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

• Type of Material: Article
• Authors: Miranda Li, University of Washington; Alyssa Brokaw, University of Washington; Anna M Furuta, University of Washington; Brahm Coler, Washington State University; Veronica Obregon-Perko, Emory University; Ann Chahroudi, Emory University; Hsuan-Yuan Wang, Weill Cornell Medicine; Sallie R Permar, Weill Cornell Medicine; Charlotte E Hotchkiss, University of Washington; Thaddeus G Golos, University of Wisconsin Madison; Lakshmi Rajagopal, University of Washington; Kristina MA Waldorf, University of Washington
• Language: English
• Date: 2021-07-05
• Publisher: FRONTIERS MEDIA SA
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Li, Brokaw, Furuta, Coler, Obregon-Perko, Chahroudi, Wang, Permar, Hotchkiss, Golos, Rajagopal and Adams Waldorf.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3389/fgene.2021.680342
• Title of Journal or Parent Work: FRONTIERS IN GENETICS
• Volume: 12
• Start Page: 680342
• End Page: 680342
• Grant/Funding Information: This work was supported by funding from the National Institutes of Health grants R01AI133976, R01AI145890, R01AI143265, and R01HD098713 to LR and KA; R01AI152268 to LR; T32AI055396 to AF (PI: Fang); T32AI074492 to VO-P; P01AI131276, R01A133706, and R01NS120182 to AC, R01AI107157 to TG; T32AI007509 to AB (PI: Campbell); P01AI129859 (SP); and seed funds from Seattle Children’s Research Institute to LR. This work was also supported by the P51OD010425, P51OD011106, and P51OD011132, which are the core grants of the Washington National Primate Research Center, Wisconsin National Primate Research Center, and Yerkes National Primate Research Center, respectively. Additional support came from a U42OD011123, which funds the breeding colony at the Washington National Primate Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: COMPLETE DNA-SEQUENCE; group B streptococcus; teratogenesis; ANIMAL-MODELS; cytomegalovirus; RHESUS CYTOMEGALOVIRUS; CONGENITAL CYTOMEGALOVIRUS DISEASE; Genetics & Heredity; SIMIAN IMMUNODEFICIENCY VIRUS; CENTRAL-NERVOUS-SYSTEM; Zika virus; UREAPLASMA-UREALYTICUM; listeria; nonhuman primate; Science & Technology; HIPPOCAMPAL NEUROGENESIS; Life Sciences & Biomedicine; preterm birth; GROUP-B STREPTOCOCCUS; HIV; ZIKA VIRUS-INFECTION
• Research Categories: Health Sciences, Obstetrics and Gynecology

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.