Interferon-Dependent Immunity Is Essential for Resistance to Primary Dengue Virus Infection in Mice, Whereas T- and B-Cell-Dependent Immunity Are Less Critical

Abstract

Dengue virus (DEN) causes dengue fever and dengue hemorrhagic fever/dengue shock syndrome, which are major public health problems worldwide. The immune factors that control DEN infection or contribute to severe disease are neither well understood nor easy to examine in humans. In this study, we used wild-type and congenic mice lacking various components of the immune system to study the immune mechanisms in the response to DEN infection. Our results demonstrate that alpha/beta interferon (IFN-␣/␤) and IFN-␥ receptors have critical, nonoverlapping functions in resolving primary DEN infection. Furthermore, we show that IFN-␣/␤ receptor-mediated action limits initial DEN replication in extraneural sites and controls subsequent viral spread into the central nervous system (CNS). In contrast, IFN-␥ receptor-mediated responses seem to act at later stages of DEN disease by restricting viral replication in the periphery and eliminating virus from the CNS. Mice deficient in B, CD4؉ T, or CD8 ؉ T cells had no increased susceptibility to DEN; however, RAG mice (deficient in both B and T cells) were partially susceptible to DEN infection. In summary, (i) IFN-␣/␤ is critical for early immune responses to DEN infection, (ii) IFN-␥-mediated immune responses are crucial for both early and late clearance of DEN infection in mice, and (iii) the IFN system plays a more important role than T-and B-cell-dependent immunity in resistance to primary DEN infection in mice.Dengue virus (DEN) is a member of the Flavivirus genus in the Flaviviridae family of single-stranded, positive-polarity, enveloped RNA viruses. DEN causes dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/ DSS), the most common mosquito-borne viral illnesses in humans (3, 5). An estimated 50 million new cases of DF and over 250,000 cases of DHF/DSS occur per year in the subtropical and tropical regions of the world (3). Typically, individuals with primary infection by any one of the four distinct DEN serotypes develop DF, an acute febrile illness with arthralgia, myalgia, and headache (13). In some cases, individuals with primary infection or secondary infection by a different serotype may develop the severe, life-threatening form of DF, called DHF/DSS, with increased vascular permeability, thrombocytopenia, focal or generalized hemorrhages, and shock in cases of DSS (15). A small subset of DHF/DSS patients also exhibit severe central nervous system (CNS) symptoms, such as reduced consciousness, convulsions, and encephalitis (4, 44, 50). Currently, no specific treatment for or vaccines against DEN exist, despite an increase in the geographic distribution of the DEN-transmitting Aedes aegypti and Aedes albopictus mosquitoes, the cocirculation of different DEN serotypes, and the increased frequency of DEN epidemics (14, 45). Thus, dengue is an emerging disease and a major public health concern.At present, the mechanisms of DEN-induced disease and immunity are poorly defined, and the protective versus the pathogenic nature of the immune response to...

Genetic and Phenotypic Properties of Vero Cell-Adapted Japanese Encephalitis Virus SA14-14-2 Vaccine Strain Variants and a Recombinant Clone, Which Demonstrates Attenuation and Immunogenicity in Mice

“…The host type I IFN response is critical for restricting replication and dissemination of flaviviruses 10,[54][55][56][57] and JEV SA14-14-2 is capable of inducing morbidity in IFN-deficient mice, 58 indicating that innate-immune antiviral mechanisms contribute to its attenuated phenotype. Studies in primary human monocyte-derived macrophages showed that JEV SA14-14-2 induced similar levels of type I IFN as WT JEV but is more sensitive to its affects.…”

Virus-Induced Decline in Soluble Vascular Endothelial Growth Receptor 2 Is Associated with Plasma Leakage in Dengue Hemorrhagic Fever

“…Such studies are challenging, since the mortality rate of DHF is significantly lower than those of other viral hemorrhagic diseases and deaths typically occur late in infection (4). The lack of a relevant animal model that mimics the pattern of plasma leakage in DHF has not allowed an in vivo experiment to precisely delineate the role of VEGF relative to other cytokines reported to be elevated in DHF, such as IL-2, IFN-␥, tumor necrosis factor alpha, and IFNs, in plasma leakage (6,19,41). However, the temporal pattern of VEGF and its known biological effects argue for its role as a mediator involved in plasma leakage in DHF.…”

A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

“…Our data demonstrate that during DENV infection, iNKT cells produce IFN-␥ and that iNKT cells trans-activate NK cells to produce it. Considering the critical function of IFN-␥ in restricting DENV replication, 48,85 the lack of function of the iNKT cell/NK cell pathway in virus containment in this system is somewhat surprising. The role of NK cells during DENV infection is unclear.…”

“…with 30 LD 50 DENV, a lethal dose that caused death of all animals between days 6 and 8. One LD 50 corresponds to the inoculum necessary to kill 50% of 4-week-old BALB/c mice, a more susceptible strain, 48 and corresponds to approximately 20 PFUs. Clinical manifestations, in particular hypernociception, were observed at about day 3.…”

“…Hematocrit concentration and extravasation of Evans blue dye into the tissues was used as an index of increased vascular permeability, as previously described. 45,48 A portion of liver was obtained from mice euthanized at day 6 and was immediately fixed in 4% buffered formalin, and tissue fragments were embedded in paraffin. Tissue sections 4 m thick were stained using H&E and examined under light microscopy for inflammatory changes using a semiquantitative score.…”