Dengue Virus (DENV), a member of the flavivirus family, is the etiologic agent of dengue fever, the most significant mosquito-borne viral disease in humans, infecting 400 million people each year. Four serotypes of DENV (DENV1-4) are present across more than 100 countries, with an estimate of 3.9 billion people at risk of infection. DENV infection causes a wide spectrum of clinical manifestations ranging from asymptomatic infection, uncomplicated dengue fever to more severe forms of dengue such as Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS). Exposure to an individual DENV serotype confers long-term immunity specifically against that serotype, but only short-term protection against the other three serotypes, thereby creating unique challenges for the development of an effective Dengue vaccine.
A key hallmark of a successful vaccine is the ability to induce immunological memory. CD8+ T cells contribute to protection against DENV by generating effector cells that migrate to the site of infection and aid in the clearance of infected cells. On the other hand, CD4+ T cells contribute by providing cues that stimulate appropriate responses in innate immune cells, B cells and CD8+ T cells. Following the clearance of infection, memory CD4+ and CD8+ T cells are established, which can survive long-term and have enhanced abilities to control reinfection. In the context of DENV, it has been suggested that during secondary infection, pre-existing low avidity and cross-reactive memory T cells are preferentially expanded, inducing a qualitatively different response compared to those induced by the original antigen. In some patients that previously experienced primary infection with DENV, these cells, which possess suboptimal anti-viral capacity towards the specific dengue serotype that leads to secondary infection, may contribute to the “cytokine storm” that underlies the immunopathology observed during DHF/DSS. However, there is evidence that T cells also play an important protective role during secondary dengue infection and, as is the case for other viral infections such as Hepatitis B or Chikungunya, these two roles of the T cell response may not be mutually exclusive. Thus, understanding the nature of CD4+ and CD8+ T cell responses involved in protective immunity and/or immunopathology during secondary dengue infection is critical for designing optimal DENV vaccines and for defining reliable correlates of protection.
Recent emergence of Zika Virus (ZIKV) has drawn attention to possible interference of DENV-specific T cell immunity with other closely-related flaviviruses such as ZIKV. These two viruses are not only endemic in largely overlapping regions, but also have significant sequence similarity, and share the same arthropod host. The issue of potential ZIKV and DENV cross-reactivity is thus of high relevance for understanding the patterns of natural immunity against these pathogens, as well as for developing diagnostic tests and vaccines and thus requires further study.
This Research Topic welcomes the submission of Original Research Articles, Reviews, Opinion and Perspective articles towards understanding the role of DENV-specific T cell response in protection from or contribution to severe disease as well as their potential to influence the outcome of infection with other flaviviruses.
Dengue Virus (DENV), a member of the flavivirus family, is the etiologic agent of dengue fever, the most significant mosquito-borne viral disease in humans, infecting 400 million people each year. Four serotypes of DENV (DENV1-4) are present across more than 100 countries, with an estimate of 3.9 billion people at risk of infection. DENV infection causes a wide spectrum of clinical manifestations ranging from asymptomatic infection, uncomplicated dengue fever to more severe forms of dengue such as Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS). Exposure to an individual DENV serotype confers long-term immunity specifically against that serotype, but only short-term protection against the other three serotypes, thereby creating unique challenges for the development of an effective Dengue vaccine.
A key hallmark of a successful vaccine is the ability to induce immunological memory. CD8+ T cells contribute to protection against DENV by generating effector cells that migrate to the site of infection and aid in the clearance of infected cells. On the other hand, CD4+ T cells contribute by providing cues that stimulate appropriate responses in innate immune cells, B cells and CD8+ T cells. Following the clearance of infection, memory CD4+ and CD8+ T cells are established, which can survive long-term and have enhanced abilities to control reinfection. In the context of DENV, it has been suggested that during secondary infection, pre-existing low avidity and cross-reactive memory T cells are preferentially expanded, inducing a qualitatively different response compared to those induced by the original antigen. In some patients that previously experienced primary infection with DENV, these cells, which possess suboptimal anti-viral capacity towards the specific dengue serotype that leads to secondary infection, may contribute to the “cytokine storm” that underlies the immunopathology observed during DHF/DSS. However, there is evidence that T cells also play an important protective role during secondary dengue infection and, as is the case for other viral infections such as Hepatitis B or Chikungunya, these two roles of the T cell response may not be mutually exclusive. Thus, understanding the nature of CD4+ and CD8+ T cell responses involved in protective immunity and/or immunopathology during secondary dengue infection is critical for designing optimal DENV vaccines and for defining reliable correlates of protection.
Recent emergence of Zika Virus (ZIKV) has drawn attention to possible interference of DENV-specific T cell immunity with other closely-related flaviviruses such as ZIKV. These two viruses are not only endemic in largely overlapping regions, but also have significant sequence similarity, and share the same arthropod host. The issue of potential ZIKV and DENV cross-reactivity is thus of high relevance for understanding the patterns of natural immunity against these pathogens, as well as for developing diagnostic tests and vaccines and thus requires further study.
This Research Topic welcomes the submission of Original Research Articles, Reviews, Opinion and Perspective articles towards understanding the role of DENV-specific T cell response in protection from or contribution to severe disease as well as their potential to influence the outcome of infection with other flaviviruses.
