ICR suckling mouse model of Zika virus infection for disease modeling and drug validation

Abstract

Background

Zika virus (ZIKV) infection causes diseases ranging from acute self-limiting febrile illness to life-threatening Guillain–Barré Syndrome and other neurological disorders in adults. Cumulative evidence suggests an association between ZIKV infection and microcephaly in newborn infants. Given the host-range restrictions of the virus, a susceptible animal model infected by ZIKV must be developed for evaluation of vaccines and antivirals. In this study, we propose a convenient mouse model for analysis of neurological disorders caused by ZIKV.

Methodology

Six-day-old immunocompetent ICR suckling mice were used in the experiment. Different inoculum virus concentrations, challenge routes, and challenge times were assessed. Viremic dissemination was determined in the liver, spleen, kidney, and brain through Western blot assay, plaque assay, absolute quantification real-time PCR, and histological observation. Azithromycin, a well-characterized anti-ZIKV compound, was used to evaluate the ICR suckling mouse model for antiviral testing.

Conclusions

Signs of illness and neurological disease and high mortality rate were observed in mice injected with ZIKV intracerebrally (10 ² to 10 ⁵) and intraperitoneally (10 ³ to 10 ⁵). Viremic dissemination was observed in the liver, spleen, kidney, and brain. ZIKV transmitted, rapid replicated, and induced monocyte infiltration into the brain approximately 5 to 6 days post inoculum. Azithromycin conferred protection against ZIKV-caused neurological and life-threatening diseases. The developed model of ZIKV infection and disease can be used for screening drugs against ZIKV and discovering the underlying mechanism of ZIKV pathogenesis.

Author summary

Mosquito-borne Zika virus (ZIKV) is an emerging threat to human health worldwide. In 2007, a ZIKV outbreak was reported in the Yap Island of Micronesia and was the first outbreak outside Africa and Asia. In 2013 and 2014, another ZIKV outbreak was reported in French Polynesia, and more than 28,800 people were infected by ZIKV. In 2015, the first ZIKV outbreak in America was reported in Brazil; the Brazilian Ministry of Health reported a 20-fold increase in cases of neonatal microcephaly, which was geographically and temporally correlated with the ZIKV outbreak. Recent evidence demonstrated that ZIKV infection leads to severe syndromes, such as Guillain–Barré syndrome and microcephaly in adults and infants, respectively. Thus far, anti-ZIKV drugs and vaccines have not been developed yet. Moreover, the underlying mechanism of ZIKV pathogenesis remains unclear. In this study, we propose a small animal model of wild-type ZIKV infection and associated neurological disorders. In the animal model, ZIKV causes signs of illness and neurological disease, potentially emulating the hallmark of ZIKV infection in human. These features can be used to study the underlying mechanism of ZIKV pathogenesis. The newly developed Zika disease model provides an immunocompetent and time saving framework for development of drugs against ZIKV and ZIKV-caused diseases.