Abstract
Flaviviruses are a group of single-stranded positive-sense RNA viruses transmitted by either mosquitoes or ticks. There are several important human pathogens within this group, many of which are global health threats, including dengue (DENV), Japanese encephalitis, tick-borne encephalitis, West Nile, yellow fever, and the recently re-emerging Zika viruses (ZIKV). Flavivirus infection induces a wide variety of clinical manifestations and complications in humans ranging from undifferentiated fever, hemorrhagic fever, congenital syndrome, encephalitis, and death. Currently, licensed vaccines and therapeutics are for the most part not available for human use. Understanding the pathogenesis of these viruses remains a high priority for research. In this special issue, several articles focus on the protective and pathogenic effects of immune factors in mammalian hosts or mosquitoes in response to flavivirus infection.
The physiological complexity of pregnancy and its impacts on maternal immunity are often associated with enhanced host susceptibility and more severe outcome of infectious diseases. ZIKV has been reported to cause congenital Zika syndrome in fetuses and infants in the outbreaks in the Americas and Caribbean, including microcephaly, spontaneous abortion, and intrauterine growth restriction (2,3). In this study, two review articles have discussed the role of immune regulation at the maternal–fetal interface and its impacts on the disease outcome upon ZIKV infection. Interferon (IFN)s, including type I, II, and III, are important for the control of congenital infection and maintaining a healthy status during pregnancy. Casazza et al. reviewed the protective and pathogenic effects of IFN signaling during pregnancy, in particular after congenital ZIKV infection in mouse and nonhuman primate (NHP) models. Nelson et al. discussed multiple mechanisms for ZIKV to traffic into the fetal brain and the eye in humans and NHPs. They have concluded that the combined effects of innate immune evasion by the virus and the maternal/fetal immune responses to ZIKV infection contribute to virus-induced fetal brain injury.
In addition to ZIKV, a research article by Liu et al. reported a high seroprevalence of DENV, another mosquito-borne flavivirus, in pregnant women while screening samples collected during an outbreak that occurred in 2014 in Guangdong, China. Their results suggest that pregnancy may increase the risk to DENV infection.
DENV increases the global incidence of hemorrhagic disease, including dengue hemorrhagic fever, and dengue shock syndrome. The pathogenesis of DENV infection is currently incompletely understood. Three other articles in this special issue provide new insights into the mechanism of DENV diseases. The mechanistic target of rapamycin (mTOR) is involved in cellular metabolism, proliferation, and autophagy processes. In this study, Kong et al. showed that DENV2 induces autophagy in human endothelial cells by mediating the mTOR signaling pathway. Inflammatory cytokines are known to be correlated with the severity of DENV infection. Meena et al. next provide evidence demonstrating that increasing levels of the proinflammatory cytokine, tumor necrosis factor-α, in the plasma of DENV patients are associated with decreased levels of blood platelets. Finally, Aedes mosquitoes are the primary vectors of DENV infection. Castillo-Méndez et al. reviewed the effects of DENV infection in mosquito tissue cells and pinpointed the immune pathways involved in this infection. The summarized results will be helpful in the future design of therapeutic targets for the treatment of DENV infection.
B cell-mediated humoral immune responses are critical in the control of disseminated flavivirus infection. Neutralizing antibodies have primarily targeted viral epitopes located on the envelope (E) protein (1,4). YFV 17D, a live attenuated vaccine, has been successful in the control of YFV infection. In this issue, Davis et al. gave an overview of the structure-functions of E proteins of YFV wild type and the attenuated 17D vaccine strains and discussed their roles in attenuation and long-term immunogenicity.