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
Summary We and others have previously shown that IL-12 is indispensable for immunity and is required for optimal antiparasitic activity of antimonials in experimental visceral leishmaniasis caused by Leishmania donovani. In this study we investigated the role of STAT4 in immunity against L. donovani using STAT4 knockout mice and also determined the effect of STAT4 deficiency in response to antimonial therapy. Upon infection with L. donovani, stat4−/− BALB/c and C57BL/6 mice showed enhanced susceptibility to Leishmania during late time points of infection which was associated with a marked reduction in Th1 responses and hepatic immunopathology. Interestingly, these defects in Th1 responses in stat4−/− did not impair the antimonial chemotherapy as both stat4−/− and WT mice showed comparable levels of parasite clearance from the liver and spleen. These findings highlight the role of STAT4 in immunity to L. donovani infection and also provide evidence that STAT4 is dispensable for antimonial based chemotherapy.
The signal transducer and activator of transcription 1 (STAT1) signaling pathway mediates the biological functions of IFN-gamma. We have previously shown that the STAT1 pathway is indispensable for host resistance against Leishmania major infection. In this study, we examined the role of STAT1 in lymphocytes and specifically CD4(+) and CD8(+) T cells in mediating immunity against L. major by transferring T cells from wild-type (WT) and STAT1(-/-) C57BL/6 mice into Rag2(-/-) C57BL/6 mice. Rag2(-/-) mice reconstituted with unfractionated STAT1(-/-) splenocytes (B cells and T cells) failed to mount an efficient Th1 response after L. major infection, produced more IL-4, and developed large lesions full of parasites. In contrast, Rag2(-/-) mice reconstituted with WT (STAT1(+/+)) splenocytes mounted a Th1 response and developed self-resolving lesions. Studies using Rag2(-/-) recipients that received a combination of purified CD4(+) and CD8(+) T cells from WT or STAT1(-/-) mice revealed that STAT1 deficiency in CD4(+) T cells, but not in CD8(+) T cells, leads to development of chronic, nonhealing lesions and systemic dissemination of parasites into the spleen after L. major infection. Further studies using Rag2(-/-) recipients of WT Thy1.1(+) and STAT1(-/-) Thy1.2(+) T cells showed that STAT1 in CD4(+) T cells was not required for Th1 differentiation during L. major infection. However, it was critical for up-regulation of CXCR3 on CD4(+) T cells and their migration to the regional lymph node and the cutaneous site of infection. Together, these studies indicate that the STAT1 pathway in CD4(+) T cells plays a critical role in immunity against L. major by controlling the migration of Th1 cells to the site of infection rather than their generation. Further, they reveal an essential role for CD4(+) T cell STAT1 in preventing systemic dissemination of L. major infection.
*Corresponding Author: Phone: (614) .edu. Δ Author Contributions: G.G., K.J.P., and D.A. contributed equally to this work Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsinfecdis.5b00081. Procedures and spectral data for the stepwise synthesis of pentalinonsterol (PDF) NotesThe authors declare no competing financial interest. HHS Public AccessAuthor manuscript ACS Infect Dis. Author manuscript; available in PMC 2017 December 15. Author Manuscript Author Manuscript Author Manuscript Author ManuscriptVisceral leishmaniasis (VL), caused by the protozoan parasite Leishmania donovani, is a global health problem affecting millions of people worldwide. Treatment of VL largely depends on therapeutic drugs such as pentavalent antimonials, amphotericin B, and others, which have major drawbacks due to drug resistance, toxicity, and high cost. In this study, for the first time, we have successfully demonstrated the synthesis and antileishmanial activity of the novel sterol pentalinonsterol (PEN), which occurs naturally in the root of a Mexican medicinal plant, Pentalinon andrieuxii. In the experimental BALB/c mouse model of VL induced by infection with L. donovani, intravenous treatment with liposome-encapsulated PEN (2.5 mg/kg) led to a significant reduction in parasite burden in the liver and spleen. Furthermore, infected mice treated with liposomal PEN showed a strong host-protective TH 1 immune response characterized by IFN-γ production and formation of matured hepatic granulomas. These results indicate that PEN could be developed as a novel drug against VL. Graphical abstractKeywords visceral leishmaniasis; liposome; novel sterol synthesis; antileishmanial Visceral leishmaniasis (VL) is caused by the obligate intracellular parasites Leishmania donovani and Leishmania infantum chagasi via transmission by a sand fly vector. Half a million people are infected with VL, and over 60 000 succumb to the disease annually. The WHO classifies VL as a neglected tropical disease of global health concern. As a potentially life-threatening disease, VL is characterized by parasitic invasion of the blood and reticuloendothelial system, which affects internal organs such as the spleen, liver, and bone marrow. 1 There are currently no licensed vaccines, and chemotherapy is the mainstay to combat the disease. Generally, treatments utilize antileishmanial drugs such as sodium stibogluconate (SSG), pentamidine, amphotericin B (AmpB), liposomal AmpB, miltefosine, and others. 2 These drugs suffer from significant drawbacks, including the need for parenteral routes of administration, poor patient compliance due to long treatment lengths and toxicity, and/or high cost, which limit their use in disease-endemic regions. For more than 50 years, the most common treatment has been antimony, which has potentially cardiotoxic side effects. 3 Additionally, AmpB has been associated with nephrotoxicity. 4 The only promising oral treatment, miltefosine (Impavido, ...
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