Male offspring born to mildly ZIKV-infected mice are at risk of developing neurocognitive disorders in adulthood

Abstract

Congenital Zika virus (ZIKV) syndrome may cause fetal microcephaly in ~1% of affected newborns. Here, we investigate whether the majority of clinically inapparent newborns might suffer from long-term health impairments not readily visible at birth. Infection of immunocompetent pregnant mice with high-dose ZIKV caused severe offspring phenotypes, such as fetal death, as expected. By contrast, low-dose (LD) maternal ZIKV infection resulted in reduced fetal birth weight but no other obvious phenotypes. Male offspring born to LD ZIKV-infected mothers had increased testosterone (TST) levels and were less likely to survive in utero infection compared to their female littermates. Males also presented an increased number of immature neurons in apical and basal hippocampal dendrites, while female offspring had immature neurons in basal dendrites only. Moreover, male offspring with high but not very high (storm) TST levels were more likely to suffer from learning and memory impairments compared to females. Future studies are required to understand the impact of TST on neuropathological and neurocognitive impairments in later life. In summary, increased sex-specific vigilance is required in countries with high ZIKV prevalence, where impaired neurodevelopment may be camouflaged by a healthy appearance at birth.

The African strain of Zika virus causes more severe in utero infection than Asian strain in a porcine fetal transmission model

“…Interestingly, pathology in viable fetuses was not apparent until brains were weighted, placental samples were stained for the specific cell marker, and in utero cortisol and IFN-α levels were quantified. Thus, similarly to Asian strains [3, 20, 21, 59], ZIKV of African lineage might cause silent pathology that is difficult to identify in asymptomatic fetuses and offspring. Altogether, these findings emphasize the need for further studies to highlight the impact of ZIKV heterogeneity on infection outcomes during pregnancy.…”

“…Moreover, the majority of congenital infections in humans is subclinical [3] and is not associated with easily identifiable brain lesions or birth defects in newborns. Asymptomatic infection and potentially detrimental life-long health outcomes in deceptively healthy offspring evoke high concerns [3, 20, 21]; however, a majority of asymptomatic cases are likely not recorded in the Americas and probably in Africa [18].…”

Implications of Sex Differences in Immunity for SARS-CoV-2 Pathogenesis and Design of Therapeutic Interventions

“…Compiled data from Europe, for example, show male to female ratios of 1.5 for COVID-19 hospitalizations and of 1.7 to 1.8 for COVID-19 case fatality rates ( Gebhard et al., 2020 ). Although sex differences in manifestations of viral infections have been established for multiple viruses, including SARS-CoV, hepatitis C virus, Zika virus, respiratory syncytial virus, human immunodeficiency virus 1 (HIV-1), and influenza virus ( Baden et al., 2014 ; Gabriel and Arck, 2014 ; Klein and Flanagan, 2016 ; Mazur et al., 2015 ; Meier et al., 2009 ; Robinson et al., 2011 ; Stanelle-Bertram et al., 2018 ; van Lunzen and Altfeld, 2014 ), sex-specific treatment strategies are rarely applied outside the field of oncology. However, sex differences in case fatality rates seem to be higher in COVID-19 than in these other infections ( Gebhard et al., 2020 ), emphasizing the need to develop treatment strategies for COVID-19 that take these differences between the sexes into account.…”

A Measles Virus-Based Vaccine Candidate Mediates Protection against Zika Virus in an Allogeneic Mouse Pregnancy Model

“…After vaccination in the standard regimen (32), immunized females were mated with BALB/c males to mimic the natural genetic heterozygosity between mothers and fetuses. A similar system has been successfully applied to assess the effects of influenza A virus infection on unborn offspring (40) and most recently also for the effects of intrauterine ZIKV infection on newborn animals and their development (41). Challenging these pregnant mice revealed the teratogenic effects of ZIKV infection, including the intrauterine growth retardation observed previously in a model that also takes advantage of the heterozygous IFN-␣/␤ receptor status of pups in IFNAR-deficient dams and a closely related challenge virus, ZIKV strain H/PF/2013 (42).…”