45 research outputs found

    Murine models of scrub typhus associated with host control of <i>Orientia tsutsugamushi</i> infection

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    <div><p>Background</p><p>Scrub typhus, a febrile illness of substantial incidence and mortality, is caused by infection with the obligately intracellular bacterium <i>Orientia tsutsugamushi</i>. It is estimated that there are more than one million cases annually transmitted by the parasitic larval stage of trombiculid mites in the Asia-Pacific region. The antigenic and genetic diversity of the multiple strains of <i>O</i>. <i>tsutsugamushi</i> hinders the advancement of laboratory diagnosis, development of long-lasting vaccine-induced protection, and interpretation of clinical infection. Despite the life-threatening severity of the illness in hundreds of thousands of cases annually, 85–93% of patients survive, often without anti-rickettsial treatment. To more completely understand the disease caused by <i>Orientia</i> infection, animal models which closely correlate with the clinical manifestations, target cells, organ involvement, and histopathologic lesions of human cases of scrub typhus should be employed. Previously, our laboratory has extensively characterized two relevant C57BL/6 mouse models using <i>O</i>. <i>tsutsugamushi</i> Karp strain: a route-specific intradermal model of infection and persistence and a hematogenously disseminated dose-dependent lethal model.</p><p>Principal findings</p><p>To complement the lethal model, here we illustrate a sublethal model in the same mouse strain using the <i>O</i>. <i>tsutsugamushi</i> Gilliam strain, which resulted in dose-dependent severity of illness, weight loss, and systemic dissemination to endothelial cells of the microcirculation and mononuclear phagocytic cells. Histopathologic lesions included expansion of the pulmonary interstitium by inflammatory cell infiltrates and multifocal hepatic lesions with mononuclear cellular infiltrates, renal interstitial lymphohistiocytic inflammation, mild meningoencephalitis, and characteristic typhus nodules.</p><p>Significance</p><p>These models parallel characteristics of human cases of scrub typhus, and will be used in concert to understand differences in severity which lead to lethality or host control of the infection and to address the explanation for short duration of heterologous immunity in <i>Orientia</i> infection.</p></div

    Body and spleen weight change of mice inoculated intravenously or intradermally with <i>O</i>. <i>tsutsugamushi</i> Gilliam strain.

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    <p>Percent body weight change (<b>A</b>) or spleen weight in milligrams (<b>B</b>) of animals inoculated intravenously with either 7.5x10<sup>6</sup> (high dose, <b>circles</b>), 7.5x10<sup>5</sup> (mid-dose, <b>squares</b>), 7.5x10<sup>3</sup> (low dose, <b>triangles</b>), or intradermally with 2.5x10<sup>5</sup> organisms (<b>asterisks</b>) as compared to sham inoculated control (<b>diamonds</b>). **, <i>p</i><0.01, ***, <i>p</i><0.001.</p

    Location <i>of O</i>. <i>tsutsugamushi</i> Gilliam antigens following i.v. or i.d. inoculation.

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    <p>Sections of the lungs at 9 dpi after i.v. inoculation reveal the presence of <i>Orientia</i> antigens (red) in interstitial capillary vessels and alveolar septa (<b>A</b>). Orientia antigens co-localize with splenic (<b>B</b>) and hepatic (<b>C</b>) macrophages. Orientia antigen in a cerebral vessel surrounded by a characteristic typhus nodule 18 dpi after i.d. inoculation (<b>D</b>, 400X, inset 1,000X, bars = 100 μm).</p

    Development of antibodies to <i>O</i>. <i>tsutsugamushi</i> Gilliam strain following challenge.

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    <p>Development of antibodies to <i>O</i>. <i>tsutsugamushi</i> Gilliam strain following challenge.</p

    Bacterial dissemination after infection with <i>O</i>. <i>tsutsugamushi</i> Gilliam strain.

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    <p>Bacterial loads in spleen (<b>A</b>), lung (<b>B</b>), liver (<b>C</b>) and kidney (<b>D</b>) after i.v. inoculation with high (<b>circles</b>), mid (<b>squares)</b>, or low dose (<b>triangles</b>), or via i.d. inoculation <b>(asterisks)</b>.</p

    Dose-dependent severity of histopathologic renal lesions and lung pathology in mice inoculated i.v. or i.d. with <i>O</i>. <i>tsutsugamushi</i> Gilliam strain.

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    <p>Representative histopathologic renal inflammatory infiltrates between tubules of the renal cortex (arrows) at 6 dpi after i.d. inoculation (<b>A</b>, left) and i.v. mid-dose at 15 dpi (<b>A</b>, right, 100X). Renal inflammatory index (<b>B</b>) or lung pathology score (<b>C</b>) after i.v. inoculation with high (<b>circles</b>), mid (<b>squares</b>) low (<b>triangles</b>) dose or i.d. (<b>asterisks</b>) with <i>O</i>. <i>tsutsugamushi</i>. *, <i>p</i><0.05, **, <i>p</i><0.01, ***, <i>p</i><0.001. Asterisks with bars indicate data points statistically different from baseline.</p

    Seroconversion after infection with <i>O</i>. <i>tsutsugamushi</i> Gilliam strain.

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    <p>Reciprocal endpoint IgG titer of mice as determined by indirect IFA after i.v. inoculation with high (<b>A</b>), mid (<b>B</b>), or low dose (<b>C</b>) or via the intradermal route (<b>D</b>). The IgG isotype response was further categorized into IgG1 (<b>E)</b> or IgG2c (<b>F</b>) at the final time point, 15 dpi for the i.v. route and 30 dpi for the i.d. route. Serum which was nonreactive at a 1:64 titer is represented by a value of zero.</p

    CpG-B-induced death of <i>R. australis</i>-infected mice is independent of pDC.

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    <p>Depletion of pDC was performed as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034062#s2" target="_blank"><i>Methods</i></a>. At day 2 after infection with <i>R. australis</i> (5×10<sup>5</sup> pfu), 50 µg of CpG-B per mouse were injected i.v. into control or pDC-depleted mice. Mouse survival (6–8 mice per group) was monitored for 14 days.</p

    Treatment with CpG-B induced cell apoptosis through IDO.

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    <p>Apoptotic cells in spleen tissues at day 5 postinfection were detected by TUNEL assay (magnification ×20). Green (fluorescein) staining of apoptotic cells and blue (DAPI) staining of nuclei. Shown are the representative results from three independent experiments.</p

    Multiple intracellular cytokines produced by CD4<sup>+</sup> and CD8<sup>+</sup> T cells.

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    <p>At day 2 after infection with 5×10<sup>5</sup> pfu of <i>R. australis</i>, 50 µg of ODN control (ODN 1826 control) and CpG-B (ODN 1826) per mouse were injected i.v. into WT and IDO<sup>−/−</sup> mice (4 mice per group). At day 5 post-infection, spleen cells (1×10<sup>6</sup>/ml) from individual mice were restimulated with PMA/Ionomycin/GolgiStop for 5 h. Multiple intracellular cytokines as indicated were measured in CD4<sup>+</sup> and CD8<sup>+</sup> T cells. The percentages of intracellular cytokine production in gated T cells were shown as mean ± SD in the corner (A). Representative statistical data are shown from one of three independent experiments. * <i>p</i><0.05 (B).</p
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