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

Autoři: Ivan Trus aff001;  Daniel Udenze aff001;  Brian Cox aff003;  Nathalie Berube aff001;  Rebecca E. Nordquist aff004;  Franz Josef van der Staay aff004;  Yanyun Huang aff006;  Gary Kobinger aff007;  David Safronetz aff008;  Volker Gerdts aff001;  Uladzimir Karniychuk aff001
Působiště autorů: Vaccine and Infectious Disease Organization-International Vaccine Centre (VIDO-InterVac), University of Saskatchewan, Saskatoon, Canada aff001;  School of Public Health, University of Saskatchewan, Saskatoon, Canada aff002;  Department of Physiology, Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada aff003;  Behavior and Welfare Group, Department of Farm Animal Health, Faculty of Veterinary Medicine, Utrecht University, Utrecht, CL, Netherlands aff004;  Brain Center Rudolf Magnus, Utrecht University, Utrecht, Netherlands aff005;  Prairie Diagnostic Services, Saskatoon, Canada aff006;  CHUL and Laval University, Québec City, QC, Canada aff007;  Canada National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada aff008;  Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada aff009
Vyšlo v časopise: 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): e32767. doi:10.1371/journal.ppat.1008038
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008038


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.

Klíčová slova:

Birth – Blood plasma – Fetuses – Pig models – placenta – Swine – Zika virus – Molecular pathology


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