Characterization of a Novel Murine Model to Study Zika Virus

Abstract

The mosquito-borne Zika virus (ZIKV) is responsible for an explosive ongoing outbreak of febrile illness across the Americas. ZIKV was previously thought to cause only a mild, flu-like illness, but during the current outbreak, an association with Guillain–Barré syndrome and microcephaly in neonates has been detected. A previous study showed that ZIKV requires murine adaptation to generate reproducible murine disease. In our study, a low-passage Cambodian isolate caused disease and mortality in mice lacking the interferon (IFN) alpha receptor (A129 mice) in an age-dependent manner, but not in similarly aged immunocompetent mice. In A129 mice, viremia peaked at ∼107 plaque-forming units/mL by day 2 postinfection (PI) and reached high titers in the spleen by day 1. ZIKV was detected in the brain on day 3 PI and caused signs of neurologic disease, including tremors, by day 6. Robust replication was also noted in the testis. In this model, all mice infected at the youngest age (3 weeks) succumbed to illness by day 7 PI. Older mice (11 weeks) showed signs of illness, viremia, and weight loss but recovered starting on day 8. In addition, AG129 mice, which lack both type I and II IFN responses, supported similar infection kinetics to A129 mice, but with exaggerated disease signs. This characterization of an Asian lineage ZIKV strain in a murine model, and one of the few studies reporting a model of Zika disease and demonstrating age-dependent morbidity and mortality, could provide a platform for testing the efficacy of antivirals and vaccines.

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

“…Thus, mouse models of ZIKV infection necessitate use of genetic deficiencies in IFNAR or antibody blockade of IFNAR 8–10 . To examine immune responses that control ZIKV neuropathogenesis, we first probed the cellular compartment responsible for the type I IFN-dependent block of ZIKV infection using irradiation-induced bone marrow chimeric mice between ZIKV-resistant C57BL/6 CD45.1 (WT) and ZIKV-susceptible interferon α/β receptor-deficient ( Ifnar1 −/− ) mice.…”

Vulnerability of primitive human placental trophoblast to Zika virus

“…Mouse models have not been altogether helpful in this respect, in part because the development of the placenta follows a different progression than in humans and also because many mouse strains are resistant to ZIKV infection, including the C57/B6 strain used so widely (9). However, mice engineered or treated in such a manner that they are unable to mount a normal antiviral response are susceptible (25,26) and can transmit the virus to their fetuses, allowing effects on the brain to be assessed (27,28). The latter studies also implicated an appropriate IFN response by the placenta as being at least partially responsible for protecting the fetus from ZIKV.…”

Características de la estructura molecular de las proteínas E del virus Zika y E1 del virus de la rubeola. Posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso

“…Dicho neurotropismo diferencial durante el desarrollo se ha observado en estudios recientes en ratones, los cuales evidenciaron altos grados de infección por el ZIKV en el cerebro, la médula espinal (6,46) y las células epiteliales (44,46). Aunque no se sabe por qué algunas células epiteliales y neuronales son más propensas a la infección por el ZIKV que otras (por ejemplo, las neuronas progenitoras lo son más que las corticales maduras) (5,8,47), se podrían presentar diferentes mecanismos de entrada mediados por distintos tipos de receptores (por ejemplo, Axl o TAR), así como tasas de infección diferentes debido a cambios en el grado de expresión de factores del huésped requeridos para la entrada (por ejemplo, TLR3), la replicación o el ensamblaje del ZIKV (42).…”

“…Esto concuerda con el hallazgo de que diversos tipos celulares en el cerebro adulto, incluidos los astrocitos, pueden estar infectados con el ZIKV y, sin embargo, sobrevivir durante largos períodos (47). En modelos de la infección por el ZIKV en ratones, las neuronas mantuvieron una morfología normal a pesar de estar infectadas por el virus, y sobrevivieron durante un período prolongado (6,46). Por otra parte, el mecanismo de desarrollo del fenotipo neuropático del adulto, es decir, el síndrome agudo de Guillain-Barré, sería diferente.…”