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Trisha Barnard is a PhD Candidate in Dr. Selena Sagan’s lab in the department of Microbiology & Immunology at McGill University. She previously earned her BSc Honours in Chemistry & Biochemistry at UBC. Trisha is interested in the molecular mechanisms of positive-sense RNA virus replication, and her PhD research on Zika virus studies how evolutionarily-acquired polymorphisms inform our understanding of virus biology and fitness. When she’s not in the lab, Trisha is an avid knitter.
Strain-dependent differences in Zika virus dsRNA accumulation and innate immune activation are determined by the NS3 and NS5 proteins
Initiation of RNA replication represents a major target of antiviral responses to positive-sense RNA viruses. Despite this, the interplay between early steps of ZIKV replication and induction of antiviral responses is not well understood. We have previously identified ZIKV isolates with differing levels of dsRNA accumulation, ZIKVPR (high dsRNA per infected cell) and ZIKVCDN (low dsRNA per infected cell), and we hypothesized that we could use reverse genetics to investigate how host and viral factors contribute to the establishment of viral RNA replication. We found that dsRNA accumulation was dependent on both the viral NS3 and NS5 proteins and host factors. Interestingly, despite increased dsRNA accumulation per infected cell, ZIKVPR dsRNA accumulation was more sensitive to Type I IFN, suggesting that differences in induction or evasion of IFN responses might contribute to strain-dependent differences in dsRNA accumulation. We observed NS3 and NS5-dependent differences in the kinetics of type I and type III IFN induction, yet we found no differences in viral evasion of IFN induction or signaling, suggesting that differences in IFN induction may be due to an inherent difference in how viral RNA is sensed by the host cell. Correspondingly, we detected significantly more negative-strand RNA synthesis for ZIKVPR at early timepoints post-infection. Current work is focused on understanding the mechanism(s) by which viral proteins contribute to initiation of viral RNA replication. This work expands our understanding of how the early steps of viral RNA replication affect induction of the innate antiviral response to ZIKV infection.