CHARACTERIZATION OF GENETIC MUTATIONS IN EPIDEMIC STRAINS OF ZIKA VIRUS

Open Access
Author:
Horan, Sean
Area of Honors:
Biochemistry and Molecular Biology
Degree:
Bachelor of Science
Document Type:
Thesis
Thesis Supervisors:
  • Joyce Jose, Thesis Supervisor
  • Santhosh Girirajan, Honors Advisor
Keywords:
  • Zika virus
  • mutation
  • NS5 polymerase
  • precursor membrane protein
  • envelope protein
  • pre-epidemic strain
  • epidemic strain
  • infection
  • virulence
  • convergent evolution
Abstract:
Zika virus (ZIKV) was initially discovered in Uganda nearly three quarters of a century ago. Until recently, the virus caused a few mild infections in humans. Genetic analysis performed on the growing number of sequenced strains has revealed the virus diverged into two distinct lineages, African and Asian. The recent rise in the prevalence of Asian lineage Zika virus infections associated with serious neurological disorders in French Polynesia and Brazil (2013 and 2015 respectively) has raised concerns regarding public health. We hypothesize mutations in pre-epidemic strains have contributed to the increased virulence of the epidemic strains associated with neurological disease. We used reverse genetic analysis to identify candidate mutations that were the most likely to cause virulence on par with epidemic strains. We individually introduced these candidate mutations into the African pre-epidemic MR766 strain (1947) and characterized infection in mosquito vector and human neuronal cells. We also substituted the NS5 polymerase region of the epidemic Senegal strain (1984) into the pre-epidemic strain to see how multiple mutations affected viral infection in vitro. We expected the mutant constructs to cause infections that were equally or more severe than the pre-epidemic strain. However, in general, we found mutant constructs caused infections that were less severe than the pre-epidemic wild type virus. Our results suggest regions of the ZIKV genome coevolved to produce the more virulent strains associated with severe neurological disease.