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 ∼10(7) 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.
Insights
Zika virus (ZIKV) causes severe disease and mortality in young A129 mice lacking interferon alpha receptors. This age-dependent murine model of Zika disease is crucial for developing new antivirals and vaccines.
Area of Science:
- Virology and Immunology
- Neuroscience
- Infectious Diseases
Background:
- The mosquito-borne Zika virus (ZIKV) outbreak in the Americas revealed severe neurological complications, including microcephaly and Guillain-Barré syndrome, contrasting with its previously mild disease profile.
- Previous research indicated that ZIKV requires adaptation in mice to cause reproducible disease, highlighting the need for suitable animal models.
- Understanding ZIKV pathogenesis and developing effective countermeasures are critical due to its significant public health impact.
Purpose of the Study:
- To characterize the disease caused by an Asian lineage ZIKV strain in a murine model.
- To investigate the age-dependent susceptibility and disease progression of ZIKV infection in mice with deficiencies in interferon responses.
- To establish a platform for evaluating potential antiviral and vaccine efficacy against ZIKV.
Main Methods:
- Infection of type I interferon receptor-deficient (A129) and type I/II interferon receptor-deficient (AG129) mice with a low-passage Cambodian ZIKV isolate.
- Assessment of ZIKV replication kinetics, viremia, viral titers in various organs (spleen, brain, testis), and disease progression.
- Evaluation of age-dependent effects on morbidity and mortality following ZIKV infection in A129 mice.
Main Results:
- ZIKV caused significant disease and mortality in young (3-week-old) A129 mice, with high viremia and viral loads in the spleen, brain, and testis.
- Neurologic signs, including tremors, were observed by day 6 post-infection in susceptible mice, with death by day 7 PI.
- Older (11-week-old) A129 mice exhibited transient illness, viremia, and weight loss but recovered, demonstrating age-dependent outcomes. AG129 mice showed exaggerated disease.
Conclusions:
- The characterized ZIKV Asian lineage strain causes age-dependent lethal neurologic disease in interferon-deficient mice, with younger mice being more susceptible.
- This murine model accurately recapitulates key aspects of ZIKV infection, including viremia, organ dissemination, and neurological manifestations.
- The established model provides a valuable platform for preclinical testing of ZIKV therapeutics and vaccines.
