouse model at 40 and 80 mg/kg/day doses. Our data demonstrate that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. As sofosbuvir is a clinically approved drug, our findings could pave the way to it becoming a therapeutic option against CF.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Arbovirus; Alphavirus; Flavivirus; Antivirals; Sofosbuvir.

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Conserved motifs in the hypervariable domain of #chikungunya virus nsP3 required for #transmission by #Aedes aegypti #mosquitoes (PLoS Negl Trop Dis., abstract)

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

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Conserved motifs in the hypervariable domain of chikungunya virus nsP3 required for transmission by Aedes aegypti mosquitoes

Giel P. Göertz, Marit Lingemann, Corinne Geertsema, Marleen H. C. Abma-Henkens, Chantal B. F. Vogels, Constantianus J. M. Koenraadt, Monique M. van Oers, Gorben P. Pijlman

Published: November 9, 2018 / DOI: https://doi.org/10.1371/journal.pntd.0006958 / This is an uncorrected proof.

 

Abstract

Background

Chikungunya virus (CHIKV) is a re-emerging arthropod-borne (arbo)virus that causes chikungunya fever in humans and is predominantly transmitted by Aedes aegypti mosquitoes. The CHIKV replication machinery consists of four non-structural proteins (nsP1-4) that additionally require the presence of a number of host proteins for replication of the viral RNA. NsP3 is essential for CHIKV replication and has a conserved macro, central and C-terminal hypervariable domain (HVD). The HVD is intrinsically disordered and interacts with various host proteins via conserved short peptide motifs: A proline-rich (P-rich) motif that has affinity for SH3-domain containing proteins and duplicate FGDF motifs with affinity for G3BP and its mosquito homologue Rasputin. The importance of these motifs for infection of mammalian cells has previously been implicated. However, their role during CHIKV infection of mosquito cells and transmission by mosquitoes remains unclear.

Methodology / Principal findings

Here, we show that in-frame deletion of the P-rich motif is lethal for CHIKV replication in both mosquito and mammalian cells. However, while mutagenesis of the P-rich motif negatively affects replication both in mammalian and mosquito cells, it did not compromise the infection and transmission of CHIKV by Ae. aegypti mosquitoes. Mutagenesis of both FGDF motifs together completely inactivated CHIKV replication in both mammalian and mosquito cells. Importantly, mutation of a single FGDF motif attenuated CHIKV replication in mammalian cells, while replication in mosquito cells was similar to wild type. Surprisingly, CHIKV mutants containing only a single FGDF motif were efficiently transmitted by Ae. aegypti.

Conclusions / Significance

The P-rich motif in CHIKV nsP3 is dispensable for transmission by mosquitoes. A single FGDF motif is sufficient for infection and dissemination in mosquitoes, but duplicate FGDF motifs are required for the efficient infection from the mosquito saliva to a vertebrate host. These results contribute to understanding the dynamics of the alphavirus transmission cycle and may help the development of arboviral intervention strategies.

 

Author summary

Chikungunya virus (CHIKV) is a re-emerging arthropod-borne virus that is transmitted predominantly by Aedes aegypti mosquitoes. In 2016 alone CHIKV caused over 100.000 infections in South-America, exemplifying the impact of CHIKV disease. Previous research has suggested that the CHIKV non-structural protein 3 (nsP3) may determine the infection of mosquitoes. NsP3 is known to interact with several host proteins through a conserved proline (P)-rich and duplicate FGDF motifs that are present in its C-terminal domain. Here we investigated the importance of these conserved motifs for the infection and replication of CHIKV in both Aedes mosquito cells and mammalian cells. Furthermore, we assessed the role of these motifs for the transmission by Ae. aegypti mosquitoes via infectious bloodmeal experiments. We show that mutation of the P-rich motif negatively affects the replication of CHIKV in both mammalian and mosquito cells. In contrast, mutating the P-rich motif did not affect the transmission by Ae. aegypti. Mutation of both FGDF motifs together completely inactivated CHIKV in mammalian and mosquito cells, while mutation of a single FGDF motif negatively affected replication only in mammalian cells. Importantly, CHIKV containing only a single FGDF motif was still efficiently transmitted by Ae. aegypti mosquitoes. These results contribute to understanding the key interactions between alphaviruses and their mosquito vector.

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Citation: Göertz GP, Lingemann M, Geertsema C, Abma-Henkens MHC, Vogels CBF, Koenraadt CJM, et al. (2018) Conserved motifs in the hypervariable domain of chikungunya virus nsP3 required for transmission by Aedes aegypti mosquitoes. PLoS Negl Trop Dis 12(11): e0006958. https://doi.org/10.1371/journal.pntd.0006958

Editor: Lyric C. Bartholomay, University of Wisconsin Madison, UNITED STATES

Received: August 3, 2018; Accepted: October 29, 2018; Published: November 9, 2018

Copyright: © 2018 Göertz 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 authors received no specific funding for this work.

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

Keywords: Chikungunya Fever; Mosquitoes; Aedes aegypti.

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#Immunogenicity, #safety, and tolerability of the #measles-vectored #chikungunya virus #vaccine MV-CHIK: a double-blind, randomised, placebo-controlled and active-controlled phase 2 trial (Lancet, abstract)

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

Immunogenicity, safety, and tolerability of the measles-vectored chikungunya virus vaccine MV-CHIK: a double-blind, randomised, placebo-controlled and active-controlled phase 2 trial

Prof Emil C Reisinger, MD,  Roland Tschismarov, PhD, Prof Eckhard Beubler, PhD, Prof Ursula Wiedermann, MD, Christa Firbas, MD, Micha Loebermann, MD, Andrea Pfeiffer, MSc, Matthias Muellner, PhD, Erich Tauber, MD, Katrin Ramsauer, PhD

Published: November 05, 2018 / DOIhttps://doi.org/10.1016/S0140-6736(18)32488-7

 

Summary

Background

Chikungunya fever is an emerging viral disease and substantial threat to public health. We aimed to assess the safety, tolerability, and immunogenicity of a live-attenuated, measles-vectored chikungunya vaccine (MV-CHIK).

Methods

In this double-blind, randomised, placebo-controlled and active-controlled phase 2 trial, we enrolled healthy volunteers aged 18–55 years at four study sites in Austria and Germany. Participants were randomly assigned to receive intramuscular injections with MV-CHIK (5 × 10 4 or 5 × 10 5 50% tissue culture infectious dose), control vaccine, or measles prime and MV-CHIK, in two different administration regimens. Randomisation was done by use of three-digit randomisation codes in envelopes provided by a data management service. The participants and investigators were masked to treatment assignment, which was maintained by use of sterile saline as a placebo injection. The primary endpoint was immunogenicity, defined as the presence of neutralising antibodies against chikungunya virus, at day 56, which is 28 days after one or two immunisations. The primary endpoint was assessed in all participants who completed the study without major protocol deviations (per-protocol population) and in all randomised participants who received at least one study treatment (modified intention-to-treat population). The safety analysis included all participants who received at least one study treatment. This trial is registered with ClinicalTrials.gov ( NCT02861586) and EudraCT (2015-004037-26) and is completed.

Findings

Between Aug 17, 2016, and May 31, 2017, we randomly assigned 263 participants to receive control vaccine (n=34), MV-CHIK (n=195), or measles prime and MV-CHIK (n=34). 247 participants were included in the per-protocol population. Neutralising antibodies against chikungunya virus were detected in all MV-CHIK treatment groups after one or two immunisations, with geometric mean titres ranging from 12·87 (95% CI 8·75–18·93) to 174·80 (119·10–256·50) and seroconversion rates ranging from 50·0% to 95·9% depending on the dose and administration schedule. Adverse events were similar between groups, with solicited adverse events reported in 168 (73%) of 229 participants assigned to MV-CHIK and 24 (71%) of 34 assigned to control vaccine (p=0·84) and unsolicited adverse events in 116 (51%) participants assigned to MV-CHIK and 17 (50%) assigned to control vaccine (p=1·00). No serious adverse events related to the vaccine were reported.

Interpretation

MV-CHIK showed excellent safety and tolerability and good immunogenicity, independent of pre-existing immunity against the vector. MV-CHIK is a promising candidate vaccine for the prevention of chikungunya fever, an emerging disease of global concern.

Funding

Themis.

Keywords: Chikungunya Fever; Vaccines.

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Potential role of #dengue virus, #chikungunya virus and #Zika virus in #neurological diseases (Mem Inst Oswaldo Cruz, abstract)

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

Mem Inst Oswaldo Cruz. 2018 Oct 29;113(11):e170538. doi: 10.1590/0074-02760170538.

Potential role of dengue virus, chikungunya virus and Zika virus in neurological diseases.

Vieira MADCES1,2,3, Costa CHN4, Linhares ADC5, Borba AS2, Henriques DF6, Silva EVPD6, Tavares FN5, Batista FMA7, Guimarães HCL7, Martins LC6, Monteiro TAF3,5, Cruz ACR6, Azevedo RDSDS6, Vasconcelos PFDC6.

Author information: 1 Secretaria de Estado da Saúde do Piauí, Instituto de Doenças Tropicais Natan Portella, Departamento de Neurologia, Teresina, PI, Brasil. 2 Fundação Municipal de Saúde de Teresina, Diretoria de Vigilância em Saúde, Teresina, PI, Brasil. 3 Instituto Evandro Chagas, Programa de Pós-Graduação em Virologia, Ananindeua, PA, Brasil. 4 Secretaria de Estado da Saúde do Piauí, Instituto de Doenças Tropicais Natan Portella, Departamento de Infectologia, Teresina, PI, Brasil. 5 Instituto Evandro Chagas, Seção de Virologia Geral, Ananindeua, PA, Brasil. 6 Instituto Evandro Chagas, Seção de Arbovirologia e Febres Hemorrágicas, Ananindeua, PA, Brasil. 7 Secretaria de Estado da Saúde do Piauí, Diretoria da Unidade de Vigilância e Assistência à Saúde, Teresina, PI, Brasil.

 

Abstract

This study showed that laboratory markers of recent infection by dengue, Zika or chikungunya arboviruses were detected in the biological samples of approximately one-third of patients with encephalitis, myelitis, encephalomyelitis or Guillain-Barré syndrome, in a surveillance programme in Piauí state, Brazil, between 2015-2016. Fever and myalgia had been associated with these cases. Since in non-tropical countries most infections or parainfectious diseases associated with the nervous system are attributed to herpesviruses, enteroviruses, and Campylobacter jejuni, the present findings indicate that in tropical countries, arboviruses may now play a more important role and reinforce the need for their surveillance and systematic investigation in the tropics.

PMID: 30379197 DOI: 10.1590/0074-02760170538

Keywords: Arbovirus; Chikungunya Fever; Dengue Fever; Zika Virus; Encephalitis; GBS; Encephalomyelitis.

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The effectiveness of #antiviral agents with broad-spectrum activity against #chikungunya virus varies between host cell lines (Antivir Chem Chemother., abstract)

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

Antivir Chem Chemother. 2018 Jan-Dec;26:2040206618807580. doi: 10.1177/2040206618807580.

The effectiveness of antiviral agents with broad-spectrum activity against chikungunya virus varies between host cell lines.

Franco EJ1,2, Rodriquez JL1, Pomeroy JJ1, Hanrahan KC1, Brown AN1.

Author information: 1 Department of Medicine, Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, FL, USA. 2 Department of Pharmaceutics, University of Florida College of Pharmacy, Orlando, FL, USA.

 

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne virus that has recently emerged in the Western Hemisphere. Approved antiviral therapies or vaccines for the treatment or prevention of CHIKV infections are not available. This study aims to evaluate the antiviral activity of commercially available broad-spectrum antivirals against CHIKV. Due to host cell-specific variability in uptake and intracellular processing of drug, we evaluated the antiviral effects of each agent in three cell lines. Antiviral activities of ribavirin (RBV), interferon-alfa (IFN-α) and favipiravir (FAV) were assessed in CHIKV-infected Vero, HUH-7, and A549 cells. CHIKV-infected cells were treated with increasing concentrations of each agent for three days and viral burden was quantified by plaque assay on Vero cells. Cytotoxic effects of RBV, FAV and IFN-α were also evaluated. Antiviral activity differed depending on the cell line used for evaluation. RBV had the greatest antiviral effect in HUH-7 cells (EC50 = 2.575 µg/mL); IFN-α was most effective in A549 cells (EC50 = 4.235 IU/mL); and FAV in HUH-7 cells (EC50 = 20.00 μg/mL). The results of our study show FAV and IFN-α are the most promising candidates, as their use led to substantial reductions in viral burden at clinically achievable concentrations in two human-derived cell lines. FAV is an especially attractive candidate for further investigation due to its oral bioavailability. These findings also highlight the importance of cell line selection for preclinical drug trials.

KEYWORDS: Chikungunya virus; antiviral agents; drug repurposing; favipiravir; interferon-alpha; ribavirin

PMID: 30354193 DOI: 10.1177/2040206618807580

Keywords: Chikungunya fever; Antivirals; Interferons; Favipiravir; Ribavirin.

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