Alexis Medders

 Introduction. Zika virus (ZIKV) is part of the family Flaviviridae and is spread primarily by mosquitoes (Aedes aegypti and Aedes albopictus). VIKV is known to cross the blood-brain and placental barriers to cause damage to the central nervous system and can be vertically transmitted from an infected mother1. This serves as a particularly high concern in utero due to associations with microcephaly and other neurological  findings2. However, a preventative vaccine or pharmacological intervention for ZIKV infection remains unknown due to the complex nature of the virus3. Therefore, better understanding of the mechanisms of nervous system damage by ZIKV is imperative for determining targets for vaccination and treatment. Methods.  Human  iPSC-derived cerebral organoids were generated and heat mapping was used to determine which receptors responded to ZIKV. Once Axl was determined as receptor, immunostaining was utilized to determine where Axl receptors were specifically located4. In order to better understand a possible link between ZIKV induced neurogenesis, apoptosis and TLR3 activation, an orthogonal human model was treated with TLR3 antagonists, TLR3 agonists, and ZIKV alone. Bright field images and RT-qPCR were utilized. Statistical significance was determined using Student’s t-test5. Neurospheres stained with fNSC markers Nestin and SOX2 were also quantified after inoculation with VIKV proteins NS4A and NS4B individually and together and then analyzed using one-way ANOVA to demonstrate inhibition of the Akt-mTOR pathway6. Results. The role of Axl was confirmed for initiation of ZIKV infection with specific affinity for astrocytes and glial cells4. The role of TLR3 was confirmed by using a TLR3 inhibitor to increase neurogenesis that was decreased by ZIKV alone. RT-qPCR studies also demonstrated that ZIKV infection lead to changes in downstream genes associated with TLR3 that lead to apoptosis and dysregulated neurogenesis5. Specific ZIKV proteins, NS4A and NS4B, were also shown to suppress the Akt- mTOR pathway, increasing autophagy and decreasing neurogenesis. NS4A and NS4B were also found to have an additive effect together and are specific for ZIKV compared to other flaviviruses and present important targets for ZIKV specific treatment6. Conclusion. Studies have found that ZIKV utilizes specific molecules, Axl and TLR3, found in developing astrocytes and glial cells to induce an infection. ZIKV proteins, NS4A and NS4B, have also been shown to have a specific role for suppressing the Akt-mTOR pathway. Overall, these mechanisms of nervous system damage present specific proteins that can be targeted in order to create effective vaccines and treatments for ZIKV infection.

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