Mechanisms of Nervous System Damage and Immunological Escape by Zika Virus
Introduction. Zika virus (ZIKV) is a single-stranded RNA flavivirus that is believed to be primarily spread through vector-born transmission such as mosquitos and can cause neurologic illness such as microcephaly. Most adult cases of ZIKV are asymptomatic. Symptomatic adult cases typically present with mild symptoms such as fever and conjunctivitis and resolve within one week. Rare cases of Guillan-Barre Syndrome have been reported. The virus has been found in nervous, lymphoid, musculoskeletal, and reproductive tissues. ZIKV was first isolated in 1947. Since its discovery, it was contained within a limited geographic area near the equator. However, it recently spread throughout the Americas, leading to the 2015-2016 Zika epidemic. Mother-to-child transmission is evident and demonstrates a link between ZIKV and microcephaly., There are no current treatments for ZIKV infection. Methods. Fetal brain preparations were analyzed for the presence of viral antigen using flow cytometry. If infection was noted in tissues, it was measured with viral RNA quantification to determine replication. Cell cultures of dendritic cells from healthy donors were grown and then infected by various strains of ZIKV. Using focus forming assay, reverse-transcriptase PCR, sequence alignment, and flow cytometry, the effects of ZIKV on type I interferon, STAT1 and STAT2, and the antiviral effects of RIG-I agonist were quantified. Mouse models deficient in innate, adaptive, and both adaptive/innate responses were infected with ZIKV and were compared to wildtype infected mice in weightloss and testicular size. Results. In human fetal tissue, ZIKV was most evident in microglia as well as in hematopoietic cells. TAM receptors are receptor tyrosine kinases that play a role in neurogenesis of the brain and neuroprogenitor cell survival. TAM receptors are a preferred target for Zika virus to enter neuroprogenitor cells. In neuroprogenitor cells infected with ZIKV, pTBK1 (a kinase essential in antiviral innate response) was dysfunctional and was associated with cell cycle disruption and cell death. In humans, ZIKV immunological escape is at least partially mediated by circumventing type I interferon through degradation of STAT2, a signaling molecule in the interferon pathway. RIG-I agonist strongly restricts ZIKV replication. Mice given interferon neutralizing antibodies were able to effectively mount a host defense against the virus and only exhibited minimal weight loss which was regained upon the end of the trial. Mice deficient in B and T-cell responses quickly succumbed due to disease.
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