Immunohistochemical Study of Scrub Typhus: A Report of Two Cases

Tseng, Bo-Yuan; Yang, Huihua; Liou, Ji-Hung; Chen, Li‐Kuang; Hsu, Yung‐Hsiang

doi:10.1016/s1607-551x(08)70103-7

Cited by 35 publications

(28 citation statements)

References 18 publications

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“…Indeed, up-regulation of IDO-1 was previously demonstrated in OT-infected monocyte-derived macrophages [10]. Besides, we believe that macrophages could be a secondary target of infection to harbour the intracellular organisms to remote organs; which was supported by the detection of OT in circulating monocyte-like blood cells of patients with acute scrub typhus [48] and in macrophages located in the liver, the spleen, and the lymph nodes of fatal cases of scrub typhus [49], [50].…”

Section: Discussionsupporting

confidence: 60%

Activation of Indoleamine 2,3-Dioxygenase in Patients with Scrub Typhus and Its Role in Growth Restriction of Orientia tsutsugamushi

et al. 2012

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BackgroundOur earlier genome-wide expression study revealed up-regulation of a tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO1), in patients with scrub typhus. This gene has been previously reported to have anti-microbial activity in a variety of infectious diseases; therefore, we aimed to prove whether it is also involved in host defense against Orientia tsutsugamushi (OT) infection.Methodology/Principal FindingsUsing LC-MS, we observed an increased ratio of serum L-kynurenine to serum L-tryptophan in patients with scrub typhus, which suggests an active catalytic function of this enzyme upon the illness. To evaluate the effect of IDO1 activation on OT infection, a human macrophage-like cell line THP-1 was used as a study model. Although transcription of IDO1 was induced by OT infection, its functional activity was not significantly enhanced unless the cells were pretreated with IFN-γ, a potent inducer of IDO1. When the degree of infection was evaluated by quantitative real-time PCR, the relative number of OT 47 kDa gene per host genes, or infection index, was markedly reduced by IFN-γ treatment as compared to the untreated cultures at five days post-infection. Inhibition of IDO1 activity in IFN-γ treated cultures by 1-methyl-L-tryptophan, a competitive inhibitor of IDO1, resulted in partial restoration of infection index; while excessive supplementation of L-tryptophan in IFN-γ treated cultures raised the index to an even higher level than that of the untreated ones. Altogether, these data implied that IDO1 was partly involved in restriction of OT growth caused by IFN-γ through deprivation of tryptophan.Conclusions/SignificanceActivation of IDO1 appeared to be a defensive mechanism downstream of IFN-γ that limited intracellular expansion of OT via tryptophan depletion. Our work provided not only the first link of in vivo activation of IDO1 and IFN-γ-mediated protection against OT infection but also highlighted the promise of this multifaceted gene in scrub typhus research.

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Section: Discussionsupporting

confidence: 60%

Activation of Indoleamine 2,3-Dioxygenase in Patients with Scrub Typhus and Its Role in Growth Restriction of Orientia tsutsugamushi

et al. 2012

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“…O. tsutsugamushi has been found in many organs of infected patients and experimental animals, including lung, heart, brain, liver, spleen, kidney, pancreas, appendix and skin [9], [30], [31], [32]. A clear organ preference of O. tsutsugamushi has never been revealed, and the route and kinetics of dissemination are unknown.…”

Section: Resultsmentioning

confidence: 99%

Dissemination of Orientia tsutsugamushi and Inflammatory Responses in a Murine Model of Scrub Typhus

et al. 2014

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Central aspects in the pathogenesis of scrub typhus, an infection caused by Orientia (O.) tsutsugamushi, have remained obscure. Its organ and cellular tropism are poorly understood.The purpose of this study was to analyze the kinetics of bacterial dissemination and associated inflammatory responses in infected tissues in an experimental scrub typhus mouse model, following infection with the human pathogenic strain Karp. We provide a thorough analysis of O. tsutsugamushi infection in inbred Balb/c mice using footpad inoculation, which is close to the natural way of infection. By a novel, highly sensitive qPCR targeting the multi copy traD genes, we quantitatively monitored the spread of O. tsutsugamushi Karp from the skin inoculation site via the regional lymph node to the internal target organs. The highest bacterial loads were measured in the lung. Using confocal imaging, we also detected O. tsutsugamushi at the single cell level in the lung and found a predominant macrophage rather than endothelial localization. Immunohistochemical analysis of infiltrates in lung and brain revealed differently composed lesions with specific localizations: iNOS-expressing macrophages were frequent in infiltrative parenchymal noduli, but uncommon in perivascular lesions within these organs. Quantitative analysis of the macrophage response by immunohistochemistry in liver, heart, lung and brain demonstrated an early onset of macrophage activation in the liver. Serum levels of interferon (IFN)-γ were increased during the acute infection, and we showed that IFN-γ contributed to iNOS-dependent bacterial growth control.Our data show that upon inoculation to the skin, O. tsutsugamushi spreads systemically to a large number of organs and gives rise to organ-specific inflammation patterns. The findings suggest an essential role for the lung in the pathogenesis of scrub typhus. The model will allow detailed studies on host-pathogen interaction and provide further insight into the pathogenesis of O. tsutsugamushi infection.

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“…The alterations in the Ang/Tie2 axis are likely to be pathogenic hallmarks in OtK-infected brains and lungs, and possibly in other major organs of OtK infection. The immunofluorescent staining data have also validated and expanded our understanding on Orientia bacterial localization in severe scrub typhus cases [40,49]. Given the relatively low bacterial loads in the brains and the complex contribution of cytokines/chemokines to neuroinflammation [50], it will be important to further examine the pathophysiological mechanisms underlying CNS involvement and immune-mediated vascular activation in severe scrub typhus.…”

Section: Discussionmentioning

confidence: 99%

Type 1-skewed neuroinflammation and vascular damage associated with Orientia tsutsugamushi infection in mice

et al. 2017

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BackgroundScrub typhus is a life-threatening disease, due to infection with O. tsutsugamushi, a Gram-negative bacterium that preferentially replicates in endothelial cells and professional phagocytes. Meningoencephalitis has been reported in scrub typhus patients and experimentally-infected animals; however, the neurological manifestation and its underlying mechanisms remain poorly understood. To address this issue, we focused on Orientia tsutsugamushi Karp strain (OtK), and examined host responses in the brain during lethal versus self-healing scrub typhus disease in our newly established murine models.Principle findingsFollowing inoculation with a lethal dose of OtK, mice had a significant increase in brain transcripts related to pathogen-pattern recognition receptors (TLR2, TLR4, TLR9), type-1 responses (IFN-γ, TNF-α, CXCL9, CXCR3), and endothelial stress/damage such as angiopoietins, but a rapid down-regulation of Tie2. Sublethal infection displayed similar trends, implying the development of type 1-skewed proinflammatory responses in infected brains, independent of time and disease outcomes. Focal hemorrhagic lesions and meningitis were evident in both infection groups, but pathological changes were more diffuse and frequent in lethal infection. At 6–10 days of lethal infection, the cortex and cerebellum sections had increased ICAM-1-positive staining in vascular cells, as well as increased detection of CD45+ leukocytes, CD3+ T cells, IBA1+ phagocytes, and GFAP+ astrocytes, but a marked loss of occludin-positive tight junction staining, implying progressive endothelial activation/damage and cellular recruitment in inflamed brains. Orientia were sparse in the brains, but readily detectable within lectin+ vascular and IBA-1+ phagocytic cells. These CNS alterations were consistent with type 1-skewed, IL-13-suppressed responses in lethally-infected mouse lungs.SignificanceThis is the first report of type 1-skewed neuroinflammation and cellular activation, accompanied with vascular activation/damage, during OtK infection in C57BL/6 mice. This study not only enhances our understanding of the pathophysiological mechanisms of scrub typhus, but also correlates the impact of immune and vascular dysfunction on disease pathogenesis.

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Immunohistochemical Study of Scrub Typhus: A Report of Two Cases

Cited by 35 publications

References 18 publications

Activation of Indoleamine 2,3-Dioxygenase in Patients with Scrub Typhus and Its Role in Growth Restriction of Orientia tsutsugamushi

Activation of Indoleamine 2,3-Dioxygenase in Patients with Scrub Typhus and Its Role in Growth Restriction of Orientia tsutsugamushi

Dissemination of Orientia tsutsugamushi and Inflammatory Responses in a Murine Model of Scrub Typhus

Type 1-skewed neuroinflammation and vascular damage associated with Orientia tsutsugamushi infection in mice

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