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Song BH, Frank JC, Yun SI, Julander JG, Mason JB, Polejaeva IA, Davies CJ, White KL, Dai X, Lee YM. Comparison of Three Chimeric Zika Vaccine Prototypes Developed on the Genetic Background of the Clinically Proven Live-Attenuated Japanese Encephalitis Vaccine SA 14-14-2. Int J Mol Sci 2024; 26:195. [PMID: 39796052 PMCID: PMC11720029 DOI: 10.3390/ijms26010195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/17/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025] Open
Abstract
Zika virus (ZIKV) is a medically important mosquito-borne orthoflavivirus, but no vaccines are currently available to prevent ZIKV-associated disease. In this study, we compared three recombinant chimeric viruses developed as candidate vaccine prototypes (rJEV/ZIKVMR-766, rJEV/ZIKVP6-740, and rJEV/ZIKVPRVABC-59), in which the two neutralizing antibody-inducing prM and E genes from each of three genetically distinct ZIKV strains were used to replace the corresponding genes of the clinically proven live-attenuated Japanese encephalitis virus vaccine SA14-14-2 (rJEV). In WHO-certified Vero cells (a cell line suitable for vaccine production), rJEV/ZIKVP6-740 exhibited the slowest viral growth, formed the smallest plaques, and displayed a unique protein expression profile with the highest ratio of prM to cleaved M when compared to the other two chimeric viruses, rJEV/ZIKVMR-766 and rJEV/ZIKVPRVABC-59, as well as their vector, rJEV. In IFNAR-/- mice, an animal model of ZIKV infection, subcutaneous inoculation of rJEV/ZIKVP6-740 caused a low-level localized infection limited to the spleen, with no clinical signs of infection, weight loss, or mortality; in contrast, the other two chimeric viruses and their vector caused high-level systemic infections involving multiple organs, consistently leading to clear clinical signs of infection, rapid weight loss, and 100% mortality. Subsequently, subcutaneous immunization with rJEV/ZIKVP6-740 proved highly effective, offering complete protection against a lethal intramuscular ZIKV challenge 28 days after a single-dose immunization. This protection was specific to ZIKV prM/E and likely mediated by neutralizing antibodies targeting ZIKV prM/E. Therefore, our data indicate that the chimeric virus rJEV/ZIKVP6-740 is a highly promising vaccine prototype for developing a safe and effective vaccine for inducing neutralizing antibody-mediated protective immunity against ZIKV.
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Affiliation(s)
- Byung-Hak Song
- Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA; (B.-H.S.); (J.C.F.); (S.-I.Y.); (J.G.J.); (I.A.P.); (C.J.D.); (K.L.W.)
| | - Jordan C. Frank
- Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA; (B.-H.S.); (J.C.F.); (S.-I.Y.); (J.G.J.); (I.A.P.); (C.J.D.); (K.L.W.)
| | - Sang-Im Yun
- Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA; (B.-H.S.); (J.C.F.); (S.-I.Y.); (J.G.J.); (I.A.P.); (C.J.D.); (K.L.W.)
| | - Justin G. Julander
- Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA; (B.-H.S.); (J.C.F.); (S.-I.Y.); (J.G.J.); (I.A.P.); (C.J.D.); (K.L.W.)
- Institute for Antiviral Research, Utah State University, Logan, UT 84322, USA
| | - Jeffrey B. Mason
- Department of Veterinary Clinical and Life Sciences, College of Veterinary Medicine, Center for Integrated BioSystems, Utah State University, Logan, UT 84322, USA;
| | - Irina A. Polejaeva
- Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA; (B.-H.S.); (J.C.F.); (S.-I.Y.); (J.G.J.); (I.A.P.); (C.J.D.); (K.L.W.)
| | - Christopher J. Davies
- Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA; (B.-H.S.); (J.C.F.); (S.-I.Y.); (J.G.J.); (I.A.P.); (C.J.D.); (K.L.W.)
| | - Kenneth L. White
- Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA; (B.-H.S.); (J.C.F.); (S.-I.Y.); (J.G.J.); (I.A.P.); (C.J.D.); (K.L.W.)
| | - Xin Dai
- Utah Agricultural Experiment Station, Utah State University, Logan, UT 84322, USA;
| | - Young-Min Lee
- Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA; (B.-H.S.); (J.C.F.); (S.-I.Y.); (J.G.J.); (I.A.P.); (C.J.D.); (K.L.W.)
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Wahaab A, Mustafa BE, Hameed M, Batool H, Tran Nguyen Minh H, Tawaab A, Shoaib A, Wei J, Rasgon JL. An Overview of Zika Virus and Zika Virus Induced Neuropathies. Int J Mol Sci 2024; 26:47. [PMID: 39795906 PMCID: PMC11719530 DOI: 10.3390/ijms26010047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 12/19/2024] [Accepted: 12/21/2024] [Indexed: 01/13/2025] Open
Abstract
Flaviviruses pose a major public health concern across the globe. Among them, Zika virus (ZIKV) is an emerging and reemerging arthropod-borne flavivirus that has become a major international public health problem following multiple large outbreaks over the past two decades. The majority of infections caused by ZIKV exhibit mild symptoms. However, the virus has been found to be associated with a variety of congenital neural abnormalities, including microcephaly in children and Guillain-Barre syndrome in adults. The exact prediction of the potential of ZIKV transmission is still enigmatic and underlines the significance of routine detection of the virus in suspected areas. ZIKV transmission from mother to fetus (including fetal abnormalities), viral presence in immune-privileged areas, and sexual transmission demonstrate the challenges in understanding the factors governing viral persistence and pathogenesis. This review illustrates the transmission patterns, epidemiology, control strategies (through vaccines, antivirals, and vectors), oncolytic aspects, molecular insights into neuro-immunopathogenesis, and other neuropathies caused by ZIKV. Additionally, we summarize in vivo and in vitro models that could provide an important platform to study ZIKV pathogenesis and the underlying governing cellular and molecular mechanisms.
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Affiliation(s)
- Abdul Wahaab
- Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA; (A.W.); (H.T.N.M.)
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA
- The Center for Infectious Disease Dynamics, Pennsylvania State University, University Park, PA 16802, USA
- The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA
| | - Bahar E Mustafa
- School of Veterinary Science, Faculty of Science, The University of Melbourne, Melbourne, VIC 3030, Australia;
- Sub Campus Toba Tek Singh, University of Agriculture, Faisalabad 36050, Pakistan;
| | - Muddassar Hameed
- Department of Biomedical Sciences and Pathobiology, VA-MD Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA;
- Center for Zoonotic and Arthropod-Borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA
- Department of Otolaryngology-Head and Neck Surgery, Department of Pathology and Immunology, Alvin J. Siteman Cancer Center, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Hira Batool
- Chughtai Lab, Head Office, 7-Jail Road, Main Gulberg, Lahore 54000, Pakistan;
| | - Hieu Tran Nguyen Minh
- Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA; (A.W.); (H.T.N.M.)
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA
- The Center for Infectious Disease Dynamics, Pennsylvania State University, University Park, PA 16802, USA
- The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA
| | - Abdul Tawaab
- Sub Campus Toba Tek Singh, University of Agriculture, Faisalabad 36050, Pakistan;
| | - Anam Shoaib
- School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA;
| | - Jianchao Wei
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China;
| | - Jason L. Rasgon
- Department of Entomology, Pennsylvania State University, University Park, PA 16802, USA; (A.W.); (H.T.N.M.)
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA
- The Center for Infectious Disease Dynamics, Pennsylvania State University, University Park, PA 16802, USA
- The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA
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Jang M, Lee M, Sohn H, Park C, Lee T. Fabrication of Rapid Electrical Pulse-Based Biosensor Consisting of Truncated DNA Aptamer for Zika Virus Envelope Protein Detection in Clinical Samples. MATERIALS (BASEL, SWITZERLAND) 2023; 16:2355. [PMID: 36984234 PMCID: PMC10054023 DOI: 10.3390/ma16062355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/09/2023] [Accepted: 03/13/2023] [Indexed: 06/18/2023]
Abstract
Zika virus (ZV) infection causes fatal hemorrhagic fever. Most patients are unaware of their symptoms; therefore, a rapid diagnostic tool is required to detect ZV infection. To solve this problem, we developed a rapid electrical biosensor composed of a truncated DNA aptamer immobilized on an interdigitated gold micro-gap electrode and alternating current electrothermal flow (ACEF) technique. The truncated ZV aptamer (T-ZV apt) was prepared to reduce the manufacturing cost for biosensor fabrication, and it showed binding affinity similar to that of the original ZV aptamer. This pulse-voltammetry-based biosensor was composed of a T-ZV apt immobilized on an interdigitated micro-gap electrode. Atomic force microscopy was used to confirm the biosensor fabrication. In addition, the optimal biosensor performance conditions were investigated using pulse voltammetry. ACEF promoted aptamer-target binding, and the target virus envelope protein was detected in the diluted serum within 10 min. The biosensor waveform increased linearly as the concentration of the Zika envelope in the serum increased, and the detection limit was 90.1 pM. Our results suggest that the fabricated biosensor is a significant milestone for rapid virus detection.
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Affiliation(s)
- Moonbong Jang
- Department of Chemical Engineering, Kwangwoon University, Seoul 01897, Republic of Korea
| | - Myoungro Lee
- Department of Chemical Engineering, Kwangwoon University, Seoul 01897, Republic of Korea
| | - Hiesang Sohn
- Department of Chemical Engineering, Kwangwoon University, Seoul 01897, Republic of Korea
| | - Chulhwan Park
- Department of Chemical Engineering, Kwangwoon University, Seoul 01897, Republic of Korea
| | - Taek Lee
- Department of Chemical Engineering, Kwangwoon University, Seoul 01897, Republic of Korea
- TL Bioindustry, 20 Kwangwoon-Ro, Nowon-Gu, Seoul 01897, Republic of Korea
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Liu Z, Zhang Y, Cheng M, Ge N, Shu J, Xu Z, Su X, Kou Z, Tong Y, Qin C, Jin X. A single nonsynonymous mutation on ZIKV E protein-coding sequences leads to markedly increased neurovirulence in vivo. Virol Sin 2022; 37:115-126. [PMID: 35234632 PMCID: PMC8922429 DOI: 10.1016/j.virs.2022.01.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 10/20/2021] [Indexed: 01/23/2023] Open
Abstract
Zika virus (ZIKV) can infect a wide range of tissues including the developmental brain of human fetus. Whether specific viral genetic variants are linked to neuropathology is incompletely understood. To address this, we have intracranially serially passaged a clinical ZIKV isolate (SW01) in neonatal mice and discovered variants that exhibit markedly increased virulence and neurotropism. Deep sequencing analysis combining with molecular virology studies revealed that a single 67D (Aspartic acid) to N (Asparagine) substitution on E protein is sufficient to confer the increased virulence and neurotropism in vivo. Notably, virus clones with D67N mutation had higher viral production and caused more severe cytopathic effect (CPE) in human neural astrocytes U251 cells in vitro, indicating its potential neurological toxicity to human brain. These findings revealed that a single mutation D67N on ZIKV envelope may lead to severe neuro lesion that may help to explain the neurovirulence of ZIKV and suggest monitoring the occurrence of this mutation during nature infection may be important.
Construction of a ZIKV adaptation mouse mode. Specific viral genetic changes of ZIKV are associated with severe neuropathology. D67N mutation on E protein markedly increase the neurovirulence of ZIKA virus.
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Affiliation(s)
- Zhihua Liu
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Vaccine and Immunology Research Center, Translational Medical Research Institute, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Yawei Zhang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China
| | - Mengli Cheng
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China
| | - Ningning Ge
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Vaccine and Immunology Research Center, Translational Medical Research Institute, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Jiayi Shu
- Vaccine and Immunology Research Center, Translational Medical Research Institute, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China
| | - Zhiheng Xu
- State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xiao Su
- Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhihua Kou
- Vaccine and Immunology Research Center, Translational Medical Research Institute, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.
| | - Yigang Tong
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China.
| | - Chengfeng Qin
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, China.
| | - Xia Jin
- Vaccine and Immunology Research Center, Translational Medical Research Institute, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.
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van Leur SW, Heunis T, Munnur D, Sanyal S. Pathogenesis and virulence of flavivirus infections. Virulence 2021; 12:2814-2838. [PMID: 34696709 PMCID: PMC8632085 DOI: 10.1080/21505594.2021.1996059] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 10/06/2021] [Accepted: 10/15/2021] [Indexed: 11/01/2022] Open
Abstract
The Flavivirus genus consists of >70 members including several that are considered significant human pathogens. Flaviviruses display a broad spectrum of diseases that can be roughly categorised into two phenotypes - systemic disease involving haemorrhage exemplified by dengue and yellow Fever virus, and neurological complications associated with the likes of West Nile and Zika viruses. Attempts to develop vaccines have been variably successful against some. Besides, mosquito-borne flaviviruses can be vertically transmitted in the arthropods, enabling long term persistence and the possibility of re-emergence. Therefore, developing strategies to combat disease is imperative even if vaccines become available. The cellular interactions of flaviviruses with their human hosts are key to establishing the viral lifecycle on the one hand, and activation of host immunity on the other. The latter should ideally eradicate infection, but often leads to immunopathological and neurological consequences. In this review, we use Dengue and Zika viruses to discuss what we have learned about the cellular and molecular determinants of the viral lifecycle and the accompanying immunopathology, while highlighting current knowledge gaps which need to be addressed in future studies.
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Affiliation(s)
| | - Tiaan Heunis
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OxfordOX1 3RE, UK
| | - Deeksha Munnur
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OxfordOX1 3RE, UK
| | - Sumana Sanyal
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OxfordOX1 3RE, UK
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Lira SMDC, Levi JE, Bub CB, Aravecchia MG, Altman SN, Sakashita AM, Kutner JM. Zika virus RNA detection in blood donors in São Paulo, Brazil. Hematol Transfus Cell Ther 2021; 44:472-477. [PMID: 34148860 PMCID: PMC9605902 DOI: 10.1016/j.htct.2021.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 03/28/2021] [Indexed: 11/30/2022] Open
Abstract
Introduction: The Zika Virus (ZIKV) is a single-stranded RNA genome virus, belonging to the family Flaviviridae, genus Flavivirus. Outbreaks around the world have demonstrated that the presence of asymptomatic viremic blood donors provides an increase in the risk of transfusion transmission (TT) and nucleic acid test (NAT) screening has been proposed to ensure the blood safety. This study implemented an “in-house” method to detect ZIKV RNA in blood sample donations. Methods: Primary plasma tubes are submitted to nucleic acid extraction on an automated platform. After extraction, the NAT set-up is performed in the robotic pipettor, in which an amplification mixture containing primers and probes for ZIKV and Polio vaccine virus (PV) are added in duplex as an internal control. The real-time polymerase chain reaction is then performed in a thermocycler, using the protocol established by the supplier. Results: From May 2016 to May 2018, 3,369 samples were collected from 3,221 blood donors (confidence coefficient 95%), of which 31 were considered false positive (0.92%), as they did not confirm initial reactivity when repeated in duplicates and 14 (0.42%) had their results invalid due to repeat failure in the internal control, 4 (0.12%), due to insufficient sample volume and 2 (0.05%), due to automatic pipettor failures. No Zika RNA reactive sample was identified. Conclusion: The test showed feasible to be incorporated into the blood screening routine. Our data do not indicate the need to screen for ZIKV RNA in São Paulo during the evaluated period. However, a generic NAT system covering a group of flaviviruses which are circulating in the region, such as DENV and YFV, among others, could be a useful tool.
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Affiliation(s)
- Sanny Marcele da Costa Lira
- Instituto de Medicina Tropical, Universidade de São Paulo Instituto de Medicina Tropical de São Paulo (IMTSP USP), São Paulo, SP, Brazil.
| | - Jose Eduardo Levi
- Instituto de Medicina Tropical, Universidade de São Paulo Instituto de Medicina Tropical de São Paulo (IMTSP USP), São Paulo, SP, Brazil
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Andrade CBV, Monteiro VRDS, Coelho SVA, Gomes HR, Sousa RPC, Nascimento VMDO, Bloise FF, Matthews SG, Bloise E, Arruda LB, Ortiga-Carvalho TM. ZIKV Disrupts Placental Ultrastructure and Drug Transporter Expression in Mice. Front Immunol 2021; 12:680246. [PMID: 34093581 PMCID: PMC8176859 DOI: 10.3389/fimmu.2021.680246] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 04/30/2021] [Indexed: 12/14/2022] Open
Abstract
Congenital Zika virus (ZIKV) infection can induce fetal brain abnormalities. Here, we investigated whether maternal ZIKV infection affects placental physiology and metabolic transport potential and impacts the fetal outcome, regardless of viral presence in the fetus at term. Low (103 PFU-ZIKVPE243; low ZIKV) and high (5x107 PFU-ZIKVPE243; high ZIKV) virus titers were injected into immunocompetent (ICompetent C57BL/6) and immunocompromised (ICompromised A129) mice at gestational day (GD) 12.5 for tissue collection at GD18.5 (term). High ZIKV elicited fetal death rates of 66% and 100%, whereas low ZIKV induced fetal death rates of 0% and 60% in C57BL/6 and A129 dams, respectively. All surviving fetuses exhibited intrauterine growth restriction (IUGR) and decreased placental efficiency. High-ZIKV infection in C57BL/6 and A129 mice resulted in virus detection in maternal spleens and placenta, but only A129 fetuses presented virus RNA in the brain. Nevertheless, pregnancies in both strains produced fetuses with decreased head sizes (p<0.05). Low-ZIKV-A129 dams had higher IL-6 and CXCL1 levels (p<0.05), and their placentas showed increased CCL-2 and CXCL-1 contents (p<0.05). In contrast, low-ZIKV-C57BL/6 dams had an elevated CCL2 serum level and increased type I and II IFN expression in the placenta. Notably, less abundant microvilli and mitochondrial degeneration were evidenced in the placental labyrinth zone (Lz) of ICompromised and high-ZIKV-ICompetent mice but not in low-ZIKV-C57BL/6 mice. In addition, decreased placental expression of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) and the lipid transporter Abca1 was detected in all ZIKV-infected groups, but Bcrp and Abca1 were only reduced in ICompromised and high-ZIKV ICompetent mice. Our data indicate that gestational ZIKV infection triggers specific proinflammatory responses and affects placental turnover and transporter expression in a manner dependent on virus concentration and maternal immune status. Placental damage may impair proper fetal-maternal exchange function and fetal growth/survival, likely contributing to congenital Zika syndrome.
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Affiliation(s)
| | | | | | - Hanailly Ribeiro Gomes
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ronny Paiva Campos Sousa
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Flavia Fonseca Bloise
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Stephen Giles Matthews
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Obstetrics & Gynecology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Enrrico Bloise
- Department of Morphology, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Luciana Barros Arruda
- Institute of Microbiology Paulo de Góes, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
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Nie S, Yao Y, Wu F, Wu X, Zhao J, Hua Y, Wu J, Huo T, Lin YL, Kneubehl AR, Vogt MB, Ferreon J, Rico-Hesse R, Song Y. Synthesis, Structure-Activity Relationships, and Antiviral Activity of Allosteric Inhibitors of Flavivirus NS2B-NS3 Protease. J Med Chem 2021; 64:2777-2800. [PMID: 33596380 DOI: 10.1021/acs.jmedchem.0c02070] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Flaviviruses, including Zika, dengue, and West Nile viruses, are important human pathogens. The highly conserved NS2B-NS3 protease of Flavivirus is essential for viral replication and therefore a promising drug target. Through compound screening, followed by medicinal chemistry studies, a novel series of 2,5,6-trisubstituted pyrazine compounds are found to be potent, allosteric inhibitors of Zika virus protease (ZVpro) with IC50 values as low as 130 nM. Their structure-activity relationships are discussed. The ZVpro inhibitors also inhibit homologous proteases of dengue and West Nile viruses, and their inhibitory activities are correlated. The most potent compounds 47 and 103 potently inhibited Zika virus replication in cells with EC68 values of 300-600 nM and in a mouse model of Zika infection. These compounds represent novel pharmacological leads for drug development against Flavivirus infections.
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Affiliation(s)
- Shenyou Nie
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Yuan Yao
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Fangrui Wu
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Xiaowei Wu
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Jidong Zhao
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Yuanda Hua
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Jingyu Wu
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Tong Huo
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Yi-Lun Lin
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Alexander R Kneubehl
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Megan B Vogt
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States.,Intragrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Josephine Ferreon
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Rebecca Rico-Hesse
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
| | - Yongcheng Song
- Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States
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Lequime S, Dehecq JS, Matheus S, de Laval F, Almeras L, Briolant S, Fontaine A. Modeling intra-mosquito dynamics of Zika virus and its dose-dependence confirms the low epidemic potential of Aedes albopictus. PLoS Pathog 2020; 16:e1009068. [PMID: 33382858 PMCID: PMC7774846 DOI: 10.1371/journal.ppat.1009068] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 10/14/2020] [Indexed: 01/01/2023] Open
Abstract
Originating from African forests, Zika virus (ZIKV) has now emerged worldwide in urbanized areas, mainly transmitted by Aedes aegypti mosquitoes. Although Aedes albopictus can transmit ZIKV experimentally and was suspected to be a ZIKV vector in Central Africa, the potential of this species to sustain virus transmission was yet to be uncovered until the end of 2019, when several autochthonous transmissions of the virus vectored by Ae. albopictus occurred in France. Aside from these few locally acquired ZIKV infections, most territories colonized by Ae. albopictus have been spared so far. The risk level of ZIKV emergence in these areas remains however an open question. To assess Ae. albopictus' vector potential for ZIKV and identify key virus outbreak predictors, we built a complete framework using the complementary combination of (i) dose-dependent experimental Ae. albopictus exposure to ZIKV followed by time-dependent assessment of infection and systemic infection rates, (ii) modeling of intra-human ZIKV viremia dynamics, and (iii) in silico epidemiological simulations using an Agent-Based Model. The highest risk of transmission occurred during the pre-symptomatic stage of the disease, at the peak of viremia. At this dose, mosquito infection probability was estimated to be 20%, and 21 days were required to reach the median systemic infection rates. Mosquito population origin, either temperate or tropical, had no impact on infection rates or intra-host virus dynamic. Despite these unfavorable characteristics for transmission, Ae. albopictus was still able to trigger and yield large outbreaks in a simulated environment in the presence of sufficiently high mosquito biting rates. Our results reveal a low but existing epidemic potential of Ae. albopictus for ZIKV, that might explain the absence of large scale ZIKV epidemics so far in territories occupied only by Ae. albopictus. They nevertheless support active surveillance and eradication programs in these territories to maintain the risk of emergence to a low level.
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Affiliation(s)
- Sebastian Lequime
- Cluster of Microbial Ecology, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands
- KU Leuven Department of Microbiology, Immunology and Transplantation, Rega Institute, Laboratory of Clinical and Epidemiological Virology, Leuven, Belgium
| | - Jean-Sébastien Dehecq
- French Ministry of Health, Agence Régionale de Santé de La Réunion, Vector control Unit, La Reunion Island, Saint-Denis, France
| | - Séverine Matheus
- Laboratory of Virology, National Reference Center for Arboviruses, Institut Pasteur, Guyane Française, Cayenne, France
- Environment and infections risks unit, Institut Pasteur, Paris, France
| | - Franck de Laval
- SSA, Service de Santé des Armées, CESPA, Centre d’épidémiologie et de santé publique des armées, Marseille, France
- Aix Marseille Univ, INSERM, IRD, SESSTIM, Sciences Economiques & Sociales de la Santé & Traitement de l’Information Médicale, Marseille, France
| | - Lionel Almeras
- Unité Parasitologie et Entomologie, Département Microbiologie et maladies infectieuses, Institut de Recherche Biomédicale des Armées (IRBA), Marseille, France
- Aix Marseille Univ, IRD, SSA, AP-HM, UMR Vecteurs–Infections Tropicales et Méditerranéennes (VITROME), Marseille, France
- IHU Méditerranée Infection, Marseille, France
| | - Sébastien Briolant
- Unité Parasitologie et Entomologie, Département Microbiologie et maladies infectieuses, Institut de Recherche Biomédicale des Armées (IRBA), Marseille, France
- Aix Marseille Univ, IRD, SSA, AP-HM, UMR Vecteurs–Infections Tropicales et Méditerranéennes (VITROME), Marseille, France
- IHU Méditerranée Infection, Marseille, France
| | - Albin Fontaine
- Unité Parasitologie et Entomologie, Département Microbiologie et maladies infectieuses, Institut de Recherche Biomédicale des Armées (IRBA), Marseille, France
- Aix Marseille Univ, IRD, SSA, AP-HM, UMR Vecteurs–Infections Tropicales et Méditerranéennes (VITROME), Marseille, France
- IHU Méditerranée Infection, Marseille, France
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10
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Agarwal A, Chaurasia D. The expanding arms of Zika virus: An updated review with recent Indian outbreaks. Rev Med Virol 2020; 31:1-9. [PMID: 33216418 DOI: 10.1002/rmv.2145] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 06/26/2020] [Accepted: 06/28/2020] [Indexed: 12/16/2022]
Abstract
Zika virus (ZIKV) outbreaks and their adverse clinical consequences have raised concerns throughout the world. ZIKV was little known during the initial outbreaks in Yap islands and French Polynesia, but it came to attention after the series of Brazil outbreaks in which severe complications like microcephaly in newborn babies was detected. During 2018, outbreaks of ZIKV occurred in two states of India which, being a tropical country, has congenial climatic conditions, abundance of highly competent mosquito vectors such as Aedes aegypti and Aedes albopictus, and an immunologically naïve population. In this review, we will briefly discuss the history, epidemiology, evolution, transmission (vector-borne and non-vector borne), pathogenesis, clinical signs and unusual presentations, laboratory diagnosis, treatment, prevention and control of ZIKV. Finally, we suggest priorities for urgent research required to address unanswered questions about Zika infections and help bring this virus under control.
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Affiliation(s)
- Ankita Agarwal
- State Virology Laboratory, Department of Microbiology, Gandhi Medical College, Bhopal, India
| | - Deepti Chaurasia
- State Virology Laboratory, Department of Microbiology, Gandhi Medical College, Bhopal, India
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11
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Flamand C, Bailly S, Fritzell C, Berthelot L, Vanhomwegen J, Salje H, Paireau J, Matheus S, Enfissi A, Fernandes-Pellerin S, Djossou F, Linares S, Carod JF, Kazanji M, Manuguerra JC, Cauchemez S, Rousset D. Impact of Zika Virus Emergence in French Guiana: A Large General Population Seroprevalence Survey. J Infect Dis 2020; 220:1915-1925. [PMID: 31418012 PMCID: PMC6834069 DOI: 10.1093/infdis/jiz396] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 08/01/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Since the identification of Zika virus (ZIKV) in Brazil in May 2015, the virus has spread throughout the Americas. However, ZIKV burden in the general population in affected countries remains unknown. METHODS We conducted a general population survey in the different communities of French Guiana through individual interviews and serologic survey during June-October 2017. All serum samples were tested for anti-ZIKV immunoglobulin G antibodies using a recombinant antigen-based SGERPAxMap microsphere immunoassay, and some of them were further evaluated through anti-ZIKV microneutralization tests. RESULTS The overall seroprevalence was estimated at 23.3% (95% confidence interval [CI], 20.9%-25.9%) among 2697 participants, varying from 0% to 45.6% according to municipalities. ZIKV circulated in a large majority of French Guiana but not in the most isolated forest areas. The proportion of reported symptomatic Zika infection was estimated at 25.5% (95% CI, 20.3%-31.4%) in individuals who tested positive for ZIKV. CONCLUSIONS This study described a large-scale representative ZIKV seroprevalence study in South America from the recent 2015-2016 Zika epidemic. Our findings reveal that the majority of the population remains susceptible to ZIKV, which could potentially allow future reintroductions of the virus.
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Affiliation(s)
| | | | | | - Léna Berthelot
- Arbovirus National Reference Center, Institut Pasteur, Cayenne, French Guiana
| | - Jessica Vanhomwegen
- Environment and Infectious Risks Unit, Unité Mixte de Recherche 2000, Centre National de la Recherche Scientifique, Paris, France
| | - Henrik Salje
- Mathematical Modelling of Infectious Diseases Unit, Unité Mixte de Recherche 2000, Centre National de la Recherche Scientifique, Paris, France
| | - Juliette Paireau
- Mathematical Modelling of Infectious Diseases Unit, Unité Mixte de Recherche 2000, Centre National de la Recherche Scientifique, Paris, France
| | - Séverine Matheus
- Arbovirus National Reference Center, Institut Pasteur, Cayenne, French Guiana.,Environment and Infectious Risks Unit, Unité Mixte de Recherche 2000, Centre National de la Recherche Scientifique, Paris, France
| | - Antoine Enfissi
- Arbovirus National Reference Center, Institut Pasteur, Cayenne, French Guiana
| | | | - Félix Djossou
- Infectious and Tropical Diseases Unit, Centre Hospitalier Andrée Rosemon, Cayenne, French Guiana
| | - Sébastien Linares
- Geographic Information and Knowledge Dissemination Unit, Direction de l'Environnement, de l'Aménagement et du Logement Guyane, Cayenne, French Guiana
| | - Jean-François Carod
- Medical Laboratory, Centre Hospitalier de l'Ouest Guyanais, Saint-Laurent du Maroni, French Guiana
| | | | - Jean-Claude Manuguerra
- Environment and Infectious Risks Unit, Unité Mixte de Recherche 2000, Centre National de la Recherche Scientifique, Paris, France
| | - Simon Cauchemez
- Mathematical Modelling of Infectious Diseases Unit, Unité Mixte de Recherche 2000, Centre National de la Recherche Scientifique, Paris, France
| | - Dominique Rousset
- Arbovirus National Reference Center, Institut Pasteur, Cayenne, French Guiana
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12
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Association of past dengue fever epidemics with the risk of Zika microcephaly at the population level in Brazil. Sci Rep 2020; 10:1752. [PMID: 32019953 PMCID: PMC7000767 DOI: 10.1038/s41598-020-58407-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 12/17/2019] [Indexed: 11/08/2022] Open
Abstract
Despite all the research done on the first Zika virus (ZIKV) epidemics, it was only after the Brazilian epidemic that the Congenital Zika Syndrome was described. This was made possible due to the large number of babies born with microcephaly in the Northeast region (NE) in a narrow time. We hypothesize that the fivefold difference in the rate of microcephalic neonates between the NE and other regions is partially an effect of the population prior immunity against Dengue viruses (DENV), that cross-react with ZIKV. In this ecological study, we analysed the interaction between dengue fever epidemics from 2001 to 2014 and the 2015/2016 microcephaly epidemic in 400 microregions in Brazil using random-effects models under a Bayesian approach. The estimated effect of the time lag between the most recent large dengue epidemic (>400/100,000 inhabitants) and the microcephaly epidemic ranged from protection (up to 6 years prior) to an increased risk (from 7 to 12 years). This sustained window of protection, larger than described in previous longitudinal studies, is possibly an effect of herd immunity and of multiple exposures to DENV that could boost immunity.
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13
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Ledur PF, Karmirian K, Pedrosa CDSG, Souza LRQ, Assis-de-Lemos G, Martins TM, Ferreira JDCCG, de Azevedo Reis GF, Silva ES, Silva D, Salerno JA, Ornelas IM, Devalle S, Madeiro da Costa RF, Goto-Silva L, Higa LM, Melo A, Tanuri A, Chimelli L, Murata MM, Garcez PP, Filippi-Chiela EC, Galina A, Borges HL, Rehen SK. Zika virus infection leads to mitochondrial failure, oxidative stress and DNA damage in human iPSC-derived astrocytes. Sci Rep 2020; 10:1218. [PMID: 31988337 PMCID: PMC6985105 DOI: 10.1038/s41598-020-57914-x] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 01/02/2020] [Indexed: 12/14/2022] Open
Abstract
Zika virus (ZIKV) has been extensively studied since it was linked to congenital malformations, and recent research has revealed that astrocytes are targets of ZIKV. However, the consequences of ZIKV infection, especially to this cell type, remain largely unknown, particularly considering integrative studies aiming to understand the crosstalk among key cellular mechanisms and fates involved in the neurotoxicity of the virus. Here, the consequences of ZIKV infection in iPSC-derived astrocytes are presented. Our results show ROS imbalance, mitochondrial defects and DNA breakage, which have been previously linked to neurological disorders. We have also detected glial reactivity, also present in mice and in post-mortem brains from infected neonates from the Northeast of Brazil. Given the role of glia in the developing brain, these findings may help to explain the observed effects in congenital Zika syndrome related to neuronal loss and motor deficit.
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Affiliation(s)
| | - Karina Karmirian
- D'Or Institute for Research and Education, Rio de Janeiro, Brazil
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | | | | | - Gabriela Assis-de-Lemos
- Institute of Medical Biochemistry Leopoldo De Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Thiago Martino Martins
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | | | - Gabriel Ferreira de Azevedo Reis
- Insitute of Biology, Department of Biophysics and Biometrics, State University of Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
| | - Eduardo Santos Silva
- Insitute of Biology, Department of Biophysics and Biometrics, State University of Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
| | - Débora Silva
- Laboratory of Neuropathology, State Institute of Brain Paulo Niemeyer, Rio de Janeiro, RJ, Brazil
| | - José Alexandre Salerno
- D'Or Institute for Research and Education, Rio de Janeiro, Brazil
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | | | - Sylvie Devalle
- D'Or Institute for Research and Education, Rio de Janeiro, Brazil
| | | | - Livia Goto-Silva
- D'Or Institute for Research and Education, Rio de Janeiro, Brazil
| | - Luiza Mendonça Higa
- Institute of Biology, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | - Adriana Melo
- Research Institute Prof. Joaquim Amorim Neto (IPESQ), Campina Grande, PB, Brazil
| | - Amilcar Tanuri
- Institute of Biology, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | - Leila Chimelli
- Laboratory of Neuropathology, State Institute of Brain Paulo Niemeyer, Rio de Janeiro, RJ, Brazil
| | - Marcos Massao Murata
- Insitute of Biology, Department of Biophysics and Biometrics, State University of Rio de Janeiro (UERJ), Rio de Janeiro, RJ, Brazil
| | - Patrícia Pestana Garcez
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | | | - Antonio Galina
- Institute of Medical Biochemistry Leopoldo De Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Helena Lobo Borges
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil
| | - Stevens Kastrup Rehen
- D'Or Institute for Research and Education, Rio de Janeiro, Brazil.
- Institute of Biomedical Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil.
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14
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Shahid F, Ashfaq UA, Javaid A, Khalid H. Immunoinformatics guided rational design of a next generation multi epitope based peptide (MEBP) vaccine by exploring Zika virus proteome. INFECTION GENETICS AND EVOLUTION 2020; 80:104199. [PMID: 31962160 DOI: 10.1016/j.meegid.2020.104199] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/13/2020] [Accepted: 01/17/2020] [Indexed: 12/16/2022]
Abstract
Zika virus (ZIKV) is an RNA virus that has spread through mosquito sting. Currently, no vaccine and antiviral medication available so far against ZIKV. Therefore, it has fostered a study to design MEBP vaccine enabling effective prevention against the ZIKV infection. In this study combination of immuno-informatics and molecular docking approach was used to constitute a MEBP vaccine. The ZIKV proteome was used for prediction of B-cell, T-cell (HTL & CTL) and IFN-γ epitopes. After prediction, highly antigenic and overlapping epitopes have been shortlisted which includes 14 CTL and 11 HTL epitopes that have been linked to the final peptide through AAY and GPGPG linkers respectively. An adjuvant at the N-end of the vaccine was added to improve the immunogenicity of the vaccine through the EAAAK linker. The final construct constitutes 435 amino acids after the addition of linkers and adjuvant. The existence of B-cell and IFN-γ epitopes affirms the humoral and cell-mediated immune responses acquired by the construct. Allergenicity, antigenicity and different physiochemical attributes of the vaccine were evaluated to assure its safety and immunogenicity profile. In fact, the construct was antigenic and non-allergenic. Docking was performed among vaccine and TLR-3 to evaluate the binding affinity and the molecular interaction. Finally, the construct was subjected to In silico cloning to confers the authenticity of its expression efficiency. However, the proposed construct need to be validate experimentally to ensure its safety and immunogenic profile.
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Affiliation(s)
- Farah Shahid
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan.
| | - Anam Javaid
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Hina Khalid
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
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15
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Wang X, Xia S, Zou P, Lu L. Erythromycin Estolate Inhibits Zika Virus Infection by Blocking Viral Entry as a Viral Inactivator. Viruses 2019; 11:v11111064. [PMID: 31731598 PMCID: PMC6893414 DOI: 10.3390/v11111064] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 10/30/2019] [Accepted: 11/10/2019] [Indexed: 12/19/2022] Open
Abstract
Recently, Zika virus (ZIKV) has attracted much attention in consideration of its association with severe neurological complications including fetal microcephaly. However, there are currently no prophylactic vaccines or therapeutic drugs approved for clinical treatments of ZIKV infection. To determine the potential anti-ZIKV inhibitors, we screened a library of clinical drugs with good safety profiles. Erythromycin estolate (Ery-Est), one of the macrolide antibiotics, was found to effectively inhibit ZIKV infection in different cell types and significantly protect A129 mice from ZIKV-associated neurological signs and mortality. Through further investigation, Ery-Est was verified to inhibit ZIKV entry by disrupting the integrity of the viral membrane which resulted in the loss of ZIKV infectivity. Furthermore, Ery-Est also showed inhibitory activity against dengue virus (DENV) and yellow fever virus (YFV). Thus, Ery-Est may be a promising drug for patients with ZIKV infection, particularly pregnant women.
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Affiliation(s)
| | | | - Peng Zou
- Correspondence: (P.Z.); (L.L.); Tel.: +86-21-37990333-5273 (P.Z.); +86-21-5423-7673 (L.L.)
| | - Lu Lu
- Correspondence: (P.Z.); (L.L.); Tel.: +86-21-37990333-5273 (P.Z.); +86-21-5423-7673 (L.L.)
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16
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Saver AE, Crawford SA, Joyce JD, Bertke AS. Route of Infection Influences Zika Virus Shedding in a Guinea Pig Model. Cells 2019; 8:E1437. [PMID: 31739508 PMCID: PMC6912420 DOI: 10.3390/cells8111437] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/04/2019] [Accepted: 11/13/2019] [Indexed: 11/16/2022] Open
Abstract
Due to the recent epidemic of Zika virus (ZIKV) infection and resulting sequelae, as well as concerns about both the sexual and vertical transmission of the virus, renewed attention has been paid to the pathogenesis of this unique arbovirus. Numerous small animal models have been used in various ZIKV pathogenicity studies, however, they are often performed using immunodeficient or immunosuppressed animals, which may impact disease progression in a manner not relevant to immunocompetent humans. The use of immunocompetent animal models, such as macaques, is constrained by small sample sizes and the need for specialized equipment/staff. Here we report the establishment of ZIKV infection in an immunocompetent small animal model, the guinea pig, using both subcutaneous and vaginal routes of infection to mimic mosquito-borne and sexual transmission. Guinea pigs developed clinical signs consistent with mostly asymptomatic and mild disease observed in humans. We demonstrate that the route of infection does not significantly alter viral tissue tropism but does impact mucosal shedding mechanics. We also demonstrate persistent infection in sensory and autonomic ganglia, identifying a previously unrecognized niche of viral persistence that could contribute to viral shedding in secretions. We conclude that the guinea pig represents a useful and relevant model for ZIKV pathogenesis.
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Affiliation(s)
- Ashley E. Saver
- Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA; (A.E.S.); (S.A.C.)
| | - Stephanie A. Crawford
- Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA; (A.E.S.); (S.A.C.)
| | - Jonathan D. Joyce
- Department of Population Health Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA;
| | - Andrea S. Bertke
- Department of Population Health Sciences, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA;
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17
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Tan CW, Huan Hor CH, Kwek SS, Tee HK, Sam IC, Goh ELK, Ooi EE, Chan YF, Wang LF. Cell surface α2,3-linked sialic acid facilitates Zika virus internalization. Emerg Microbes Infect 2019; 8:426-437. [PMID: 30898036 PMCID: PMC6455136 DOI: 10.1080/22221751.2019.1590130] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The emergence of neurotropic Zika virus (ZIKV) raised a public health emergency of global concern. ZIKV can cross the placental barrier and infect foetal brains, resulting in microcephaly, but the pathogenesis of ZIKV is poorly understood. With recent findings reporting AXL as a type I interferon antagonist rather than an entry receptor, the exact entry mechanism remains unresolved. Here we report that cell surface sialic acid plays an important role in ZIKV infection. Removal of cell surface sialic acid by neuraminidase significantly abolished ZIKV infection in Vero cells and human induced-pluripotent stem cells-derived neural progenitor cells. Furthermore, knockout of the sialic acid biosynthesis gene encoding UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase resulted in significantly less ZIKV infection of both African and Asian lineages. Huh7 cells deficient in α2,3-linked sialic acid through knockout of ST3 β-galactoside-α2,3-sialyltransferase 4 had significantly reduced ZIKV infection. Removal of membrane-bound, un-internalized virus with pronase treatment revealed the role of sialic acid in ZIKV internalization but not attachment. Sialyllactose inhibition studies showed that there is no direct interaction between sialic acid and ZIKV, implying that sialic acid could be mediating ZIKV-receptor complex internalization. Identification of α2,3-linked sialic acid as an important host factor for ZIKV internalization provides new insight into ZIKV infection and pathogenesis.
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Affiliation(s)
- Chee Wah Tan
- a Programme in Emerging Infectious Diseases , Duke-NUS Medical School , Singapore , Singapore
| | - Catherine Hong Huan Hor
- b Neuroscience Academic Clinical Programme , Duke-NUS Medical School , Singapore , Singapore
| | - Swee Sen Kwek
- a Programme in Emerging Infectious Diseases , Duke-NUS Medical School , Singapore , Singapore
| | - Han Kang Tee
- c Department of Medical Microbiology, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia
| | - I-Ching Sam
- c Department of Medical Microbiology, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia
| | - Eyleen L K Goh
- b Neuroscience Academic Clinical Programme , Duke-NUS Medical School , Singapore , Singapore
| | - Eng Eong Ooi
- a Programme in Emerging Infectious Diseases , Duke-NUS Medical School , Singapore , Singapore
| | - Yoke Fun Chan
- c Department of Medical Microbiology, Faculty of Medicine , University of Malaya , Kuala Lumpur , Malaysia
| | - Lin-Fa Wang
- a Programme in Emerging Infectious Diseases , Duke-NUS Medical School , Singapore , Singapore
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18
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Bustamante FA, Miró MP, VelÁsquez ZD, Molina L, Ehrenfeld P, Rivera FJ, BÁtiz LF. Role of adherens junctions and apical-basal polarity of neural stem/progenitor cells in the pathogenesis of neurodevelopmental disorders: a novel perspective on congenital Zika syndrome. Transl Res 2019; 210:57-79. [PMID: 30904442 DOI: 10.1016/j.trsl.2019.02.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 01/08/2019] [Accepted: 02/28/2019] [Indexed: 12/18/2022]
Abstract
Radial glial cells (RGCs) are the neural stem/progenitor cells (NSPCs) that give rise to most of neurons and glial cells that constitute the adult central nervous system. A hallmark of RGCs is their polarization along the apical-basal axis. They extend a long basal process that contacts the pial surface and a short apical process to the ventricular surface. Adherens junctions (AJs) are organized as belt-like structures at the most-apical lateral plasma membrane of the apical processes. These junctional complexes anchor RGCs to each other and allow the recruitment of cytoplasmic proteins that act as apical-basal determinants. It has been proposed that disruption of AJs underlies the onset of different neurodevelopmental disorders. In fact, studies performed in different animal models indicate that loss of function of AJs-related proteins in NSPCs can disrupt cell polarity, imbalance proliferation and/or differentiation rates and increase cell death, which, in turn, lead to disruption of the cytoarchitecture of the ventricular zone, protrusion of non-polarized cells into the ventricles, cortical thinning, and ventriculomegaly/hydrocephalus, among other neuropathological findings. Recent Zika virus (ZIKV) outbreaks and the high comorbidity of ZIKV infection with congenital neurodevelopmental defects have led to the World Health Organization to declare a public emergency of international concern. Thus, noteworthy advances have been made in clinical and experimental ZIKV research. This review summarizes the current knowledge regarding the function of AJs in normal and pathological corticogenesis and focuses on the neuropathological and cellular mechanisms involved in congenital ZIKV syndrome, highlighting the potential role of cell-to-cell junctions between NSPCs in the etiopathogenesis of such syndrome.
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Affiliation(s)
- Felipe A Bustamante
- Laboratory of Developmental Neuropathology, Institute of Anatomy, Histology & Pathology, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia Chile
| | - MarÍa Paz Miró
- Laboratory of Developmental Neuropathology, Institute of Anatomy, Histology & Pathology, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia Chile
| | - Zahady D VelÁsquez
- Laboratory of Developmental Neuropathology, Institute of Anatomy, Histology & Pathology, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Institute für Parasitologie, Biomedizinisches Forschungszentrum Seltersberg, Justus Liebig Universität, Gießen, Germany
| | - Luis Molina
- Laboratory of Cellular Pathology, Institute of Anatomy, Histology & Pathology, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Departamento de Ciencias Biológicas y Químicas, Facultad de Ciencia, Universidad San Sebastián, Puerto Montt, Chile
| | - Pamela Ehrenfeld
- Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia Chile; Laboratory of Cellular Pathology, Institute of Anatomy, Histology & Pathology, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Francisco J Rivera
- Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia Chile; Laboratory of Stem Cells and Neuroregeneration, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile; Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria; Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
| | - Luis Federico BÁtiz
- Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia Chile; Centro de Investigación Biomédica (CIB), Facultad de Medicina, Universidad de los Andes, Santiago, Chile.
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Pomar L, Musso D, Malinger G, Vouga M, Panchaud A, Baud D. Zika virus during pregnancy: From maternal exposure to congenital Zika virus syndrome. Prenat Diagn 2019; 39:420-430. [PMID: 30866073 DOI: 10.1002/pd.5446] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 02/27/2019] [Accepted: 03/06/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Léo Pomar
- Department "Woman-Mother-Child", Lausanne University Hospital, Materno-Fetal and Obstetrics Research Unit, Lausanne, Switzerland
| | - Didier Musso
- Aix Marseille University, IRD, AP-HM, SSA, VITROME, IHU-Méditerranée infection, Marseille, France
- Private practitioner, Punaauia, Tahiti, French Polynesia
| | - Gustavo Malinger
- Division of Ultrasound in Obstetrics & Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center & Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Manon Vouga
- Department "Woman-Mother-Child", Lausanne University Hospital, Materno-Fetal and Obstetrics Research Unit, Lausanne, Switzerland
| | - Alice Panchaud
- School of Pharmaceutical Sciences, Geneva University and Service of Pharmacy, Lausanne University Hospital, Lausanne, Switzerland
| | - David Baud
- Department "Woman-Mother-Child", Lausanne University Hospital, Materno-Fetal and Obstetrics Research Unit, Lausanne, Switzerland
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20
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Hugo LE, Stassen L, La J, Gosden E, Ekwudu O, Winterford C, Viennet E, Faddy HM, Devine GJ, Frentiu FD. Vector competence of Australian Aedes aegypti and Aedes albopictus for an epidemic strain of Zika virus. PLoS Negl Trop Dis 2019; 13:e0007281. [PMID: 30946747 PMCID: PMC6467424 DOI: 10.1371/journal.pntd.0007281] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 04/16/2019] [Accepted: 03/05/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Recent epidemics of Zika virus (ZIKV) in the Pacific and the Americas have highlighted its potential as an emerging pathogen of global importance. Both Aedes (Ae.) aegypti and Ae. albopictus are known to transmit ZIKV but variable vector competence has been observed between mosquito populations from different geographical regions and different virus strains. Since Australia remains at risk of ZIKV introduction, we evaluated the vector competence of local Ae. aegypti and Ae. albopictus for a Brazilian epidemic ZIKV strain. In addition, we evaluated the impact of daily temperature fluctuations around a mean of 28°C on ZIKV transmission and extrinsic incubation period. METHODOLOGY/PRINCIPAL FINDINGS Mosquitoes were orally challenged with a Brazilian ZIKV strain (8.8 log CCID50/ml) and maintained at either 28°C constant or fluctuating temperature conditions. At 3, 7 and 14 days post-infection (dpi), ZIKV RNA copies were quantified in mosquito bodies, as well as wings and legs, using qRT-PCR, while virus antigen in saliva (a proxy for transmission) was detected using a cell culture ELISA. Despite high body and disseminated infection rates in both vectors, the transmission rates of ZIKV in saliva of Ae. aegypti (50-60%) were significantly higher than in Ae. albopictus (10%) at 14 dpi. Both species supported a high viral load in bodies, with no significant differences between constant and fluctuating temperature conditions. However, a significant difference in viral load in wings and legs between species was observed, with higher titres in Ae. aegypti maintained at constant temperature conditions. For ZIKV transmission to occur in Ae. aegypti, a disseminated virus load threshold of 7.59 log10 copies had to be reached. CONCLUSIONS/SIGNIFICANCE Australian Ae. aegypti are better able to transmit a Brazilian ZIKV strain than Ae. albopictus. The results are in agreement with the global consensus that Ae. aegypti is the major vector of ZIKV.
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Affiliation(s)
- Leon E. Hugo
- Mosquito Control Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Liesel Stassen
- Institute of Health and Biomedical Innovation, and School of Biomedical Sciences Queensland University of Technology, Brisbane, Queensland, Australia
| | - Jessica La
- Institute of Health and Biomedical Innovation, and School of Biomedical Sciences Queensland University of Technology, Brisbane, Queensland, Australia
| | - Edward Gosden
- Institute of Health and Biomedical Innovation, and School of Biomedical Sciences Queensland University of Technology, Brisbane, Queensland, Australia
| | - O’mezie Ekwudu
- Institute of Health and Biomedical Innovation, and School of Biomedical Sciences Queensland University of Technology, Brisbane, Queensland, Australia
| | - Clay Winterford
- QIMR Berghofer Histotechnology Facility, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Elvina Viennet
- Research and Development, Australian Red Cross Blood Service, Brisbane, Queensland, Australia
| | - Helen M. Faddy
- Research and Development, Australian Red Cross Blood Service, Brisbane, Queensland, Australia
| | - Gregor J. Devine
- Mosquito Control Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Francesca D. Frentiu
- Institute of Health and Biomedical Innovation, and School of Biomedical Sciences Queensland University of Technology, Brisbane, Queensland, Australia
- * E-mail:
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21
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Diagnosing Zika virus infection against a background of other flaviviruses: Studies in high resolution serological analysis. Sci Rep 2019; 9:3648. [PMID: 30842564 PMCID: PMC6403343 DOI: 10.1038/s41598-019-40224-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 02/11/2019] [Indexed: 11/21/2022] Open
Abstract
Zika virus (ZIKV) is a mosquito-borne flavivirus. Homologous proteins of different flaviviruses display high degrees of sequence identity, especially within subgroups. This leads to extensive immunological cross-reactivity and corresponding problems for developing a ZIKV-specific serological assay. In this study, peptide microarrays were employed to identify individual ZIKV antibody targets with promise in differential diagnosis. A total of 1643 overlapping oligopeptides were synthesized and printed onto glass slides. Together, they encompass the full amino acid sequences of ZIKV proteomes of African, Brazilian, USA, and French Polynesian origins. The resulting ZIKV scanning microarray chips were used to screen three pools of sera from recent Zika outbreaks in Senegal and Cape Verde, in Brazil, and from overseas travelers returning to the EU. Together with a mixed pool of well characterized, archived sera of patients suffering from infections by dengue, yellow fever, tick-borne encephalitis, and West Nile viruses, a total of 42 sera went into the study. Sixty-eight antibody target regions were identified. Most of which were hitherto unknown. Alignments and sequence comparisons revealed 13 of which could be classified as bona fide ZIKV-specific. These identified antibody target regions constitute a founding set of analytical tools for serological discrimination of ZIKV from other flaviviruses.
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22
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Marques VDM, Santos CS, Santiago IG, Marques SM, Nunes Brasil MDG, Lima TT, Costa PS. Neurological Complications of Congenital Zika Virus Infection. Pediatr Neurol 2019; 91:3-10. [PMID: 30591235 DOI: 10.1016/j.pediatrneurol.2018.11.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 10/30/2018] [Accepted: 11/02/2018] [Indexed: 01/04/2023]
Abstract
BACKGROUND In utero Zika virus infection resulted in many newborns with congenital defects; this public health issue was followed by unprecedented scientific productivity in this field. Many questions remain about congenital Zika virus infection and its maternal transmission, pathogenesis, clinical events, and the resulting neurological damage. There are few review articles that synthesize the current knowledge of congenital neurological complications as well as the gaps in the pediatric literature. OBJECTIVE We review the full range of data on neurological complications in the newborns and infants born to Zika virus-infected women. METHODS A research question (PCC: Population, newborns and infants of infected mothers; Concept, neurological outcomes at birth; Context, congenital Zika virus infection) was created to guide our review in searching several databases: PubMed, Lilacs, CINAHL, Cochrane Library, and OpenGrey literature. A total of 34 articles were included in the final review. RESULTS Central nervous system calcifications, mainly at the cortical-subcortical junction, were the most prevalent neurological birth defects related to Zika infection (104/112, 92.9% from seven studies). Also, microcephaly occurred in 39.7% of all infected infants (1561/3931 patients in all the studies) and ventriculomegaly and/or hydrocephalus occurred in 63.1% (157/249 patients analyzed in 12 studies). A total of 10 articles detailed ocular findings, including macular lesions, focal pigment mottling of the retina, chorioretinal atrophy, optic nerve abnormalities, cataract, microphthalmia, and strabismus, among others. CONCLUSIONS Neurological and related malformations are common lesions in individuals with congenital Zika syndrome. Long-term follow-up studies in this field are lacking.
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Affiliation(s)
- Vinícius de Melo Marques
- Department of Pediatrics, School of Medicine, Universidade Federal de Goiás - UFG, Goiânia, GO, Brazil
| | - Camilla Sousa Santos
- Department of Pediatric Neurology, Universidade Federal de São Paulo - UNIFESP, São Paulo, SP, Brazil
| | - Isabella Godinho Santiago
- Department of Pediatric Neurology, Hospital das Clínicas, Universidade Federal de Goiás - UFG, Goiânia, GO, Brazil
| | - Solomar Martins Marques
- Department of Pediatrics, School of Medicine, Universidade Federal de Goiás - UFG, Goiânia, GO, Brazil
| | | | - Talita Toledo Lima
- Department of Ophtalmology, Hospital das Clínicas, Universidade Federal de Goiás - UFG, Goiânia, GO, Brazil
| | - Paulo Sucasas Costa
- Department of Pediatrics, School of Medicine, Universidade Federal de Goiás - UFG, Goiânia, GO, Brazil.
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Kakooza-Mwesige A, Tshala-Katumbay D, Juliano SL. Viral infections of the central nervous system in Africa. Brain Res Bull 2019; 145:2-17. [PMID: 30658129 DOI: 10.1016/j.brainresbull.2018.12.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 12/17/2018] [Accepted: 12/19/2018] [Indexed: 12/26/2022]
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.
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Affiliation(s)
- Angelina Kakooza-Mwesige
- 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.
| | - Desire Tshala-Katumbay
- Department of Neurology and School of Public Health, Oregon Health & Science University, Portland, OR, USA; Department of Neurology, University of Kinshasa, and Institut National de Recherches Biomedicales, University of Kinshasa, Democratic Republic of the Congo.
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Growth and adaptation of Zika virus in mammalian and mosquito cells. PLoS Negl Trop Dis 2018; 12:e0006880. [PMID: 30418969 PMCID: PMC6258428 DOI: 10.1371/journal.pntd.0006880] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 11/26/2018] [Accepted: 09/28/2018] [Indexed: 01/02/2023] Open
Abstract
The recent emergence of Zika virus (ZIKV) in the Americas coincident with increased caseloads of microcephalic infants and Guillain-Barre syndrome has prompted a flurry of research on ZIKV. Much of the research is difficult to compare or repeat because individual laboratories use different virus isolates, growth conditions, and quantitative assays. Here we obtained three readily available contemporary ZIKV isolates and the prototype Ugandan isolate. We generated stocks of each on Vero mammalian cells (ZIKVmam) and C6/36 mosquito cells (ZIKVmos), determined titers by different assays side-by-side, compared growth characteristics using one-step and multi-step growth curves on Vero and C6/36 cells, and examined plaque phenotype. ZIKV titers consistently peaked earlier on Vero cells than on C6/36 cells. Contemporary ZIKV isolates reached peak titer most quickly in a multi-step growth curve when the amplifying cell line was the same as the titering cell line (e.g., ZIKVmam titered on Vero cells). Growth of ZIKVmam on mosquito cells was particularly delayed. These data suggest that the ability to infect and/or replicate in insect cells is limited after growth in mammalian cells. In addition, ZIKVmos typically had smaller, more homogenous plaques than ZIKVmam in a standard plaque assay. We hypothesized that the plaque size difference represented early adaptation to growth in mammalian cells. We plaque purified representative-sized plaques from ZIKVmos and ZIKVmam. ZIKVmos isolates maintained the initial phenotype while plaques from ZIKVmam isolates became larger with passaging. Our results underscore the importance of the cells used to produce viral stocks and the potential for adaptation with minimal cell passages. In addition, these studies provide a foundation to compare current and emerging ZIKV isolates in vitro and in vivo.
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25
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Alves MP, Vielle NJ, Thiel V, Pfaender S. Research Models and Tools for the Identification of Antivirals and Therapeutics against Zika Virus Infection. Viruses 2018; 10:v10110593. [PMID: 30380760 PMCID: PMC6265910 DOI: 10.3390/v10110593] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 10/24/2018] [Accepted: 10/26/2018] [Indexed: 12/13/2022] Open
Abstract
Zika virus recently re-emerged and caused global outbreaks mainly in Central Africa, Southeast Asia, the Pacific Islands and in Central and South America. Even though there is a declining trend, the virus continues to spread throughout different geographical regions of the world. Since its re-emergence in 2015, massive advances have been made regarding our understanding of clinical manifestations, epidemiology, genetic diversity, genomic structure and potential therapeutic intervention strategies. Nevertheless, treatment remains a challenge as there is no licensed effective therapy available. This review focuses on the recent advances regarding research models, as well as available experimental tools that can be used for the identification and characterization of potential antiviral targets and therapeutic intervention strategies.
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Affiliation(s)
- Marco P Alves
- Institute of Virology and Immunology, 3012 Bern, Switzerland.
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
| | - Nathalie J Vielle
- Institute of Virology and Immunology, 3012 Bern, Switzerland.
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
- Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland.
| | - Volker Thiel
- Institute of Virology and Immunology, 3012 Bern, Switzerland.
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
| | - Stephanie Pfaender
- Institute of Virology and Immunology, 3012 Bern, Switzerland.
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
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Quintana-Domeque C, Carvalho JR, de Oliveira VH. Zika virus incidence, preventive and reproductive behaviors: Correlates from new survey data. ECONOMICS AND HUMAN BIOLOGY 2018; 30:14-23. [PMID: 29772278 DOI: 10.1016/j.ehb.2018.04.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 04/28/2018] [Indexed: 05/27/2023]
Abstract
During the outbreak of the Zika virus, Brazilian health authorities recommended that pregnant women take meticulous precaution to avoid mosquito bites and that women in general use contraceptive methods to postpone/delay pregnancies. In this article, we present new estimates on the Zika virus incidence, its correlates and preventive behaviors in the Northeast of Brazil, where the outbreak initiated, using survey data collected between March 30th and June 3rd of 2016. The target population were women aged 15-49 in the capital cities of the nine states of the Northeast region of Brazil. We find that more educated women were less likely to report suffering from Zika (or its symptoms) and more likely to report having taken precaution against Zika, such as having used long and light-colored clothes, having used mosquito repellent or insecticides, having used mosquito protective screens or kept windows closed, and having dumped standing water where mosquitoes can breed. In addition, more educated women were more likely to report being informed about the association between Zika and microcephaly and to avoid pregnancy in the last 12 months. Finally, we also find that women who reported experiencing sexual domestic violence in the last 12 months were more likely to report suffering from Zika.
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27
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de Sousa JR, Azevedo RSS, Martins Filho AJ, Araujo MTF, Moutinho ERC, Baldez Vasconcelos BC, Cruz ACR, Oliveira CS, Martins LC, Baldez Vasconcelos BH, Casseb LMN, Chiang JO, Quaresma JAS, Vasconcelos PFC. Correlation between Apoptosis and in Situ Immune Response in Fatal Cases of Microcephaly Caused by Zika Virus. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:2644-2652. [PMID: 30121258 DOI: 10.1016/j.ajpath.2018.07.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 07/12/2018] [Accepted: 07/16/2018] [Indexed: 12/27/2022]
Abstract
Zika virus (ZIKV) is a single-stranded positive-sense RNA flavivirus that possesses a genome approximately 10.7 Kb in length. Although pro-inflammatory and anti-inflammatory cytokines and apoptotic markers belonging to the extrinsic and intrinsic pathways are suggested to be involved in fatal cases of ZIKV-induced microcephaly, their exact roles and associations are unclear. To address this, brain tissue samples were collected from 10 individuals, five of whom were diagnosed as ZIKV positive with microcephaly and a further five were flavivirus-negative controls that died because of other causes. Examination of material from the fatal cases of microcephaly revealed lesions in the cerebral cortex, edema, vascular proliferation, neuronal necrosis, gliosis, neuronophagy, calcifications, apoptosis, and neuron loss. The expression of various apoptosis markers in the neural parenchyma, including FasL, FAS, BAX, BCL2, and caspase 3 differed between ZIKV-positive cases and controls. Further investigation of type 1 and 2 helper T-cell cytokines confirmed a greater anti-inflammatory response in fatal ZIKV-associated microcephaly cases. Finally, an analysis of the linear correlation between tumor necrosis factor-α, IL-1β, IL-4, IL-10, transforming growth factor-β, and IL-33 expression and various apoptotic markers suggested that the immune response may be associated with the apoptotic phenomenon observed in ZIKV-induced microcephaly.
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Affiliation(s)
- Jorge R de Sousa
- Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil
| | - Raimunda S S Azevedo
- Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil
| | | | - Marialva T F Araujo
- Department of Pathology, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil
| | - Ermelinda R C Moutinho
- Department of Pathology, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil
| | | | - Ana C R Cruz
- Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil; Center of Biological and Health Sciences, State University of Pará, Belém, Brazil
| | - Consuelo S Oliveira
- Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil
| | - Lívia C Martins
- Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil
| | | | - Livia M N Casseb
- Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil
| | - Jannifer O Chiang
- Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil
| | - Juarez A S Quaresma
- Department of Pathology, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil; Center of Biological and Health Sciences, State University of Pará, Belém, Brazil; Tropical Medicine Center, Federal University of Pará, Belém, Brazil.
| | - Pedro F C Vasconcelos
- Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Brazil; Center of Biological and Health Sciences, State University of Pará, Belém, Brazil.
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Carabali M, Austin N, King NB, Kaufman JS. The Zika epidemic and abortion in Latin America: a scoping review. Glob Health Res Policy 2018; 3:15. [PMID: 29750204 PMCID: PMC5932843 DOI: 10.1186/s41256-018-0069-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 03/28/2018] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Latin America presently has the world's highest burden of Zika virus, but there are unexplained differences in national rates of congenital malformations collectively referred to as Congenital Zika Syndrome (CZS) in the region. While Zika virulence and case detection likely contribute to these differences, policy-related factors, including access to abortion, may play important roles. Our goal was to assess perspectives on, and access to, abortion in Latin America in the context of the Zika epidemic. METHODS We conducted a scoping review of peer-reviewed and gray literature published between January 2015 and December 2016, written in English, Spanish, Portuguese, or French. We searched PubMed, Scielo, and Google Scholar for literature on Zika and/or CZS and abortion, and used automated and manual review methods to synthesize the existing information. RESULTS 36 publications met our inclusion criteria, the majority of which were qualitative. Publications were generally in favor of increased access to safe abortion as a policy-level response for mitigating the impact of CZS, but issues with implementation were cited as the main challenge. Aside from the reform of abortion regulation in Colombia, we did not find evidence that the Zika epidemic had triggered shifts in abortion policy in other countries. CONCLUSION Abortion policy in the region remained largely unchanged following the Zika epidemic. Further empirical research on abortion access and differential rates of CZS across Latin American countries is required.
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Affiliation(s)
- Mabel Carabali
- Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University, 1020 Pine Avenue West, Purvis Hall Room 17A, Montreal, QC H3A 1A2 Canada
| | - Nichole Austin
- Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University, 1020 Pine Avenue West, Purvis Hall Room 17A, Montreal, QC H3A 1A2 Canada
| | - Nicholas B. King
- Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University, 1020 Pine Avenue West, Purvis Hall Room 17A, Montreal, QC H3A 1A2 Canada
- Biomedical Ethics Unit, McGill University, Montreal, QC Canada
| | - Jay S. Kaufman
- Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University, 1020 Pine Avenue West, Purvis Hall Room 17A, Montreal, QC H3A 1A2 Canada
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Abstract
INTRODUCTION Zika virus (ZIKV) disease is a vector-borne infectious disease transmitted by Aedes mosquitoes. Recently, ZIKV has caused outbreaks in most American countries. Areas covered: Publications about neurological complications of ZIKV infection retrieved from pubmed searchers were reviewed, and reference lists and relevant articles from review articles were also examined. Vertical/intrauterine transmission leads to congenital infection and causes microcephaly and congenital ZIKV syndrome. ZIKV preferentially infects human neural progenitor cells and triggers cell apoptosis. ZIKV RNA has been identified in foetal brain tissue and brains of microcephalic infants who died; amniotic fluid and placentas of pregnant mothers; and umbilical cord, cerebro-spinal fluid and meninges of newborns. The increase in the number of Guillain-Barre syndrome (GBS) cases during the ZIKV outbreak in the Americas provides epidemiological evidence for the link between ZIKV infection and GBS. Less frequently reported ZIKV neurological complications include encephalitis/meningoencephalitis, acute disseminated encephalomyelitis, myelitis, cerebrovascular complications (ischemic infarction; vasculopathy), seizures and encephalopathy, sensory polyneuropathy and sensory neuronopathy. Analysis of GBS incidence could serve as an epidemiological 'marker' or sentinel for ZIKV disease and other neurological complications associated to ZIKV. Expert commentary: An expanding spectrum of neurological complications associated with ZIKV infection is being recognised.
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Affiliation(s)
- Francisco Javier Carod-Artal
- a Neurology Department , Raigmore Hospital , Inverness , UK.,b International Master in Tropical Neurology , International University of Catalonia (UIC) , Barcelona , Spain
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30
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Flamand C, Fritzell C, Matheus S, Dueymes M, Carles G, Favre A, Enfissi A, Adde A, Demar M, Kazanji M, Cauchemez S, Rousset D. The proportion of asymptomatic infections and spectrum of disease among pregnant women infected by Zika virus: systematic monitoring in French Guiana, 2016. ACTA ACUST UNITED AC 2018; 22. [PMID: 29113627 PMCID: PMC5710134 DOI: 10.2807/1560-7917.es.2017.22.44.17-00102] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Zika virus (ZIKV) infection has been associated with complications during pregnancy. Although the presence of symptoms might be a risk factor for complication, the proportion of ZIKV-infected pregnant women with symptoms remains unknown. Following the emergence of ZIKV in French Guiana, all pregnancies in the territory were monitored by RT-PCR and/or detection of ZIKV antibodies. Follow-up data collected during pregnancy monitoring interviews were analysed from 1 February to 1 June 2016. We enrolled 3,050 pregnant women aged 14–48 years and 573 (19%) had laboratory-confirmed ZIKV infection. Rash, arthralgia, myalgia and conjunctival hyperaemia were more frequently observed in ZIKV-positive women; 23% of them (95% confidence interval (CI): 20–27) had at least one symptom compatible with ZIKV infection. Women 30 years and older were significantly more likely to have symptoms than younger women (28% vs 20%). The proportion of symptomatic infections varied from 17% in the remote interior to 35% in the urbanised population near the coast (adjusted risk ratio: 1.6; 95% CI: 1.4–1.9.). These estimates put findings on cohorts of symptomatic ZIKV-positive pregnant women into the wider context of an epidemic with mainly asymptomatic infections. The proportion of symptomatic ZIKV infections appears to vary substantially between populations.
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Affiliation(s)
- Claude Flamand
- Epidemiology unit, Institut Pasteur in French Guiana, Cayenne, French Guiana
| | - Camille Fritzell
- Epidemiology unit, Institut Pasteur in French Guiana, Cayenne, French Guiana
| | - Séverine Matheus
- National Reference Center for arboviruses, Institut Pasteur in French Guiana, Cayenne, French Guiana
| | - Maryvonne Dueymes
- Laboratory, Centre Hospitalier Andrée Rosemon, Cayenne, French Guiana
| | - Gabriel Carles
- Gynaecology-Obstetrics Department, Centre Hospitalier de l'Ouest Guyanais, Saint-Laurent du Maroni, French Guiana
| | - Anne Favre
- Neonatology Department, Centre Hospitalier Andrée Rosemon, Cayenne, French Guiana
| | - Antoine Enfissi
- National Reference Center for arboviruses, Institut Pasteur in French Guiana, Cayenne, French Guiana
| | - Antoine Adde
- Epidemiology unit, Institut Pasteur in French Guiana, Cayenne, French Guiana
| | - Magalie Demar
- Laboratory, Centre Hospitalier Andrée Rosemon, Cayenne, French Guiana
| | - Mirdad Kazanji
- Epidemiology unit, Institut Pasteur in French Guiana, Cayenne, French Guiana
| | - Simon Cauchemez
- These authors contributed equally to the study.,Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris, France.,Centre National de la Recherche Scientifique, URA3012, Paris, France.,Mathematical Modelling of Infectious Diseases Unit, Institut Pasteur, Paris, France
| | - Dominique Rousset
- These authors contributed equally to the study.,National Reference Center for arboviruses, Institut Pasteur in French Guiana, Cayenne, French Guiana
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Epelboin S, Dulioust E, Epelboin L, Benachi A, Merlet F, Patrat C. Zika virus and reproduction: facts, questions and current management. Hum Reprod Update 2018; 23:629-645. [PMID: 28961800 DOI: 10.1093/humupd/dmx024] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 08/02/2017] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Zika virus (ZIKV) is an arthropod-borne virus of the family Flaviviridae, genus Flavivirus. ZIKV is currently the focus of an ongoing pandemic and worldwide public health emergency. Although originally isolated in 1947, its pathogenesis was poorly known and very few documented infections were published until recently. Its route of transmission and its impact on reproduction and pregnancy have only recently begun to be disclosed. OBJECTIVE AND RATIONALE This review summarizes the most recent knowledge about ZIKV infection and pathogenesis and focuses on its impacts on male and female genital tracts, including the risks of sexual transmission and to pregnancy. The consequences of ZIKV infection for pregnancy planning and ART are also discussed. SEARCH METHODS The PubMed and EMBASE databases were inter-rogated using specific terms, such as 'ZIKV', 'transmission', 'male', 'female', fertility', 'pregnancy, 'semen', 'testis', 'ovary' and 'genital tract', up to 17 March 2017. OUTCOMES ZIKV has long been considered a harmless virus, but increasing evidence suggests that it has adverse effects on the neurological system and on pregnancy outcomes. In mice, ZIKV slows foetal growth and damages the foetal brain. In humans, the virus is able to cross the placental barrier and to induce foetal death and major anomalies, such as microcephaly, brain defects and long-term neurologic sequelae, i.e. the 'congenital Zika syndrome'. In addition to its transmission by mosquitoes, ZIKV may be transmitted sexually. Currently available data indicate that ZIKV RNA can remain detectable in semen for several months, whereas shedding in the female genital tract appears to be rare and of short duration. Current guidance on preventing the sexual transmission of ZIKV is based on the assumption that transmission occurs from a male partner to a receptive partner. Furthermore, in mouse models, the virus can actively replicate in male genital organs and induce severe orchitis, which raises concerns about its possible impact on human male fertility. WIDER IMPLICATIONS These new and relevant findings have led many countries and institutions to release updated and regular guidance for preconception counselling and ART to prevent the sexual transmission of ZIKV. Progress in understanding the sexual transmission of ZIKV and its dissemination to genital systems would also help to better anticipate and control outbreaks of potentially sexually transmissible infectious agents.
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Affiliation(s)
- Sylvie Epelboin
- Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Service de Gynécologie, Obstétrique et Reproduction, 46 rue Henri Huchard, 75018 Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, France
| | - Emmanuel Dulioust
- Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Centre d'Etudes et de Conservation des Ovocytes et du Sperme, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.,Université Paris Descartes, Sorbonne Paris Cité, France
| | - Loïc Epelboin
- Hôpital Andrée Rosemon, Avenue des Flamboyants, Cayenne 97300, France.,Université de Guyane, Equipe EA 3593, Ecosystèmes Amazoniens et Pathologie Tropicale, Cayenne, Guyane Française
| | - Alexandra Benachi
- Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Antoine Béclère, Service de Gynécologie-Obstétrique, 147 rue de la Porte de Trivaux, 92140 Clamart, France.,Université Paris Sud, Clamart, France
| | - Françoise Merlet
- Agence de la Biomédecine, 1 Avenue du Stade de France, 93212 La Plaine Saint Denis, France
| | - Catherine Patrat
- Université Paris Diderot, Sorbonne Paris Cité, France.,Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Service de Biologie de la Reproduction, 46 rue Henri Huchard, 75018 Paris, France
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Abstract
Zika virus (ZIKV) infection is an emergent worldwide public health problem. Historically, 84 countries have reported vector-borne ZIKV transmission, 61 of which report on-going transmission. It is a Flavivirus transmitted through arthropods belonging to the Aedes genus. Since 2015, ZIKV infections have increased dramatically; with 1.3 million people infected during 2015 in Brazil alone. This paper's objective is to highlight the conjectural epidemiological points of the virus' dissemination. The digital archives Pubmed, MEDLINE, EMBASE and Cochrane were searched for papers that assessed aspects of ZIKV transmission and epidemiology. The first isolation occurred in Uganda in 1947. Since then, important outbreaks were documented globally. Consequently, an emergent public health problem arose from a rapidly increasing incidence and its association with the development of neurological diseases such as microcephaly and Guillain-Barré syndrome. Key factors in the successful containment of outbreaks include surveillance of mosquitos in the neighbourhood, an early mosquito control treatment, an assertive information campaign, and the involvement of the local population and healthcare workers. As such, while ZIKV seems to be spreading globally in a similar manner to other arboviruses, such as Dengue and Chikungunya viruses, it can also be rapidly contained due to the pre-existing availability of necessary resources and regulatory tools as control measures. This review aims to provide a description of those characteristics of ZIKV infection that may be useful in the construction of effective outbreak control strategies.
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Abstract
Despite being discovered approximately 70 years ago, Zika virus (ZIKV) has received little attention, until the occurrence of alarming epidemics in the Pacific Islands and Latin America between 2013 and 2016. These series of outbreaks resulted in crippling neurological complications in adults, and congenital deformities in new-borns. The dire outcomes marked ZIKV as a re-emerging pathogen of public health concern. Over a period of two years, extensive studies have been conducted to understand different aspects of ZIKV from pathogen biology to infection, including the immune response during virus-host interplay in established animal models, as well as potential therapeutics against ZIKV infection. The vast diversity of novel findings has added value to ZIKV research, and a strategic consolidation is crucial to encompass the latest advances and developments, as well as missing pieces of the puzzle. This review thus aims to provide a concise yet extensive update on current ZIKV studies.
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Affiliation(s)
- Cheryl Yi-Pin Lee
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
| | - Lisa F P Ng
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Infection and Global Health, University of Liverpool, UK.
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Braack L, Gouveia de Almeida AP, Cornel AJ, Swanepoel R, de Jager C. Mosquito-borne arboviruses of African origin: review of key viruses and vectors. Parasit Vectors 2018; 11:29. [PMID: 29316963 PMCID: PMC5759361 DOI: 10.1186/s13071-017-2559-9] [Citation(s) in RCA: 149] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 11/27/2017] [Indexed: 12/28/2022] Open
Abstract
Key aspects of 36 mosquito-borne arboviruses indigenous to Africa are summarized, including lesser or poorly-known viruses which, like Zika, may have the potential to escape current sylvatic cycling to achieve greater geographical distribution and medical importance. Major vectors are indicated as well as reservoir hosts, where known. A series of current and future risk factors is addressed. It is apparent that Africa has been the source of most of the major mosquito-borne viruses of medical importance that currently constitute serious global public health threats, but that there are several other viruses with potential for international challenge. The conclusion reached is that increased human population growth in decades ahead coupled with increased international travel and trade is likely to sustain and increase the threat of further geographical spread of current and new arboviral disease.
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Affiliation(s)
- Leo Braack
- School of Health Systems & Public Health, University of Pretoria, Pretoria, South Africa.
| | - A Paulo Gouveia de Almeida
- Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal.,Department of Medical Virology, University of Pretoria, Pretoria, South Africa
| | - Anthony J Cornel
- School of Health Systems & Public Health, University of Pretoria, Pretoria, South Africa.,Department of Entomology and Nematology, Mosquito Control Research Laboratory, Kearney Agricultural Center, UC Davis, Parlier, CA, USA
| | - Robert Swanepoel
- Department of Veterinary Tropical Diseases, University of Pretoria, Pretoria, South Africa
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Kong W, Li H, Zhu J. Zika virus: The transboundary pathogen from mosquito and updates. Microb Pathog 2018; 114:476-482. [DOI: 10.1016/j.micpath.2017.12.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 12/08/2017] [Accepted: 12/09/2017] [Indexed: 01/01/2023]
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Arragain L, Dupont-Rouzeyrol M, O'Connor O, Sigur N, Grangeon JP, Huguon E, Dechanet C, Cazorla C, Gourinat AC, Descloux E. Vertical Transmission of Dengue Virus in the Peripartum Period and Viral Kinetics in Newborns and Breast Milk: New Data. J Pediatric Infect Dis Soc 2017; 6:324-331. [PMID: 27760799 DOI: 10.1093/jpids/piw058] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Accepted: 08/01/2016] [Indexed: 11/13/2022]
Abstract
SUMMARY We investigated 10 mother-newborn pairs and found a 90% rate of dengue virus (DENV) transmission during the perinatal period. Here, we describe DENV kinetics in the sera of newborns before the onset of disease. Of the breast-milk samples analyzed, 75% tested positive for DENV. BACKGROUND Dengue is the most common mosquito-borne viral disease in humans. With this study, we aimed to investigate the risk of vertical (DENV) transmission during the peripartum period and to describe its viral kinetics in serum and breast milk. METHODS We carried out a prospective study during the 2012-2013 dengue epidemic in New Caledonia, its most severe on record. All mothers hospitalized at the Centre Hospitalier Territorial in Nouméa, New Caledonia, with symptoms of dengue infection between 7 days before and 2 days after delivery and/or whose infant was infected during breastfeeding were investigated. DENV was detected and quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) in sera and breast milk (mothers), sera and gastric fluid (newborns), cord blood, and placentas. DENV kinetics and sequences in sera and breast milk were studied. Clinical presentation and biological evolution in mother-newborn pairs were analyzed. RESULTS Ten mother-newborn pairs were investigated over an 11-month period. One premature birth, 3 hemorrhagic complications, and 1 maternal death occurred. Nine newborns were infected and symptomatic. One case of deep thrombocytopenia and 1 case of anoxic encephalopathy occurred. DENV was detected in breast milk samples from 9 (75%) of 12 infected breastfeeding mothers. Original DENV kinetics in sera and breast milk were described. CONCLUSIONS The occurrence of vertical DENV transmission was high (90%) in viremic mothers at delivery, and these mothers and their infants were at major risk for obstetric and neonatal complications. The modes of viral transmission are difficult to clarify. The risk of DENV transmission through breast milk seems plausible. Close follow-up of mothers and prolonged surveillance of their newborns are required for minimizing complications. Complementary studies are needed to elaborate preventive recommendations.
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Affiliation(s)
| | - Myrielle Dupont-Rouzeyrol
- Department of Dengue and Arboviruses Expertise and Research Unit, Institut Pasteur in New Caledonia, Institut Pasteur International Network
| | - Olivia O'Connor
- Department of Dengue and Arboviruses Expertise and Research Unit, Institut Pasteur in New Caledonia, Institut Pasteur International Network
| | - Nathalie Sigur
- Department of Neonatology, Centre Hospitalier Territorial
| | - Jean-Paul Grangeon
- Health Department, Direction of Health and Social Affairs of New Caledonia
| | - Emilie Huguon
- Department of Pediatrics, Centre Hospitalier Territorial
| | | | - Cécile Cazorla
- Internal Medicine and Infectious Diseases, Centre Hospitalier Territorial
| | - Ann-Claire Gourinat
- Immuno-Serology and Molecular Biology Lab, Institut Pasteur in New Caledonia, Institut Pasteur International Network, Nouméa
| | - Elodie Descloux
- Internal Medicine and Infectious Diseases, Centre Hospitalier Territorial
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Jaenisch T, Rosenberger KD, Brito C, Brady O, Brasil P, Marques ET. Risk of microcephaly after Zika virus infection in Brazil, 2015 to 2016. Bull World Health Organ 2017; 95:191-198. [PMID: 28250532 PMCID: PMC5328112 DOI: 10.2471/blt.16.178608] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Objective To estimate the risk of microcephaly in babies born to women infected by the Zika virus during pregnancy in Brazil in an epidemic between 2015 and 2016. Methods We obtained data on the number of notified and confirmed microcephaly cases in each Brazilian state between November 2015 and October 2016 from the health ministry. For Pernambuco State, one of the hardest hit, weekly data were available from August 2015 to October 2016 for different definitions of microcephaly. The absolute risk of microcephaly was calculated using the average number of live births reported in each state in the corresponding time period between 2012 and 2014 and assuming two infection rates: 10% and 50%. The relative risk was estimated using the reported background frequency of microcephaly in Brazil of 1.98 per 10 000 live births. Findings The estimated absolute risk of a notified microcephaly case varied from 0.03 to 17.1% according to geographical area, the definition of microcephaly used and the infection rate. Assuming a 50% infection rate, there was an 18–127 fold higher probability of microcephaly in children born to mothers with infection during pregnancy compared with children born to mothers without infection during pregnancy in Pernambuco State. For a 10% infection rate, the probability was 88–635 folds higher. Conclusion A large variation in the estimated risk of microcephaly was found in Brazil. Research is needed into possible effect modifiers, reliable measures of Zika virus infection and clear endpoints for congenital malformations.
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Affiliation(s)
- Thomas Jaenisch
- Section of Clinical Tropical Medicine, Department of Infectious Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 324, Heidelberg, 69120, Germany
| | - Kerstin Daniela Rosenberger
- Section of Clinical Tropical Medicine, Department of Infectious Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 324, Heidelberg, 69120, Germany
| | - Carlos Brito
- Department of Internal Medicine, Federal University of Pernambuco, Recife, Brazil
| | - Oliver Brady
- Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, England
| | | | - Ernesto Ta Marques
- Virology and Experimental Therapeutics Laboratory, Aggeu Magalhães Research Center, Recife, Brazil
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Mace P, Milh M, Girard N, Sigaudy S, Quarello E. [How to deal with a fetal head circumference lower than the third percentile?]. ACTA ACUST UNITED AC 2017; 45:491-511. [PMID: 28870427 DOI: 10.1016/j.gofs.2017.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 07/17/2017] [Indexed: 11/29/2022]
Abstract
The prenatal finding of a head circumference (HC) below the 3rd percentile (p) remains, in the same way as short femur or increased nuchal translucency with normal karyotype, one the most difficult situations for the praticionner in the setting of prenatal diagnosis. Microcephaly is a gateway to possible cerebral pathologies, but the main objective is to identify serious prenatal situations. A standardized HC measurement, the use of adapted reference tools and charts, longitudinal following of cephalic biometrics in high-risk situations, and systematic central nervous system analysis can increase the diagnostic performance of ultrasound which is often disappointing for microcephaly. The early distinction between associated or isolated microcephaly makes it possible to quickly orient the prenatal management and counseling. Fetal MRI and genetic counseling are fundamental in this context, making it possible to specify at best the etiological diagnosis and to provide assistance to the neuropediatrician in the establishment of an often uncertain prognosis. The recent increase in cases of microcephaly concomitant with the epidemic of the ZIKA virus is an additional argument to improve our practices and the daily apprehension of HC<3rd p.
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Affiliation(s)
- P Mace
- Centre de diagnostic prénatal, hôpital La Timone enfant, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France
| | - M Milh
- Centre de diagnostic prénatal, hôpital La Timone enfant, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France; Service de neurologie pédiatrique, hôpital La Timone enfants, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France; Inserm, GMGF UMR_S 910, Aix Marseille université, 13385 Marseille, France
| | - N Girard
- CRMBM UMR CNRS 7339, faculté de médecine, Aix Marseille université (AMU), 13385 Marseille, France; Service de neuroradiologie diagnostique et interventionnelle, hôpital La Timone, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France
| | - S Sigaudy
- Centre de diagnostic prénatal, hôpital La Timone enfant, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France; Département de génétique médicale, hôpital La Timone enfant, AP-HM, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France
| | - E Quarello
- Unité d'échographie et de diagnostic prénatal, hôpital Saint-Joseph, 26, boulevard de Louvain, 13285 Marseille cedex 08, France; Institut de médecine de la reproduction, 6, rue Rocca, 13008 Marseille, France.
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Westra SJ. Prenatal screening for Zika encephalopathy with ultrasound: what is the optimal time window? THE LANCET. CHILD & ADOLESCENT HEALTH 2017; 1:6-8. [PMID: 30169228 DOI: 10.1016/s2352-4642(17)30002-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 06/01/2017] [Accepted: 06/02/2017] [Indexed: 06/08/2023]
Affiliation(s)
- Sjirk Jan Westra
- Department of Radiology, Massachusetts General Hospital, Boston, MA 02114, USA.
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Saiz JC, Martín-Acebes MA, Bueno-Marí R, Salomón OD, Villamil-Jiménez LC, Heukelbach J, Alencar CH, Armstrong PK, Ortiga-Carvalho TM, Mendez-Otero R, Rosado-de-Castro PH, Pimentel-Coelho PM. Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic? Front Microbiol 2017; 8:1554. [PMID: 28878742 PMCID: PMC5572254 DOI: 10.3389/fmicb.2017.01554] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 07/31/2017] [Indexed: 01/03/2023] Open
Abstract
Zika is a viral disease transmitted mainly by mosquitoes of the genus Aedes. In recent years, it has expanded geographically, changing from an endemic mosquito-borne disease across equatorial Asia and Africa, to an epidemic disease causing large outbreaks in several areas of the world. With the recent Zika virus (ZIKV) outbreaks in the Americas, the disease has become a focus of attention of public health agencies and of the international research community, especially due to an association with neurological disorders in adults and to the severe neurological and ophthalmological abnormalities found in fetuses and newborns of mothers exposed to ZIKV during pregnancy. A large number of studies have been published in the last 3 years, revealing the structure of the virus, how it is transmitted and how it affects human cells. Many different animal models have been developed, which recapitulate several features of ZIKV disease and its neurological consequences. Moreover, several vaccine candidates are now in active preclinical development, and three of them have already entered phase I clinical trials. Likewise, many different compounds targeting viral and cellular components are being tested in in vitro and in experimental animal models. This review aims to discuss the current state of this rapidly growing literature from a multidisciplinary perspective, as well as to present an overview of the public health response to Zika and of the perspectives for the prevention and treatment of this disease.
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Affiliation(s)
- Juan-Carlos Saiz
- Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y AlimentariaMadrid, Spain
| | - Miguel A. Martín-Acebes
- Department of Biotechnology, Instituto Nacional de Investigación y Tecnología Agraria y AlimentariaMadrid, Spain
| | - Rubén Bueno-Marí
- Departamento de Investigación y Desarrollo (I+D), Laboratorios LokímicaValencia, Spain
| | | | | | - Jorg Heukelbach
- Department of Community Health, School of Medicine, Federal University of CearáFortaleza, Brazil
- College of Public Health, Medical and Veterinary Sciences, Division of Tropical Health and Medicine, James Cook University, TownsvilleQLD, Australia
| | - Carlos H. Alencar
- Department of Community Health, School of Medicine, Federal University of CearáFortaleza, Brazil
| | - Paul K. Armstrong
- Communicable Disease Control Directorate, Western Australia Department of Health, PerthWA, Australia
| | - Tania M. Ortiga-Carvalho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil
| | - Rosalia Mendez-Otero
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil
| | - Paulo H. Rosado-de-Castro
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil
- Instituto D’Or de Pesquisa e EnsinoRio de Janeiro, Brazil
| | - Pedro M. Pimentel-Coelho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de JaneiroRio de Janeiro, Brazil
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Tutiven JL, Pruden BT, Banks JS, Stevenson M, Birnbach DJ. Zika Virus: Obstetric and Pediatric Anesthesia Considerations. Anesth Analg 2017; 124:1918-1929. [PMID: 28525510 DOI: 10.1213/ane.0000000000002047] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
As of November 2016, the Florida Department of Health (FDH) and the Centers for Disease Control and Prevention have confirmed more than 4000 travel-related Zika virus (ZIKV) infections in the United States with >700 of those in Florida. There have been 139 cases of locally acquired infection, all occurring in Miami, Florida. Within the US territories (eg, Puerto Rico, US Virgin Islands), >30,000 cases of ZIKV infection have been reported. The projected number of individuals at risk for ZIKV infection in the Caribbean and Latin America approximates 5 million. Similar to Dengue and Chikungunya viruses, ZIKV is spread to humans by infected Aedes aegypti mosquitoes, through travel-associated local transmission, via sexual contact, and through blood transfusions. South Florida is an epicenter for ZIKV infection in the United States and the year-round warm climate along with an abundance of mosquito vectors that can harbor the flavivirus raise health care concerns. ZIKV infection is generally mild with clinical manifestations of fever, rash, conjunctivitis, and arthralgia. Of greatest concern, however, is growing evidence for the relationship between ZIKV infection of pregnant women and increased incidence of abnormal pregnancies and congenital abnormalities in the newborn, now medically termed ZIKA Congenital Syndrome. Federal health officials are observing 899 confirmed Zika-positive pregnancies and the FDH is currently monitoring 110 pregnant women with evidence of Zika infection. The University of Miami/Jackson Memorial Hospital is uniquely positioned just north of downtown Miami and within the vicinity of Liberty City, Little Haiti, and Miami Beach, which are currently "hot spots" for Zika virus exposure and transmissions. As the FDH works fervently to prevent a Zika epidemic in the region, health care providers at the University of Miami and Jackson Memorial Hospital prepare for the clinical spectrum of ZIKV effects as well as the safe perioperative care of the parturients and their affected newborns. In an effort to meet anesthetic preparedness for the care of potential Zika-positive patients and perinatal management of babies born with ZIKA Congenital Syndrome, this review highlights the interim guidelines from the Centers for Disease Control and Prevention and also suggest anesthetic implications and recommendations. In addition, this article reviews guidance for the evaluation and anesthetic management of infants with congenital ZIKV infection. To better manage the perioperative care of affected newborns, this article also reviews the comparative anesthetic implications of babies born with related congenital malformations.
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Affiliation(s)
- Jacqueline L Tutiven
- From *Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, Florida; †Jackson Memorial Hospital, Miami, Florida; ‡Department of Radiology, University of Miami Miller School of Medicine, Miami, Florida; §Division of Infectious Diseases, Department of Medicine, University of Miami, Miami Miller School of Medicine, Miami, Florida; and ‖UM-JMH Center for Patient Safety, Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, Florida
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Azar SR, Roundy CM, Rossi SL, Huang JH, Leal G, Yun R, Fernandez-Salas I, Vitek CJ, Paploski IAD, Stark PM, Vela J, Debboun M, Reyna M, Kitron U, Ribeiro GS, Hanley KA, Vasilakis N, Weaver SC. Differential Vector Competency of Aedes albopictus Populations from the Americas for Zika Virus. Am J Trop Med Hyg 2017; 97:330-339. [PMID: 28829735 PMCID: PMC5544086 DOI: 10.4269/ajtmh.16-0969] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 02/22/2017] [Indexed: 01/15/2023] Open
Abstract
To evaluate the potential role of Aedes albopictus (Skuse) as a vector of Zika virus (ZIKV), colonized mosquitoes of low generation number (≤ F5) from Brazil, Houston, and the Rio Grande Valley of Texas engorged on viremic mice infected with ZIKV strains originating from Senegal, Cambodia, Mexico, Brazil, or Puerto Rico. Vector competence was established by monitoring infection, dissemination, and transmission potential after 3, 7, and 14 days of extrinsic incubation. Positive saliva samples were assayed for infectious titer. Although all three mosquito populations were susceptible to all ZIKV strains, rates of infection, dissemination, and transmission differed among mosquito and virus strains. Aedes albopictus from Salvador, Brazil, were the least efficient vectors, demonstrating susceptibility to infection to two American strains of ZIKV but failing to shed virus in saliva. Mosquitoes from the Rio Grande Valley were the most efficient vectors and were capable of shedding all three tested ZIKV strains into saliva after 14 days of extrinsic incubation. In particular, ZIKV strain DakAR 41525 (Senegal 1954) was significantly more efficient at dissemination and saliva deposition than the others tested in Rio Grande mosquitoes. Overall, our data indicate that, while Ae. albopictus is capable of transmitting ZIKV, its competence is potentially dependent on geographic origin of both the mosquito population and the viral strain.
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Affiliation(s)
- Sasha R. Azar
- Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas
- Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
| | - Christopher M. Roundy
- Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas
- Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
| | - Shannan L. Rossi
- Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas
- Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas
| | - Jing H. Huang
- Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas
- Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas
| | - Grace Leal
- Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas
- Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas
| | - Ruimei Yun
- Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas
- Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas
| | | | | | - Igor A. D. Paploski
- Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Candeal, Salvador, Brazil
- Instituto de Saúde Coletiva, Universidade Federal da Bahia, Salvador, Brazil
| | - Pamela M. Stark
- Mosquito and Vector Control Division, Harris County Public Health, Houston, Texas
| | - Jeremy Vela
- Mosquito and Vector Control Division, Harris County Public Health, Houston, Texas
| | - Mustapha Debboun
- Mosquito and Vector Control Division, Harris County Public Health, Houston, Texas
| | - Martin Reyna
- Mosquito and Vector Control Division, Harris County Public Health, Houston, Texas
| | - Uriel Kitron
- Population Biology, Ecology, and Evolution Graduate Program, Graduate Division of Biological and Biomedical Sciences, Department of Environmental Sciences, Emory University, Atlanta, Georgia
| | - Guilherme S. Ribeiro
- Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Ministério da Saúde, Candeal, Salvador, Brazil
- Instituto de Saúde Coletiva, Universidade Federal da Bahia, Salvador, Brazil
| | - Kathryn A. Hanley
- Department of Biology, New Mexico State University, Las Cruces, New Mexico
| | - Nikos Vasilakis
- Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas
- Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas
| | - Scott C. Weaver
- Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas
- Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas
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Song BH, Yun SI, Woolley M, Lee YM. Zika virus: History, epidemiology, transmission, and clinical presentation. J Neuroimmunol 2017; 308:50-64. [DOI: 10.1016/j.jneuroim.2017.03.001] [Citation(s) in RCA: 148] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 03/01/2017] [Accepted: 03/01/2017] [Indexed: 10/20/2022]
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Bueno FTC. Vigilância e resposta em saúde no plano regional: um estudo preliminar do caso da febre do Zika vírus. CIENCIA & SAUDE COLETIVA 2017; 22:2305-2314. [DOI: 10.1590/1413-81232017227.07012017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 11/28/2016] [Indexed: 11/22/2022] Open
Abstract
Resumo Apesar de ser conhecido desde os anos 50, o Zika vírus não havia despertado interesse da comunidade internacional. Entre 2015 e 2016, o vírus se alastrou pelo Brasil com a suspeita de que o aumento de casos de distúrbios neurológicos poderia ter vínculos com a infecção, configurando uma Emergência Nacional de Saúde Pública em novembro de 2015. Em 1º de fevereiro de 2016, a OMS declarou esta suspeita como uma Emergência de Saúde Pública de Importância Internacional (ESPII), deflagrando resposta conforme o Regulamento Sanitário Internacional (2005). O Zika está presente também em quase todos os países da América do Sul. Nesse sentido, organizações internacionais como a OPAS/OMS, Unasul e Mercosul estão desenvolvendo ações de resposta à epidemia. O objetivo deste artigo é analisar criticamente as respostas regional sul-americana e brasileira de fevereiro a setembro de 2016 com relação à esta declaração de ESPII, utilizando metodologia qualitativa, por meio do levantamento bibliográfico e análise documental. Nesse contexto, a OPAS/OMS teve atuação destacada em relação às demais organizações. Além disso, a conjuntura política da região parece ter papel importante na instabilidade do Mercosul e da Unasul, o que pode afetar sua capacidade e efetividade de resposta.
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Abstract
In February 2016, the World Health Organization declared Zika virus (ZIKV) infection a public health emergency of international concern, given the precipitous spread of the virus across the Americas. Unlike arboviruses such as Chikungunya and Dengue, which have also recently emerged in the western hemisphere, ZIKV was identified in communities where concurrent neurologic conditions such as microcephaly and Guillain-Barre (GB) syndrome were occurring at alarming rates. Thus, investigations to systematically evaluate the link between ZIKV, congenital malformations (including microcephaly) and GB syndrome remain a top priority.
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Affiliation(s)
- Candice J McNeil
- Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Avinash K Shetty
- Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
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Pomar L, Malinger G, Benoist G, Carles G, Ville Y, Rousset D, Hcini N, Pomar C, Jolivet A, Lambert V. Association between Zika virus and fetopathy: a prospective cohort study in French Guiana. ULTRASOUND IN OBSTETRICS & GYNECOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY 2017; 49:729-736. [PMID: 28078779 DOI: 10.1002/uog.17404] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 12/27/2016] [Accepted: 01/09/2017] [Indexed: 06/06/2023]
Abstract
OBJECTIVE To establish the incidence of fetal central nervous system (CNS) anomalies (including microcephaly), signs of congenital infection and fetal loss in pregnant women infected with Zika virus (ZIKV) and non-infected pregnant women in western French Guiana. METHODS This prospective cohort study was conducted between 1 January and 15 July 2016. We evaluated and compared clinical and fetal ultrasound examinations of 301 pregnant women with biological confirmation of ZIKV infection and 399 pregnant women who were negative for ZIKV infection. RESULTS Overall, the total number of fetuses with CNS involvement was higher in the infected than in the control group (9.0% vs 4.3%; relative risk, 2.11 (95% CI, 1.18-4.13)). Anomalies of the corpus callosum and presence of cerebral hyperechogenicities were significantly more common in the infected group. There was an increased risk of microcephaly in the infected compared with the control group (1.7% vs 0.3%; relative risk, 6.63 (95% CI, 0.78-57.83)), although this was not statistically significant. When the mother was infected during the first or second trimester, there was a greater risk of severe CNS involvement, more signs of infection and intrauterine fetal death than with infection in the third trimester. The rate of vertical transmission in the exposed group was 10.9%. CONCLUSION ZIKV infection during pregnancy is associated with a significant risk of fetal CNS involvement and intrauterine fetal death, particularly when infection occurs during the first or second trimesters. Microcephaly was not present in every case of congenital ZIKV syndrome that we observed. Until more is known about this disease, it is paramount to evaluate suspected cases by detailed neurosonography on a monthly basis, paying particular attention to the corpus callosum and the presence of hyperechogenic foci. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
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Affiliation(s)
- L Pomar
- Department of Obstetrics and Gynecology, St-Laurent du Maroni's Hospital, Centre Hospitalier de l'Ouest Guyanais, Saint-Laurent du Maroni, French Guiana
| | - G Malinger
- Division of Ultrasound in Obstetrics and Gynecology, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - G Benoist
- Service de Gynécologie-Obstétrique et Médecine de la Reproduction, CHU de Caen, Université de Caen, Caen, Normandy, France
| | - G Carles
- Department of Obstetrics and Gynecology, St-Laurent du Maroni's Hospital, Centre Hospitalier de l'Ouest Guyanais, Saint-Laurent du Maroni, French Guiana
| | - Y Ville
- Department of Obstetrics and Fetal Medicine, Université Paris Descartes, Hospital Necker-Enfants Malades, Paris, France
| | - D Rousset
- Institut Pasteur of French Guiana, Laboratory of Virology, National Referral Center for Arboviruses, Cayenne, French Guiana
| | - N Hcini
- Department of Obstetrics and Gynecology, St-Laurent du Maroni's Hospital, Centre Hospitalier de l'Ouest Guyanais, Saint-Laurent du Maroni, French Guiana
| | - C Pomar
- Department of Obstetrics and Gynecology, St-Laurent du Maroni's Hospital, Centre Hospitalier de l'Ouest Guyanais, Saint-Laurent du Maroni, French Guiana
| | - A Jolivet
- Sorbonne Universités, UPMC Universités Paris 06, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Department of Social Epidemiology, Paris, France
- Public Health Department, St-Laurent du Maroni's Hospital, Centre Hospitalier de l'Ouest Guyanais, Saint-Laurent du Maroni, French Guiana
| | - V Lambert
- Department of Obstetrics and Gynecology, St-Laurent du Maroni's Hospital, Centre Hospitalier de l'Ouest Guyanais, Saint-Laurent du Maroni, French Guiana
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Bookstaver PB, Mohorn PL, Shah A, Tesh LD, Quidley AM, Kothari R, Bland CM, Weissman S. Management of Viral Central Nervous System Infections: A Primer for Clinicians. J Cent Nerv Syst Dis 2017; 9:1179573517703342. [PMID: 28579869 PMCID: PMC5415352 DOI: 10.1177/1179573517703342] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 01/22/2017] [Indexed: 12/11/2022] Open
Abstract
Viruses are a common cause of central nervous system (CNS) infections with many host, agent, and environmental factors influencing the expression of viral diseases. Viruses can be responsible for CNS disease through a variety of mechanisms including direct infection and replication within the CNS resulting in encephalitis, infection limited to the meninges, or immune-related processes such as acute disseminated encephalomyelitis. Common pathogens including herpes simplex virus, varicella zoster, and enterovirus are responsible for the greatest number of cases in immunocompetent hosts. Other herpes viruses (eg, cytomegalovirus, John Cunningham virus) are more common in immunocompromised hosts. Arboviruses such as Japanese encephalitis virus and Zika virus are important pathogens globally, but the prevalence varies significantly by geographic region and often season. Early diagnosis from radiographic evidence and molecular (eg, rapid) diagnostics is important for targeted therapy. Antivirals may be used effectively against some pathogens, although several viruses have no effective treatment. This article provides a review of epidemiology, diagnostics, and management of common viral pathogens in CNS disease.
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Affiliation(s)
- P Brandon Bookstaver
- Department of Clinical Pharmacy and Outcomes Sciences, University of South Carolina College of Pharmacy, Columbia, SC, USA
| | - Phillip L Mohorn
- Department of Pharmacy, Spartanburg Medical Center, Spartanburg Regional Healthcare System, Spartanburg, SC, USA
| | - Ansal Shah
- Division of Infectious Diseases, School of Medicine, University of South Carolina, Columbia, SC, USA
| | - Lauren D Tesh
- Division of Advisory Committee and Consultant Management, Office of Executive Programs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - April M Quidley
- Department of Pharmacy Services, Vidant Medical Center, Greenville, NC, USA
| | - Ravish Kothari
- Department of Neurology, University of South Carolina/Palmetto Medical Group, Columbia, SC, USA
| | - Christopher M Bland
- Department of Clinical and Administrative Pharmacy, University of Georgia College of Pharmacy, Savannah, GA, USA
| | - Sharon Weissman
- Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, University of South Carolina, Columbia, SC, USA
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From the perception of a cluster of cases of children with microcephaly to congenital Zika syndrome in Brazil: the lessons we have learned and the challenges that lie ahead of us. J Venom Anim Toxins Incl Trop Dis 2017; 23:15. [PMID: 28331488 PMCID: PMC5359848 DOI: 10.1186/s40409-017-0107-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 03/07/2017] [Indexed: 11/10/2022] Open
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Widman DG, Young E, Yount BL, Plante KS, Gallichotte EN, Carbaugh DL, Peck KM, Plante J, Swanstrom J, Heise MT, Lazear HM, Baric RS. A Reverse Genetics Platform That Spans the Zika Virus Family Tree. mBio 2017; 8:e02014-16. [PMID: 28270583 PMCID: PMC5340872 DOI: 10.1128/mbio.02014-16] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 02/14/2017] [Indexed: 01/08/2023] Open
Abstract
Zika virus (ZIKV), a mosquito-borne flavivirus discovered in 1947, has only recently caused large outbreaks and emerged as a significant human pathogen. In 2015, ZIKV was detected in Brazil, and the resulting epidemic has spread throughout the Western Hemisphere. Severe complications from ZIKV infection include neurological disorders such as Guillain-Barré syndrome in adults and a variety of fetal abnormalities, including microcephaly, blindness, placental insufficiency, and fetal demise. There is an urgent need for tools and reagents to study the pathogenesis of epidemic ZIKV and for testing vaccines and antivirals. Using a reverse genetics platform, we generated six ZIKV infectious clones and derivative viruses representing diverse temporal and geographic origins. These include three versions of MR766, the prototype 1947 strain (with and without a glycosylation site in the envelope protein), and H/PF/2013, a 2013 human isolate from French Polynesia representative of the virus introduced to Brazil. In the course of synthesizing a clone of a circulating Brazilian strain, phylogenetic studies identified two distinct ZIKV clades in Brazil. We reconstructed viable clones of strains SPH2015 and BeH819015, representing ancestral members of each clade. We assessed recombinant virus replication, binding to monoclonal antibodies, and virulence in mice. This panel of molecular clones and recombinant virus isolates will enable targeted studies of viral determinants of pathogenesis, adaptation, and evolution, as well as the rational attenuation of contemporary outbreak strains to facilitate the design of vaccines and therapeutics.IMPORTANCE Viral emergence is a poorly understood process as evidenced by the sudden emergence of Zika virus in Latin America and the Caribbean. Malleable reagents that both predate and span an expanding epidemic are key to understanding the virologic determinants that regulate pathogenesis and transmission. We have generated representative cDNA molecular clones and recombinant viruses that span the known ZIKV family tree, including early Brazilian isolates. Recombinant viruses replicated efficiently in cell culture and were pathogenic in immunodeficient mice, providing a genetic platform for rational vaccine and therapeutic design.
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Affiliation(s)
- Douglas G Widman
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Ellen Young
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Boyd L Yount
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Kenneth S Plante
- Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Emily N Gallichotte
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Derek L Carbaugh
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Kayla M Peck
- Department of Biology, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Jessica Plante
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Jesica Swanstrom
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Mark T Heise
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
- Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Helen M Lazear
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Ralph S Baric
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
- Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
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50
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Abstract
Our understanding of the effects of maternal Zika virus infection on the newborn continues to evolve. First discovered in 1947 in the Zika Forest in Uganda, the world became more aware of the virus in 2015, with reports of hundreds of cases of microcephaly in Brazilian newborns whose mothers reported symptoms related to Zika viral infection during pregnancy. This article reviews the current guidelines for laboratory evaluation of newborns with possible congenital Zika virus infection.
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