RESUMEN
The contribution of placental immune responses to congenital Zika virus (ZIKV) syndrome remains poorly understood. Here, we leveraged a mouse model of ZIKV infection to identify mechanisms of innate immune restriction exclusively in the fetal compartment of the placenta. ZIKV principally infected mononuclear trophoblasts in the junctional zone, which was limited by mitochondrial antiviral-signaling protein (MAVS) and type I interferon (IFN) signaling mechanisms. Single nuclear RNA sequencing revealed MAVS-dependent expression of IFN-stimulated genes (ISGs) in spongiotrophoblasts but not in other placental cells that use alternate pathways to induce ISGs. ZIKV infection of Ifnar1-/- or Mavs-/- placentas was associated with greater infection of the adjacent immunocompetent decidua, and heterozygous Mavs+/- or Ifnar1+/- dams carrying immunodeficient fetuses sustained greater maternal viremia and tissue infection than dams carrying wild-type fetuses. Thus, MAVS-IFN signaling in the fetus restricts ZIKV infection in junctional zone trophoblasts, which modulates dissemination and outcome for both the fetus and the pregnant mother.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Decidua , Feto , Interferón Tipo I , Placenta , Receptor de Interferón alfa y beta , Transducción de Señal , Trofoblastos , Infección por el Virus Zika , Virus Zika , Femenino , Animales , Embarazo , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Transducción de Señal/inmunología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Placenta/inmunología , Placenta/virología , Placenta/metabolismo , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/virología , Virus Zika/inmunología , Virus Zika/fisiología , Ratones , Decidua/inmunología , Decidua/virología , Decidua/metabolismo , Feto/inmunología , Feto/virología , Trofoblastos/inmunología , Trofoblastos/virología , Trofoblastos/metabolismo , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Inmunidad Innata , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/virología , Modelos Animales de EnfermedadRESUMEN
Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus responsible for epidemics of neurological disease across the Americas. Low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3) is a recently reported entry receptor for VEEV. Here, using wild-type and Ldlrad3-deficient mice, we define a critical role for LDLRAD3 in controlling steps in VEEV infection, pathogenesis, and neurotropism. Our analysis shows that LDLRAD3 is required for efficient VEEV infection and pathogenesis prior to and after central nervous system invasion. Ldlrad3-deficient mice survive intranasal and intracranial VEEV inoculation and show reduced infection of neurons in different brain regions. As LDLRAD3 is a determinant of pathogenesis and an entry receptor required for VEEV infection of neurons of the brain, receptor-targeted therapies may hold promise as countermeasures.