Development and characterization of an animal model of perinatal infection with Zika virus: assessment of long-term neurological deficits

Project Overview

Zika virus (ZIKV) is an emerging mosquito-borne pathogen. Between 2014 and 2017 Zika spread over 84 countries infecting >2 million people. In the US alone, over 35,000 people were infected by Zika virus including 3500 pregnant women. Understanding and measuring the potential sequelae is critical to assessing the safety and efficacy of prospective therapies or vaccines, particularly as therapies may not clear immunoprivileged sites such as the CNS effectively. This study will support animal modeling of long term consequences of disease, which may help alert clinicians to possible sequelae and help provide timely support to minimize the long-term neurological consequences of infection. The results will provide guidance to the product developers as well as the reviewers reading the parameters that need to be monitored in animals to model product efficacy.

Infections early in pregnancy lead to severe malformations in newborn babies including microcephaly, hydrocephaly and brain calcifications, as well as chorioretinitis and arthrogryposis (deformed joints) (CDC incidence estimated 10%). Infections later in pregnancy have lower incidence of microcephaly (6%), but can still lead to tissue damage and developmental abnormalities.  Indeed, new data is emerging that shows that apparently healthy babies exposed to Zika in utero have higher frequency of seizures.  It is still too early to know whether additional learning or behavioral issues will manifest later in life.  Of note, long term sequelae have been observed in children infected with other flavivirus.  Lastly, infections in adults are usually mild, but ZIKV has been associated with Guillain-Barre syndrome, encephalitis, encephalopathies, transverse myelitis and chorioretinal lesions of the retina suggesting that infections of the CNS are possible even in adults.

This group developed the first symptomatic model of Zika virus infection where the animals survive the infection.  Preliminary studies indicate that 1) there is extensive neuronal death during the acute infection when the animal is symptomatic, 2) viral antigen can be detected months after recovery, and 3) the areas where the virus persists show foci of apoptosis and neurodegeneration that suggest that there is permanent damage to the CNS architecture.  The virus and the inflammatory and immune response it induces are thought to contribute tissue damage.

• The first phase of the study is designed to detect and quantify long-term defects in motor skills, behavior or learning in convalescent mice.  Our group will correlate any motor or behavioral sequelae with immunohistochemical and transcriptome anomalies as well as MRI imaging in these mice. 
• In a second phase, if defects are identified, the group will create a targeted panel of motor and behavioral tests that can be used to monitor the impact of candidate therapeutics on neurological sequalae in infected mice.