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

Abstract

A wide array of pathogens has the potential to injure the fetus and induce teratogenesis, the process by which mutations in fetal somatic cells lead to congenital malformations. Rubella virus was the first infectious disease to be linked to congenital malformations due to an infection in pregnancy, which can include congenital cataracts, microcephaly, hearing impairment and congenital heart disease. Currently, human cytomegalovirus (HCMV) is the leading infectious cause of congenital malformations globally, affecting 1 in every 200 infants. However, our knowledge of teratogenic viruses and pathogens is far from complete. New emerging infectious diseases may induce teratogenesis, similar to Zika virus (ZIKV) that caused a global pandemic in 2016–2017; thousands of neonates were born with congenital microcephaly due to ZIKV exposure in utero, which also included a spectrum of injuries to the brain, eyes and spinal cord. In addition to congenital anomalies, permanent injury to fetal and neonatal organs, preterm birth, stillbirth and spontaneous abortion are known consequences of a broader group of infectious diseases including group B streptococcus (GBS), Listeria monocytogenes, Influenza A virus (IAV), and Human Immunodeficiency Virus (HIV). Animal models are crucial for determining the mechanism of how these various infectious diseases induce teratogenesis or organ injury, as well as testing novel therapeutics for fetal or neonatal protection. Other mammalian models differ in many respects from human pregnancy including placentation, labor physiology, reproductive tract anatomy, timeline of fetal development and reproductive toxicology. In contrast, non-human primates (NHP) most closely resemble human pregnancy and exhibit key similarities that make them ideal for research to discover the mechanisms of injury and for testing vaccines and therapeutics to prevent teratogenesis, fetal and neonatal injury and adverse pregnancy outcomes (e.g., stillbirth or spontaneous abortion). In this review, we emphasize key contributions of the NHP model pre-clinical research for ZIKV, HCMV, HIV, IAV, L. monocytogenes, Ureaplasma species, and GBS. This work represents the foundation for development and testing of preventative and therapeutic strategies to inhibit infectious injury of human fetuses and neonates.

Primate Models as a Translational Tool for Understanding Prenatal Origins of Neurodevelopmental Disorders Associated With Maternal Infection

“…NHP models account for a very small percentage of research in the US ( 71 ), with the majority of NHP studies performed in macaques ( 72 ). We focus this review primarily on the rhesus macaque ( Macaca mulatta ), but also incorporate the common marmoset ( Callithrix jacchus ) that is playing an increasing role in gestational research ( 73 ). NHPs are the closest model to human pregnancy, sharing similarities in placental and pregnancy physiology, maternal-fetal interface, gestational timeline and fetal brain development.…”

Modeling of vertical transmission and pathogenesis of cytomegalovirus in pregnancy: Opportunities and challenges

“…The guinea pig model of congenital CMV infection came about after the findings by Connor and Johnson reported in 1976 that direct guinea pig CMV (gpCMV) inoculation in weanling guinea pigs resulted in high-titer infection in the salivary glands, thymus, and resulted in multifocal inclusion cell encephalitis with intracerebral inoculation (18). Like humans, guinea pigs also exhibit hemochorial placentation, although they utilize a labyrinth rather than villous strategy, with a dense meshwork of maternal and vascular channels (7,19). Transplacental transmission of gpCMV in guinea pigs was subsequently demonstrated two years later, with successful fetal infection occurring in 24% of pregnancies in which maternal primary infection occurred during what would correspond to the second and third trimesters of human gestation (20).…”

“…The human placenta forms from cytotrophoblasts creating anchoring villi into the uterine decidua basalis beginning during the second and third weeks of pregnancy (6). Humans have hemochorial, villous, discoid placentas, in which fetal and maternal circulations are separated by a single layer of trophoblast cells, facilitating efficient exchange of oxygen and nutrients (7). Indeed, the placenta becomes the sole source of gas, nutrients, antibodies, and waste exchange between maternal and fetal circulation (8).…”

Role of hormones in the pregnancy and sex‐specific outcomes to infections with respiratory viruses*

“…This is in part due to a lack of animal models that recapitulate the natural progression of human IAV disease, endocrinology, and pregnancy. Nonhuman primates are an excellent model of pregnancy 319 and viral respiratory infections, [319][320][321][322][323][324][325] but most have differences in the hormonal cascade associated with parturition (labor onset). A combination of in vitro and in vivo models is necessary to dissect the complex interactions between sex hormones, pregnancy, and the pathogenesis of viral respiratory infections.…”