Abstract
Most of the world is at risk of being infected with a flavivirus such as dengue virus, West Nile virus, yellow fever virus, Japanese encephalitis virus, tick-borne encephalitis virus, and Zika virus, significantly impacting millions of lives. Importantly, many of these genetically similar viruses co-circulate within the same geographic regions, making it likely for individuals living in areas of high flavivirus endemicity to be infected with multiple flaviviruses during their lifetime. Following a flavivirus infection, a robust virus-specific T cell response is generated and the memory recall of this response has been demonstrated to provide long-lasting immunity, protecting against reinfection with the same pathogen. However, multiple studies have shown that this flavivirus specific T cell response can be cross-reactive and active during heterologous flavivirus infection, leading to the question: How does immunity to one flavivirus shape immunity to the next, and how does this impact disease? It has been proposed that in some cases unfavorable disease outcomes may be caused by lower avidity cross-reactive memory T cells generated during a primary flavivirus infection that preferentially expand during a secondary heterologous infection and function sub optimally against the new pathogen. While in other cases, these cross-reactive cells still have the potential to facilitate cross-protection. In this review, we focus on cross-reactive T cell responses to flaviviruses and the concepts and consequences of T cell cross-reactivity, with particular emphasis linking data generated using murine models to our new understanding of disease outcomes following heterologous flavivirus infection.
Highlights
Both historically and currently, flaviviruses have had a huge global impact on human health
We have recently shown that a robust and polyfunctional CD4+ T cell response is elicited during Zika virus (ZIKV) infection in mice [6]
During Epstein-Barr virus (EBV) infection, patients with influenza A virus (IAV)-EBV crossreactive T cell responses, had altered cytokine profiles and experienced severe acute infectious mononucleosis (AIM) [92]. As these studies were conducted with human volunteers, a distinct correlation between less severe disease and specific cytokine profiles could not be made, this study did support much of the scientific concepts developed using murine models demonstrating that heterologous immunity can impact T cell functionality, which can play a key role in determining pathogenesis vs. protection
Summary
Flaviviruses have had a huge global impact on human health. This was demonstrated in an HLAA∗11 Vietnamese cohort of DENV-infected patients In addition to these altered avidities, altered cytokine profiles in responses to the same cross-reactive variant peptide ligand as a consequence of secondary heterologous infection were observed [78]. During EBV infection, patients with IAV-EBV crossreactive T cell responses, had altered cytokine profiles and experienced severe AIM [92] As these studies were conducted with human volunteers, a distinct correlation between less severe disease and specific cytokine profiles could not be made, this study did support much of the scientific concepts developed using murine models demonstrating that heterologous immunity can impact T cell functionality, which can play a key role in determining pathogenesis vs protection.
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