#Subclinical in #utero #Zika virus #infection is associated with #interferon alpha #sequelae and sex-specific molecular #brain #pathology in asymptomatic porcine offspring (PLoS Pathog., abstract)

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

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Subclinical in utero Zika virus infection is associated with interferon alpha sequelae and sex-specific molecular brain pathology in asymptomatic porcine offspring

Ivan Trus , Daniel Udenze, Brian Cox , Nathalie Berube, Rebecca E. Nordquist, Franz Josef van der Staay, Yanyun Huang, Gary Kobinger, David Safronetz, Volker Gerdts, Uladzimir Karniychuk

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Published: November 14, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008038

 

Abstract

Zika virus (ZIKV) infection during human pregnancy may lead to severe fetal pathology and debilitating impairments in offspring. However, the majority of infections are subclinical and not associated with evident birth defects. Potentially detrimental life-long health outcomes in asymptomatic offspring evoke high concerns. Thus, animal models addressing sequelae in offspring may provide valuable information. To induce subclinical infection, we inoculated selected porcine fetuses at the mid-stage of development. Inoculation resulted in trans-fetal virus spread and persistent infection in the placenta and fetal membranes for two months. Offspring did not show congenital Zika syndrome (e.g., microcephaly, brain calcifications, congenital clubfoot, arthrogryposis, seizures) or other visible birth defects. However, a month after birth, a portion of offspring exhibited excessive interferon alpha (IFN-α) levels in blood plasma in a regular environment. Most affected offspring also showed dramatic IFN-α shutdown during social stress providing the first evidence for the cumulative impact of prenatal ZIKV exposure and postnatal environmental insult. Other eleven cytokines tested before and after stress were not altered suggesting the specific IFN-α pathology. While brains from offspring did not have histopathology, lesions, and ZIKV, the whole genome expression analysis of the prefrontal cortex revealed profound sex-specific transcriptional changes that most probably was the result of subclinical in utero infection. RNA-seq analysis in the placenta persistently infected with ZIKV provided independent support for the sex-specific pattern of in utero-acquired transcriptional responses. Collectively, our results provide strong evidence that two hallmarks of fetal ZIKV infection, altered type I IFN response and molecular brain pathology can persist after birth in offspring in the absence of congenital Zika syndrome.

 

Author summary

A number of studies showed that Zika virus (ZIKV) can cause severe abnormalities in fetuses, e.g., brain lesions, and subsequently life-long developmental and cognitive impairment in children. However, the majority of infections in pregnant women are subclinical and are not associated with developmental abnormalities in fetuses and newborns. It is known that disruptions to the in utero environment during fetal development can program increased risks for disease in adulthood. For this reason, children affected in utero even by mild ZIKV infection can appear deceptively healthy at birth but develop immune dysfunction and brain abnormalities during postnatal development. Here, we used the porcine model of subclinical fetal ZIKV infection to determine health sequelae in offspring which did not show apparent signs of the disease. We demonstrated that subclinical fetal infection was associated with abnormal immunological responses in apparently healthy offspring under normal environmental conditions and during social stress. We also showed silent sex-specific brain pathology as represented by altered gene expression. Our study provides new insights into potential outcomes of subclinical in utero ZIKV infection. It also emphasizes that further attempts to better understand silent pathology and develop alleviative interventions in ZIKV-affected offspring should take into account interactions of host factors, like sex, and environmental insults, like social stress.

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Citation: Trus I, Udenze D, Cox B, Berube N, Nordquist RE, van der Staay FJ, et al. (2019) Subclinical in utero Zika virus infection is associated with interferon alpha sequelae and sex-specific molecular brain pathology in asymptomatic porcine offspring. PLoS Pathog 15(11): e1008038. https://doi.org/10.1371/journal.ppat.1008038

Editor: Ted C. Pierson, NIH, UNITED STATES

Received: May 8, 2019; Accepted: August 21, 2019; Published: November 14, 2019

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

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

Funding: Financial support was provided by Genome Canada, Emerging Issue Program grant #418402, the Public Health Agency of Canada and the Government of Saskatchewan through Innovation Saskatchewan #418836. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. https://www.genomecanada.ca/ https://innovationsask.ca/research/saskatchewan-advantage-innovation-fund

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

Keywords: Zika Virus; Pregnancy; Zika Congenital Infection; Zika Congenital Syndrome; Animal models.

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#Clinical #findings in #congenital #infection by #Zika virus: a retrospective study in a reference hospital in Central-West #Brazil (BMC Pediatr., abstract)

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

BMC Pediatr. 2019 Oct 29;19(1):389. doi: 10.1186/s12887-019-1762-6.

Clinical findings in congenital infection by Zika virus: a retrospective study in a reference hospital in Central-West Brazil.

de Paula Guimarães C1, Macedo MS2, Barbosa MA3, Marques SM4, Costa PS4, de Oliveira ÊC4.

Author information: 1 Hospital das Clínicas da UFG/EBSERH, Goiânia, GO, Brazil. enfguimaraes@yahoo.com.br. 2 Secretaria Municipal de Saúde, Goiânia, GO, Brazil. 3 Faculdade de Enfermagem da UFG, Goiânia, GO, Brazil. 4 Faculdade de Medicina da UFG, Goiânia, GO, Brazil.

 

Abstract

BACKGROUND:

An increased number of congenital Zika virus infections with neurological and musculoskeletal malformations have been diagnosed worldwide, however, there are still several gaps in the knowledge about this infection, its associated mechanism, timing of transmission, and description of throughout findings of signs and symptoms, which is described in this paper. The purpose of this study is to describe aspects of congenital Zika syndrome (CZS) beyond the central nervous system comprising detailed delineation of all the other clinical findings.

METHODS:

A retrospective research developed using electronic medical records. We analyzed the files of 69 children with an initial diagnosis of microcephaly by Zika vírus who were born in 2015, 2016 and 2017, treated during the period from 2016 to 2017.

RESULTS:

The newborns presented several neurological and musculoskeletal malformations, eye damage, hearing impairment and other malformations.

CONCLUSIONS:

The present study has significant impact for health care teams following lactents with Congenital Zika Syndrome.

KEYWORDS: Malformations; Microcephaly; Zika virus

PMID: 31660908 DOI: 10.1186/s12887-019-1762-6

Keywords: Zika Virus; Zika Congenital Syndrome; Pediatrics; Brazil.

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#Congenital #Zika Syndrome in a #Brazil – #Paraguay – #Bolivia #border region: #Clinical features of cases diagnosed between 2015 and 2018 (PLoS One, abstract)

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

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Congenital Zika Syndrome in a Brazil-Paraguay-Bolivia border region: Clinical features of cases diagnosed between 2015 and 2018

Fabio Antonio Venancio  , Maria Eulina Quilião Bernal , Maria da Conceição de Barros Vieira Ramos, Neuma Rocha Chaves, Marcos Vinicius Hendges, Mattheus Marques Rodrigues de Souza, Márcio José de Medeiros , Cláudia Du Bocage Santos Pinto , Everton Falcão de Oliveira

Published: October 4, 2019 / DOI: https://doi.org/10.1371/journal.pone.0223408

 

Abstract

Congenital Zika Syndrome (CZS) is a unique pattern of congenital abnormalities found in fetuses and neonates infected with the Zika virus (ZIKV). Here, we clinically identify and characterize infants with CZS between 2015 and 2018 in Mato Grosso do Sul, Brazil—a border area with Paraguay and Bolivia. This cross-sectional study, based on primary and secondary data, tracks the cases registered in the Brazilian Public Health Reporting System through the following stages: (1) preliminary data analysis, (2) identification of the congenital syndrome cases, (3) etiologic classification of the cases, (4) active search, and (5) clinical assessment. Of the 72 investigated cases, 16 were probable cases of CZS. Of these, it was only possible to clinically assess 11 infants. Considering the 16 probable cases of CZS, nine were classified as confirmed cases, and five as potential cases of the syndrome. Regarding clinical features, brain palsy was identified in all analyzed infants. Moreover, microcephaly and pseudobulbar syndrome were found in eight infants, and hydrocephalus was found in three individuals. In addition to these conditions, seven children were malnourished. Our study may provide significant insights for other researches that aim to elucidate CZS and its clinical and populational consequences.

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Citation: Venancio FA, Bernal MEQ, Ramos MdCdBV, Chaves NR, Hendges MV, Souza MMRd, et al. (2019) Congenital Zika Syndrome in a Brazil-Paraguay-Bolivia border region: Clinical features of cases diagnosed between 2015 and 2018. PLoS ONE 14(10): e0223408. https://doi.org/10.1371/journal.pone.0223408

Editor: Angela Lupattelli, University of Oslo, NORWAY

Received: July 16, 2019; Accepted: September 21, 2019; Published: October 4, 2019

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

Data Availability: All relevant data are within the paper.

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

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

Keywords: Zika Virus; Zika Congenital Syndrome; Microcephaly; Brazil; Paraguay; Bolivia; Neurology; Pediatrics.

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The association of #depression, #anxiety, and #stress with #caring for a #child with Congenital #Zika #Syndrome in #Brazil; Results of a cross-sectional study (PLoS Negl Trop Dis., abstract)

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

PLoS Negl Trop Dis. 2019 Sep 30;13(9):e0007768. doi: 10.1371/journal.pntd.0007768. [Epub ahead of print]

The association of depression, anxiety, and stress with caring for a child with Congenital Zika Syndrome in Brazil; Results of a cross-sectional study.

Kuper H1, Lopes Moreira ME2, Barreto de Araújo TV3, Valongueiro S3, Fernandes S4, Pinto M2, Lyra TM5,6.

Author information: 1 International Centre for Evidence in Disability, Clinical Research Department, London School of Hygiene & Tropical Medicine, London, United Kingdom. 2 Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira, Fundação Oswaldo Cruz, Rio de Janeiro, Brasil. 3 Postgraduate Programme in Public Health, Federal University of Pernambuco, Recife, Brazil. 4 Faculty of Public Health and Policy, London School of Hygiene & Tropical Medicine, London, United Kingdom. 5 Aggeu Magalhães Institute, FIOCRUZ/PE, Recife, Brazil. 6 Faculty of Medicine, University of Pernambuco, Recife, Brazil.

 

Abstract

BACKGROUND:

Zika virus (ZIKV) infection in pregnancy can cause microcephaly and a wide spectrum of severe adverse outcomes, collectively called “Congenital Zika Syndrome” (CZS). Parenting a child with disabilities can have adverse mental health impacts, but these associations have not been fully explored in the context of CZS in Brazil.

METHODOLOGY/PRINCIPAL FINDINGS:

A cross-sectional study was undertaken in Recife and Rio de Janeiro, including 163 caregivers of a child with CZS (cases) and 324 caregivers with an unaffected child (comparison subjects), identified from existing studies. The primary caregiver, almost always the mother, was interviewed using a structured questionnaire to collect information on: depression, anxiety, and stress (Depression, Anxiety, and Stress Scale-DASS-21), social support (Medical Outcomes Study Social Support Scale-MOS-SSS), and socio-demographic data. Data was collected May 2017-January 2018. Ethical standards were adhered to throughout the research. A high proportion of mothers reported experiencing severe or extremely severe levels of depression (18%), anxiety (27%) and stress (36%). Mothers of children with CZS were more likely to experience symptoms of depression, anxiety andstress, compared to mothers of comparison children. These associations of were more apparent among mothers living in Rio de Janeiro. These differences were reduced after adjustment for socio-economic status and social support. Among mothers of children with CZS, low social support was linked to higher levels of depression, anxiety and stress, but there was no association with socio-economic status.

CONCLUSIONS/SIGNIFICANCE:

Depression, anxiety and stress were very common among mothers of young children in Brazil, regardless of whether they were parenting a child with disabilities. Mothers of children with CZS may be particularly vulnerable to poor mental health, and this association may be buffered through better social support.

PMID: 31568478 DOI: 10.1371/journal.pntd.0007768

Keywords: Zika Virus; Pregnancy; Psychiatry; Brazil.

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The Transcriptional and Protein Profile From #Human Infected #Neuroprogenitor Cells Is Strongly Correlated to #Zika Virus #Microcephaly #Cytokines Phenotype Evidencing a Persistent Inflammation in the #CNS (Front Immunol., abstract)

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

Front Immunol. 2019 Aug 16;10:1928. doi: 10.3389/fimmu.2019.01928. eCollection 2019.

The Transcriptional and Protein Profile From Human Infected Neuroprogenitor Cells Is Strongly Correlated to Zika Virus Microcephaly Cytokines Phenotype Evidencing a Persistent Inflammation in the CNS.

Lima MC1, de Mendonça LR1, Rezende AM1, Carrera RM2, Aníbal-Silva CE1, Demers M3, D’Aiuto L3, Wood J3, Chowdari KV3, Griffiths M2, Lucena-Araujo AR4, Barral-Netto M5, Azevedo EAN1, Alves RW1, Farias PCS1, Marques ETA1,6, Castanha PMS6, Donald CL7, Kohl A7, Nimgaonkar VL3,8, Franca RFO1.

Author information: 1 Oswaldo Cruz Foundation/Fiocruz, Institute Aggeu Magalhães, Recife, Brazil. 2 Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom. 3 Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States. 4 Federal University of Pernambuco/UFPE, Recife, Brazil. 5 Oswaldo Cruz Foundation/Fiocruz, Institute Gonçalo Moniz, Salvador, Brazil. 6 Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, United States. 7 MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom. 8 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States.

 

Abstract

Zika virus (ZIKV) infection during pregnancy is associated with microcephaly, a congenital malformation resulting from neuroinflammation and direct effects of virus replication on the developing central nervous system (CNS). However, the exact changes in the affected CNS remain unknown. Here, we show by transcriptome analysis (at 48 h post-infection) and multiplex immune profiling that human induced-neuroprogenitor stem cells (hiNPCs) respond to ZIKV infection with a strong induction of type-I interferons (IFNs) and several type-I IFNs stimulated genes (ISGs), notably cytokines and the pro-apoptotic chemokines CXCL9 and CXCL10. By comparing the inflammatory profile induced by a ZIKV Brazilian strain with an ancestral strain isolated from Cambodia in 2010, we observed that the response magnitude differs among them. Compared to ZIKV/Cambodia, the experimental infection of hiNPCs with ZIKV/Brazil resulted in a diminished induction of ISGs and lower induction of several cytokines (IFN-α, IL-1α/β, IL-6, IL-8, and IL-15), consequently favoring virus replication. From ZIKV-confirmed infant microcephaly cases, we detected a similar profile characterized by the presence of IFN-α, CXCL10, and CXCL9 in cerebrospinal fluid (CSF) samples collected after birth, evidencing a sustained CNS inflammation. Altogether, our data suggest that the CNS may be directly affected due to an unbalanced and chronic local inflammatory response, elicited by ZIKV infection, which contributes to damage to the fetal brain.

KEYWORDS: Zika congenital syndrome and cytokines; Zika virus; central nervous system; inflammation; interferonopathy; microcephaly; type-I interferon

PMID: 31474994 PMCID: PMC6707094 DOI: 10.3389/fimmu.2019.01928

Keywords: Zika Virus; Microcephaly; Zika Congenital Syndrome.

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#Zika Virus #Infection and #Microcephaly: A Case-Control Study in #Brazil (Ann Glob Health, abstract)

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

Ann Glob Health. 2019 Aug 28;85(1). pii: 116. doi: 10.5334/aogh.2394.

Zika Virus Infection and Microcephaly: A Case-Control Study in Brazil.

Rocha SGMO1, Correia LL1, Da Cunha AJLA2, Rocha HAL1,3, Leite ÁJM1, Campos JS3, Bandeira TJPG3, Do Nascimento LS1, E Silva AC3.

Author information: 1 Federal University of Ceará, Community Health Department, Fortaleza, Ceará, BR. 2 Federal University of Rio de Janeiro, Rio de Janeiro, BR. 3 Christus University Center (Unichristus), Fortaleza, Ceará, BR.

 

Abstract

BACKGROUND:

Brazil presented an alarming number of newborns with microcephaly in the years 2015 and 2016. The investigation of the cases raised the suspicion of the association of these cases with maternal infections by the zika virus. Also, in 2015, there was an epidemic of zika virus infection in Brazil, reinforcing this hypothesis.

OBJECTIVE:

The objective of this study was to identify factors associated with the diagnosis of microcephaly in newborns, including zika virus infection.

METHODS:

We conducted a case-control study. The cases were defined as children who received clinical and imaging diagnosis of microcephaly, born after October 2015 in Ceará, Brazil, which recorded the highest number of microcephaly cases in Brazil during the outbreak. The cases were identified in medical records of public and private maternity hospitals and in child development stimulation clinics tracked until June 2017. Epidemiological, clinical, and socioeconomic variables were collected, visiting their homes and confirming data from their medical records. Controls were children without microcephaly identified in the vicinity of the residence of each case. Logistic regression models were used to control confounding.

FINDINGS:

We evaluated 58 cases and 116 controls. The odds of having a baby with microcephaly was 14 times higher among mothers who had zika virus infection (p < 0.001), after multivariate analysis. Arboviruses infections symptoms, as fever (p = 0.220), skin change (p < 0.001), and joint pain (p = 0.002) also demonstrated an association with microcephaly.

CONCLUSIONS:

Maternal infection zika virus was associated with a diagnosis of microcephaly. Our study contributes to the investigation of the epidemiological factors associated with the diagnosis of microcephaly.

© 2019 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/.

PMID: 31468955 DOI: 10.5334/aogh.2394

Keywords: Zika Virus; Zika Congenital Syndrome; Microcephaly; Brazil.

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Early Gross #Motor #Development Among Brazilian #Children with #Microcephaly Born Right After #Zika Virus #Infection #Outbreak (J Dev Behav Pediatr., abstract)

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

J Dev Behav Pediatr. 2019 Aug 22. doi: 10.1097/DBP.0000000000000722. [Epub ahead of print]

Early Gross Motor Development Among Brazilian Children with Microcephaly Born Right After Zika Virus Infection Outbreak.

A Ventura P1,2, C Lage ML1, L de Carvalho A2, S Fernandes A2, B Taguchi T2, Nascimento-Carvalho CM1,3.

Author information: 1 Post-graduation Program in Health Sciences, Federal University of Bahia School of Medicine, Salvador, Brazil. 2 SARAH Network of Rehabilitation Hospital, Salvador, Brazil. 3 Department of Paediatrics, Federal University of Bahia School of Medicine, Salvador, Brazil.

 

Abstract

OBJECTIVE:

To assess the gross motor development of children with presumed congenital Zika virus (ZIKV) infection over the first 2 years of their lives.

METHODS:

Seventy-seven children were assessed at the median ages of 11, 18, and 24 months, using the evaluative instrument Gross Motor Function Measure (GMFM-66). At the third assessment, the children with diagnoses of cerebral palsy (CP) were classified by severity through the Gross Motor Function Classification System (GMFCS) and stratified by topography indicating the predominantly affected limbs. With these instruments in combination and using the motor development curves as reference, the rate of development and functional ability were estimated.

RESULTS:

At 2 years of age, all children had the diagnosis of CP. Seventy-four (96.1%) presented gross motor skills similar to those of children aged 4 months or younger, according to the World Health Organization’s standard. The GMFM-66 median score among the 73 (94.8%) children with quadriplegia and GMFCS level V showed significant change between 11 and 18 months (p < 0.001) and between 11 and 24 months (p < 0.001). No significant difference (p = 0.076) was found between 18 and 24 months.

CONCLUSION:

Despite showing some gross motor progress during the initial 18 months of life, these children with presumed congenital ZIKV infection and CP experienced severe motor impairment by 2 years of age. According to the motor development curves, these children with quadriplegia have probably already reached about 90% of their motor development potential.

PMID: 31453893 DOI: 10.1097/DBP.0000000000000722

Keywords: Zika Virus; Zika Congenital Syndrome; Neurology; Pediatrics; Brazil.

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