Brain pathology and function in a chronic mouse model of ZIKV transmission - Project Summary
Zika virus (ZIKV) is primarily transmitted to people through the bite of an infected mosquito from the Aedes
genus, mainly Aedes aegypti, although the virus can also be transmitted through sexual intercourse. There is
scientific consensus that ZIKV is a causative agent of microcephaly, a birth defect in children born to infected
mothers and neuroimmune Guillain-Barré syndrome in infected adults. Even more troubling, vertical
transmission of ZIKV is not limited to microcephaly alone, but it is now directly linked to multiple, albeit still
severe, dysfunctions in the development of the brain and the eyes, called the Congenital Zika Syndrome.
Because ZIKV continues to spread through the Americas, a better understanding of ZIKV pathology along with
an efficient means to treat the infection is urgently needed. Accordingly, the focus of our MPI research
proposal is to greatly increase our understanding of the changes to brain pathology caused by long-term ZIKV
infections, and a practical means to control the virus in a pharmacologically-beneficial manner by repurposing
the current FDA-approved anti-viral and anti-malarial pharmaceuticals as cocktails. Importantly, a
physiologically-relevant SJL mouse model of ZIKV vertical transmission and chronic infection is employed in
our in-depth studies, rather than interferon-knockout animals that perish in a few days post-infection. This
project is firmly grounded on volumes of our preliminary data. Our Specific Aims are: (1) Determine the
dynamics of fetal brain infection and investigate perinatal consequences following ZIKV vertical transmission in
SJL mice, (2) Determine structural and functional consequences to the adult brain following congenital ZIKV
infection in SJL mice, and (3) Determine the best treatment regimens for ZIKV infection using inhibitors of
different stages of the viral life cycle and their combinations to prevent vertical transmission of ZIKV. Our
exceptional and well-balanced multidisciplinary team includes experienced professionals with complementary
expertise in the diverse areas of virology, biochemistry, neuro- and stem cell biology, drug design, in silico
modeling and statistics, brain development and magnetic resonance microscopy. To accomplish our
interrelated Specific Aims in their entirety and in a timely fashion, we will use a plethora of the advanced
cellular, molecular and imaging techniques and methodologies which, especially if combined, are not readily
available for many others. An additional advantage of our multi-talented team is our extensive, decade-long,
studies in flaviviruses. Because our ZIKV-centered research has been already on-going for over a 2-year
period, we have already acquired significant momentum in our studies that bodes well for the success of this
proposed research project.
