[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
Published: November 14, 2019 / DOI: https://doi.org/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.
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.
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.