The Mechanism of Zika Virus Infection Including the Role of Nonstructural Proteins in the Pathogenesis of Microcephaly and Guillain-Barre Syndrome

Heather Villarreal

Introduction. Zika virus (ZIKV) is a growing epidemic affecting several countries, whose effects include severe neurological damage such as Guillain-Barre syndrome and microcephaly. The virus infects peripheral dendritic tissue and transports axonally to neurons, especially neuroprogenitor cells, where it causes down-regulation of growth and development genes, apoptosis, and overall atrophy of developing neural tissues. The mechanism of this virus’s pathogenesis is important in current research in order to develop future treatment methods or preventative strategies. Studies have shown that an important aspect of the infection includes the mechanism by which the virus evades the host immune response and replicates within the host, involving the virus’s nonstructural proteins. Other studies have begun to elucidate the structures of these proteins as well as their products to determine potential targets of antiviral therapy. Methods. In the study on ZIKV nonstructural protein 5 (NS5), the crystal structure of ZIKV NS5 was extracted from ZIKV samples, and the extracted protein structure was assessed for the percentage of amino acids in variable regions, such as favorable regions, allowed regions, and outlier regions. The secondary structure was predicted with a renumbered ZIKV NS5 structure. A topology diagram was generated with PDBsum. The protein was subjected to molecular simulation mimicking the biological environment, and energy minimization was performed to determine probable structures in the environment. The structures were then put into interface HADDOCK server and analyzed for protein-protein interactions. Visual molecular dynamic was used for the visualization of the NS5 protein. PDBsum was used to analyze intramolecular and intermolecular attractions. Results. NS5 residues involved in interaction with SIAH2 and/or STAT2 were mostly conserved among Flaviviruses, including ZIKV. Conclusions. Further understanding of the NS5 protein structure and interactions, among other ZIKV nonstructural protein structure and interactions, can elucidate potential leads for developing ZIKV antiviral therapies or vaccines.

  1. Best SM. The many faces of the flavivirus NS5 protein in antagonism of type 1 interferon J Virol. 2017; 91(3): e01970-16.
  2. Coutard B, Barral K, Lichiere J, Selisko B, Martin B, Lombardia MO, Debart F, Vasseur JJ, Guillemot JC, Canard B, Decroly Zika virus methyltransferase: structure and functions for drug design perspectives. J Virol. 2017; 91(5): e02202-16.
  3. Cumberworth SL, Clark JJ, Kohl A, Donald Inhibition of type 1 interferon induction and signaling by mosquito-borne flaviviruses. Cellular microbiology. 2017; 19: e12737.
  4. Dar HA, Zaheer T, Paracha RZ, Ali Structural analysis and insight into Zika virus NS5 mediated interferon inhibition. Infect Genet Evol. 2017; 51: 143-152.
  5. Faizan MI, Abdullah M, Ali S, Naqvi IH, Ahmed A, Parveen Zika Virus-Induced Microcephaly and Its Possible Molecular Mechanism. Intervirology. 2016; 59: 152-158.
  6. Lucchese G, Kanduc Zika virus and autoimmunity: From microcephaly to Guillan-Barré syndrome, and beyond. Autoimmunity Reviews.2016; 15: 801-808.
  7. Song BH, Yun SI, Woolley M, Lee Zika virus: History, epidemiology, transmission, and clinical presentation. Journal of Neuroimmunology.2017,
  8. Stephen P, Baz M, Boivin G, Lin Structural insight into NS5 of Zika virus leading to the discovery of MTase inhibitors. J Am Chem Soc. 2016; 138(50): 16212-16215.
  9. van den Pol AN, Mao G, Yang Y, Ornaghi S, Davis Zika Virus Targeting in the Developing Brain. J. Neurosci. 2017; 37(8): 2161-2175.
  10. Wu Y, Liu Q, Zhou J, Xie W, Chen C, Wang Z, Yang H, Cui J. Zika virus evades interferon-mediated antiviral response through the co-operation of multiple nonstructural proteins in Cell Discov. 2017; 3: 17006.
  11. Zhou H, Wang F, Wang H, Chen C, Zhang T, Han X, Wang D, Chen C, Wu C, Xie W, Wang Z, Zhang L, Wang L, Yang The conformational changes of Zika virus methyltransferase upon converting SAM to SAH. Oncotarget. 2017; 8(9): 14830-14834.