Diagnostic differentiation of Zika and dengue virus exposure by analyzing T cell receptor sequences from peripheral blood of infected HLA-A2 transgenic mice

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).

Diagnosing Viral Infections Through T-Cell Receptor Sequencing of Activated CD8+ T Cells

“…Of note, since underlying active coinfections (like human immunodeficiency virus, hepatitis C virus, and hepatitis B virus) were excluded from the study, we cannot exclude their potential impact on our classifier. While the CDR3β region has been explored most in TCR-based exposure classifiers [ 6 , 7 , 9 , 33 , 34 ], we observed that the combination of both the CDR3α and CDR3β regions of the TCR tended towards greater diagnostic performance than either of the regions separately (however, no statistical significance was reached).…”

“…Recently developed TCR repertoire profiling technology (through TCR sequencing) allows identification of infectious disease–associated T-cell imprints. For instance, an exposure classifier based on the TCR repertoire distinguished naive from smallpox-vaccinated mice [ 8 ], Zika virus–exposed from dengue virus–exposed mice [ 7 ], and CMV-seropositive from CMV-seronegative human individuals [ 5 , 6 ]. Recently, the first test based on this technology received US Food and Drug Administration approval for the detection of SARS-CoV-2 exposure (T-Detect, Adaptive Biotechnologies [ 9 ]).…”

“…Such cross-reactive TCRs have been involved in response to SARS-CoV-2 infection and are thus part of the SARS-CoV-2 epitope–TCR database [ 36 , 37 ]. Interestingly, TCR repertoire profiling was shown to differentiate exposure with similar viruses (Zika virus from dengue virus [ 7 ]). Since our study population does not include patients infected with co-circulating viruses related to SARS-CoV-2 such as seasonal coronaviruses, we cannot demonstrate whether our classifier differentiates acute SARS-CoV-2 from acute seasonal coronavirus infection.…”