Animal models of congenital zika syndrome provide mechanistic insight into viral pathogenesis during pregnancy

Abstract

In utero Zika virus (ZIKV; family Flaviviridae ) infection causes a distinct pattern of birth defects and disabilities in the developing fetus and neonate that has been termed congenital zika syndrome (CZS). Over 8,000 children were affected by the 2016 to 2017 ZIKV outbreak in the Americas, many of whom developed CZS as a result of in utero exposure. To date, there is no consensus about how ZIKV causes CZS; animal models, however, are providing mechanistic insights. Using nonhuman primates, immunocompromised mice, immunocompetent mice, and other animal models (e.g., pigs, sheep, guinea pigs, and hamsters), studies are showing that maternal immunological responses, placental infection and inflammation, as well as viral genetic factors play significant roles in predicting the downstream consequences of in utero ZIKV infection on the development of CZS in offspring. There are thousands of children suffering from adverse consequences of CZS. Therefore, the animal models developed to study ZIKV-induced adverse outcomes in offspring could provide mechanistic insights into how other viruses, including influenza and hepatitis C viruses, impact placental viability and fetal growth to cause long-term adverse outcomes in an effort to identify therapeutic treatments.

Zika Virus and Neuropathogenesis: The Unanswered Question of Which Strain Is More Prone to Causing Microcephaly and Other Neurological Defects

“…In addition, subcutaneous inoculation of ZIKV results in productive vertical transmission to the offspring similar to humans. The most utilised NHPs include olive baboons, pigtail macaques, rhesus macaques and marmosets ( Narasimhan et al, 2020 ). However, studies using NHP models are arduous, lengthy, and very expensive.…”

Non-human Primate Models to Investigate Mechanisms of Infection-Associated Fetal and Pediatric Injury, Teratogenesis and Stillbirth

“…Common laboratory animal models have contributed significantly to an understanding of fetal development. Researchers have used the chick embryo, frog, and zebrafish embryos and eggs to study the effect of teratogens and pathogens like ZIKV on the early precursors of the peripheral nervous system by loss of function analysis ( Barriga et al, 2015 ; Narasimhan et al, 2020 ). Rabbit models have also been used to study the impact of factors like maternal dietary restriction and environmental pollutants on early embryonic and fetal-placental development ( Fischer et al, 2012 ; Lopez-Tello et al, 2019 ; Carter, 2020 ).…”

“…For example, the pregnant mouse model is useful for investigating how the host immune system balances the need to maintain fetal tolerance with pathogen defense; the murine immune system is well characterized and research tools are commercially available ( Lowe et al, 2018 ). Additionally, some animal models are natural hosts for the disease of interest, like adenoviruses for rodents and guinea pigs ( Safronetz et al, 2013 ), and ZIKV for NHP ( Narasimhan et al, 2020 ). However, many human pathogens need to be adapted to a specific animal model that may not adequately manifest human disease and pathology, like the mouse-adapted or guinea-pig-adapted Ebola virus ( Safronetz et al, 2013 ).…”

Young at Gut—Turning Back the Clock with the Gut Microbiome

“…It is important, however, to note that majority of the current mechanistic studies are limited to rodent or other animal models. The complexity and nature of interactions between the gut microbiome and the aging immune system could drastically vary between animal models and humans due to the presence of species-specific microbial populations [ 194 , 195 ]. It is therefore critical to increasingly conduct clinical studies and validate findings obtained from animal models in order to develop effective strategies to promote healthy aging in humans.…”