Abstract
Zika virus (ZIKV) is a significant global health threat due to its potential for rapid emergence and association with severe congenital malformations during infection in pregnancy. Despite the urgent need, accurate diagnosis of ZIKV infection is still a major hurdle that must be overcome. Contributing to the inaccuracy of most serologically-based diagnostic assays for ZIKV, is the substantial geographic and antigenic overlap with other flaviviruses, including the four serotypes of dengue virus (DENV). Within this study, we have utilized a novel T cell receptor (TCR) sequencing platform to distinguish between ZIKV and DENV infections. Using high-throughput TCR sequencing of lymphocytes isolated from DENV and ZIKV infected mice, we were able to develop an algorithm which could identify virus-associated TCR sequences uniquely associated with either a prior ZIKV or DENV infection in mice. Using this algorithm, we were then able to separate mice that had been exposed to ZIKV or DENV infection with 97% accuracy. Overall this study serves as a proof-of-principle that T cell receptor sequencing can be used as a diagnostic tool capable of distinguishing between closely related viruses. Our results demonstrate the potential for this innovative platform to be used to accurately diagnose Zika virus infection and potentially the next emerging pathogen(s).
Highlights
Zika virus (ZIKV) is a member of the Flaviviridae family which includes West Nile (WNV), yellow fever (YFV), and the four serotypes of dengue (DENV1-4)
We used a novel T cell receptor sequencing platform to identify T cell receptor sequences significantly associated with either dengue or Zika virus infection in HLA-A2 transgenic mice
As a proof-of-principle, we set out to determine if TCRβ sequencing could be used in a diagnostic assay capable of discriminating between infection with dengue virus (DENV) and ZIKV, two serologically cross-reactive flaviviruses (S1 Fig). 6–8 week old HLA-A2 transgenic mice were infected with either ZIKV (n = 8) or DENV2 (n = 7) to elicit a robust T cell response
Summary
Zika virus (ZIKV) is a member of the Flaviviridae family which includes West Nile (WNV), yellow fever (YFV), and the four serotypes of dengue (DENV1-4). Because co-circulating flaviviruses are genetically and structurally very similar [2,3,4,5,6,7,8,9] antibodies generated in response to individual flaviviruses are often cross-reactive. These confounding factors, have resulted in serologically-based diagnostic assays that poorly differentiate between infections with the different flaviviruses [10,11]. A diagnostic tool which can accurately distinguish ZIKV from related flaviviruses would inform surveillance and public health both within endemic regions and unaffected areas where the virus might spread
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