Orientia tsutsugamushi induced endothelial cell activation via the NOD1-IL-32 pathway

Cho, Kyung Ah; Jun, Yoon Hee; Suh, Jee Won; Kang, Jae Seung; Choi, Hee Jung; Woo, So Youn

doi:10.1016/j.micpath.2010.05.001

Cited by 41 publications

(43 citation statements)

References 44 publications

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“…As stated above, using an adenoviral delivery vector, IL-32γ increased expression of NOD2 and TLR2 (13). Silencing of endogenous NOD1 resulted in a reduction of IL-32 but also of IL-1β, IL-6, IL-8, and ICAM-1 (31). In summary, the in vivo effect of IL-32γ expression during DSS colitis exhibits the dual function of innate responses in the intestine.…”

Section: Protective Role For Tnfα In the Innate Response Of The Intesmentioning

confidence: 62%

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

Choi

Bae

Hong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Inflammatory cytokines mediate inflammatory bowel diseases (IBDs) and cytokine blocking therapies often ameliorate the disease severity. IL-32 affects inflammation by increasing the production of IL-1, TNFα, and several chemokines. Here, we investigated the role of IL-32 in intestinal inflammation by generating a transgenic (TG) mouse expressing human IL-32γ (IL-32γ TG). Although IL-32γ TG mice are healthy, constitutive serum and colonic tissue levels of TNFα are elevated. Compared with wild-type (WT) mice, IL-32γ TG mice exhibited a modestly exacerbated acute inflammation early following the initiation of dextran sodium sulfate (DSS)-induced colitis. However, after 6 d, there was less colonic inflammation, reduced tissue loss, and improved survival rate compared with WT mice. Associated with attenuated tissue damage, colonic levels of TNFα and IL-6 were significantly reduced in the IL-32γ TG mice whereas IL-10 was elevated. Cultured colon explants from IL-32γ TG mice secreted higher levels of IL-10 compared with WT mice and lower levels of TNFα and IL-6. Constitutive levels of IL-32γ itself in colonic tissues were significantly lower following DSS colitis. Although the highest level of serum IL-32γ occurred on day 3 of colitis, IL-32 was below constitutive levels on day 9. The ability of IL-32γ to increase constitutive IL-10 likely reduces TNFα, IL-6, and IL-32 itself accounting for less inflammation. In humans with ulcerative colitis (UC), serum IL-32 is elevated and colonic biopsies contain IL-32 in inflamed tissues but not in uninvolved tissues. Thus IL-32γ emerges as an example of how innate inflammation worsens as well as protects intestinal integrity.

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Section: Protective Role For Tnfα In the Innate Response Of The Intesmentioning

confidence: 62%

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

Choi

Bae

Hong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In vivo, tlr2 Ϫ/Ϫ mice had no defect in cytokine transcription, as measured between days 12 and 18 p.i. Rather than suggesting incongruence, these results reflect two fundamentally different phases of infection: while TLR2 appears to have a role in early recognition, as shown in vitro, TLR2-independent pathways are able to maintain inflammation once the infection is established in vivo, e.g., via cytosolic receptors such as NOD1 (57) or via the inflammasome (53). tlr2 Ϫ/Ϫ mouse BMDCs may equally be able to respond to O. tsutsugamushi infection with cytokine secretion at time points later than 24 h p.i.…”

Section: Discussionmentioning

confidence: 76%

Toll-Like Receptor 2 Recognizes Orientia tsutsugamushi and Increases Susceptibility to Murine Experimental Scrub Typhus

et al. 2016

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Scrub typhus is a potentially lethal infection that is caused by the obligate intracellular bacterium Orientia tsutsugamushi. The roles of Toll-like receptor 2 (TLR2) and TLR4 in innate recognition of O. tsutsugamushi have not been elucidated. By overexpression of TLR2 or TLR4 in HEK293 cells, we demonstrated that TLR2, but not TLR4, recognizes heat-stable compounds of O. tsutsugamushi that were sensitive to treatment with sodium hydroxide, hydrogen peroxide, and proteinase K. TLR2 was required for the secretion of tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6) by dendritic cells. In an intradermal mouse infection model, TLR2-deficient mice did not show impaired control of bacterial growth or reduced survival. Moreover, after intraperitoneal infection, TLR2-deficient mice were even more resistant to lethal infection than C57BL/6 wild-type mice, which showed stronger symptoms and lower survival rates during the convalescent phase. Compared to the time of reduction of bacterial loads in TLR2-deficient mice, the reduction of bacterial loads in infected organs was accelerated in wild-type mice. The higher mortality of wild-type mice was associated with increased concentrations of serum alkaline phosphatase but not aspartate aminotransferase. The transcription of mRNA for TNF-␣ and IL-6 decreased more rapidly in peritoneum samples from wildtype mice than in those from TLR2-deficient mice and was therefore not a correlate of increased susceptibility. Thus, although TLR2 is an important mediator of the early inflammatory response, it is dispensable for protective immunity against O. tsutsugamushi. Increased susceptibility to O. tsutsugamushi infection in TLR2-competent mice rather suggests a TLR2-related immunopathologic effect. Scrub typhus is a neglected chigger-borne zoonosis caused by the obligate intracellular bacterium Orientia tsutsugamushi. Although scrub typhus has lost much of its former threat thanks to the advent of antibiotic therapy, fatal infections continue to be reported, yet it remains largely unknown how bacterial virulence factors and host immunity mutually contribute to the pathogenesis of scrub typhus (1).In mammals, the Toll-like receptor (TLR) system has evolved as a germ line-encoded, ancient repertoire of pattern recognition receptors. Conserved structures on the surface of microorganisms consisting of lipoproteins and lipopeptides (2, 3) and of lipopolysaccharide (LPS) in Gram-negative bacteria (4) are recognized by TLR2 and TLR4, respectively, and trigger immediate antimicrobial responses. As part of the first line of immune defense, these responses help to limit infection success and shape the development of protective adaptive immunity. TLR ligation, mediated by MyD88-or TRIF-dependent pathways, results in activation of transcription factors, such as nuclear factor (NF)-B, activated protein-1 (AP-1), or interferon regulatory transcription factors (IRFs) (5).Many studies have supported a protective effect for TLR2 and TLR4 during bacterial and fungal infections in mouse models...

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“…Intracellular PRRs, including nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-related pathway, are known to contribute to inflammasome activation in O . tsutsugamushi -infected EC and IL-1β production from infected macrophages [26,27]. However, unlike other Gram-negative bacteria or closely related bacteria from the genus Rickettsia , TLR4 and TLR2 seem to play no or limited roles in the uptake of or defense against Orientia , due to the lack of lipopolysaccharide and peptidoglycan in its cell wall [28].…”

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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Orientia tsutsugamushi induced endothelial cell activation via the NOD1-IL-32 pathway

Cited by 41 publications

References 44 publications

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

Paradoxical effects of constitutive human IL-32γ in transgenic mice during experimental colitis

Toll-Like Receptor 2 Recognizes Orientia tsutsugamushi and Increases Susceptibility to Murine Experimental Scrub Typhus

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

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