title: Vaginal Exposure to Zika Virus during Pregnancy Leads to Fetal Brain Infection.
abstract: Zika virus (ZIKV) can be transmitted sexually between humans. However, it is unknown whether ZIKV replicates in the vagina and impacts the unborn fetus. Here, we establish a mouse model of vaginal ZIKV infection and demonstrate that, unlike other routes, ZIKV replicates within the genital mucosa even in wild-type (WT) mice. Mice lacking RNA sensors or transcription factors IRF3 and IRF7 resulted in higher levels of local viral replication. Furthermore, mice lacking the type I interferon (IFN) receptor (IFNAR) became viremic and died of infection after a high-dose vaginal ZIKV challenge. Notably, vaginal infection of pregnant dams during early pregnancy led to fetal growth restriction and infection of the fetal brain in WT mice. This was exacerbated in mice deficient in IFN pathways, leading to abortion. Our study highlights the vaginal tract as a highly susceptible site of ZIKV replication and illustrates the dire disease consequences during pregnancy.
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520 USA.
authors: Laura J
authors: LJ
authors: Yockey
authors: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520 USA.
authors: Luis
authors: L
authors: Varela
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520 USA.
authors: Tasfia
authors: T
authors: Rakib
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520 USA.
authors: William
authors: W
authors: Khoury-Hanold
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520 USA; Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT, 06520 USA.
authors: Susan L
authors: SL
authors: Fink
authors: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520 USA.
authors: Bernardo
authors: B
authors: Stutz
authors: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520 USA.
authors: Klara
authors: K
authors: Szigeti-Buck
authors: Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, 06520 USA.
authors: Anthony
authors: A
authors: Van den Pol
authors: Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, 06520 USA.
authors: Brett D
authors: BD
authors: Lindenbach
authors: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520 USA.
authors: Tamas L
authors: TL
authors: Horvath
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520 USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, 06520 USA. Electronic address: akiko.iwasaki@yale.edu.
authors: Akiko
authors: A
authors: Iwasaki
mesh_terms: D000026:Abortion, Habitual / Q000821:virology; D000818:Animals; D001921:Brain / Q000821:virology*; D001927:Brain Diseases / Q000276:immunology / Q000821:virology*; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000276:immunology / Q000821:virology*; D050838:Interferon Regulatory Factor-3 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology / Q000821:virology*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D014621:Vagina / Q000821:virology*; D014779:Virus Replication; D000071244:Zika Virus / Q000502:physiology*; D000071243:Zika Virus Infection / Q000635:transmission*
chemical_list: D050838:Interferon Regulatory Factor-3; D053633:Receptor, Interferon alpha-beta
keywords: antiviral defense; female reproductive tract; flavivirus; innate immunity; mucosal immunity; pattern recognition receptors; sexually transmitted infections; type I interferons