Gamma Interferon (IFN-γ) Receptor Restricts Systemic Dengue Virus Replication and Prevents Paralysis in IFN-α/β Receptor-Deficient Mice

Abstract

T he four serotypes of dengue virus (DENV1 to -4) belong to the Flaviviridae family, which also includes West Nile virus (WNV), St. Louis encephalitis virus (SLEV), Japanese encephalitis virus (JEV), and yellow fever virus (YFV). More than 2.5 billion people live in areas where DENV is endemic, and approximately 50 million people are infected each year (17). DENV generally manifests as an acute systemic infection that is cleared within 14 days (46). In most cases, infected individuals develop a febrile illness (dengue fever [DF]) characterized by flu-like symptoms, often accompanied by retro-orbital pain, ostealgia, and maculopapular rash. In nearly 500,000 cases per year, patients develop severe vascular leakage, which may result in hypovolemic shock (dengue hemorrhagic fever/dengue shock syndrome [DHF/ DSS]), ultimately leading to fatality rates as high as 10 to 15% in some countries or more than 25,000 deaths worldwide each year (15,17). In a subset of both DF and DHF/DSS cases (16), DENV infection was linked to encephalitis and signs of encephalopathy, including lethargy, confusion, seizure, and coma, as well as delayed neurological symptoms, such as paralysis of extremities, loss of sensation, and psychosis (2,21,23,30,36,38,43). DENVinduced neurological disease is being increasingly recognized as an important component of dengue disease in humans independent of DF and DHF/DSS (24). The prevalence of DENV-induced neurological disease has been estimated to be 4.2% of DENV cases (44) and as high as 18% of undiagnosed suspected viral central nervous system (CNS) infections in regions where DENV is endemic (21, 23).In the last decade, DENV has increasingly been linked to neurological disease in both the presence and absence of DF. Viruses of the Flaviviridae family generally cluster in a phylogenetic pattern that mirrors the typical disease manifestations they cause (13); for example, encephalitic flaviviruses cluster together. DENV, however, usually causes hemorrhagic illness but is genetically more homologous to the encephalitic viruses, including WNV, SLEV, and JEV, than it is to other hemorrhagic flaviviruses, such as YFV, based on several analyses of the nonstructural (NS) proteins NS3 and NS5 (11, 13). The close relationship of DENV to encephalitic flaviviruses may help explain the capacity of DENV to cause neurological disease and, possibly, infection of the CNS in humans (6, 37). Additionally, DENV-induced paralysis has been reported in numerous mouse models (4, 49), but only a few studies have investigated this phenomenon (1,18,20). Presently, whether DENV infects the CNS in natural human infections continues to be a subject of debate (25,30,32).Mice lacking the alpha/beta interferon and gamma interferon receptors (IFN-␣/␤R and IFN-␥R) in the 129/Sv genetic background (AG129) are highly susceptible to disease resembling human DHF/DSS, as well as paralysis, following infection with mouse-passaged variants of DENV2 clinical isolate PL046 (5,35,40,51). In contrast, congenic mice lacking only IFN-␣/␤R (A12...

Spleen Tyrosine Kinase (Syk) Mediates IL-1β Induction by Primary Human Monocytes during Antibody-enhanced Dengue Virus Infection

“…This is particularly informative because DENV does not cause relevant disease in immunocompetent mice unless extremely high inoculums are used (43)(44)(45)(46)(47)(48)(49)(50)(51). Using these valuable antibodies in ADE studies with primary human monocytes allows identification of important signaling pathways that represent potential therapeutic targets for the treatment of severe dengue disease.…”

Type I Interferon Signals in Macrophages and Dendritic Cells Control Dengue Virus Infection: Implications for a New Mouse Model To Test Dengue Vaccines

“…As well as the AG129 mice (11), mice lacking signaling elements downstream of the IFN receptors (IFNRs) (STAT1/ 2), and STAT1 IFNAR double knockout mice are all highly susceptible to DENV infection (12,13). Mice deficient in just the type I IFN receptor are also susceptible to high-titer DENV challenge (14), while mice lacking the type II IFN receptor alone can resist even large doses of DENV without developing significant viremia or pathology (14,15). Besides being important for the initial clearance of the virus, type I IFNs also enhance B cell responses, Ig class switch (16)(17)(18), cell migration (19,20), cross-presentation (21-24), CD4 ϩ T-cell activation (20,25,26), and cytotoxic T-lymphocyte (CTL) expansion (27)(28)(29).…”

Respiratory syncytial virus-like nanoparticle vaccination induces long-term protection without pulmonary disease by modulating cytokines and T-cells partially through alveolar macrophages

“…In line with this, IFN-γ receptor signaling was found to be critical in controlling dengue virus replication. 38 Infection of unimmunized naïve mice with RSV usually does not induce severe lung histopathology since mice are not highly permissive to RSV. 6,8,23 In this study, we observed a substantial degree of lung histopathology in naïve mice after RSV infection probably due to the nature of 1-year-old aged mice and high lung viral loads.…”