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...

Dengue virus (DEN), a flavivirus, causes dengue fever and dengue hemorrhagic fever/dengue shock syndrome, the most common mosquito-borne viral illnesses in humans worldwide. In this study, using STAT1−/− mice bearing two different mutant stat1 alleles in the 129/Sv/Ev background, we demonstrate that IFNR-dependent control of primary DEN infection involves both STAT1-dependent and STAT1-independent mechanisms. The STAT1 pathway is necessary for clearing the initial viral load, whereas the STAT1-independent pathway controls later viral burden and prevents DEN disease in mice. The STAT1-independent responses in mice with primary DEN infection included the early activation of B and NK cells as well as the up-regulation of MHC class I molecules on macrophages and dendritic cells. Infection of bone marrow-derived dendritic cell cultures with either DEN or Sindbis virus, another positive-strand RNA virus, confirmed the early vs late natures of the STAT1-dependent and STAT1-independent pathways. Collectively, these data begin to define the nature of the STAT1-dependent vs the STAT1-independent pathway in vivo.

Sex-associated hormones such as estradiol, testosterone and progesterone have all been shown to modulate immune responses, which can result in differential disease outcomes between males and females, as well as between pregnant and nonpregnant females. Most parasitic diseases, including leishmaniasis, usually result in more severe disease in males compared with females. This review highlights our current knowledge concerning the role of sex hormones in modulating leishmaniasis in both clinical settings and experimental disease models.

T-bet and STAT1 regulate IFN-γ gene transcription in CD4+ T cells, which mediate protection against Leishmania. Here we show that T-bet and STAT1 are required for the induction of an efficient Th1 response during Leishmania donovani infection, but they play distinct roles in determining disease outcome. Both STAT1−/− and T-bet−/− mice failed to mount a Th1 response, but STAT1−/− mice were highly resistant to L. donovani and developed less immunopathology, whereas T-bet−/− mice were highly susceptible and eventually developed liver inflammation. Adoptive cell transfer studies showed that RAG2−/− recipients receiving STAT1+/+ or STAT1−/− T cells developed comparable liver pathology, but those receiving STAT1−/− T cells were significantly more susceptible to infection. These unexpected findings reveal distinct roles for T-bet and STAT1 in mediating host immunity and liver pathology during visceral leishmaniasis.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that is involved in the host