Significantly Higher Cytokine and Chemokine Levels in Patients with Japanese Spotted Fever than in Those with Tsutsugamushi Disease

Kojima, Tai; Iwasaki, Hiromichi; Ikegaya, Satoshi; Takada, Nobuhiro; Tamaki, Yukiko; Tabara, Kenji; Ueda, Takanori

doi:10.1128/jcm.03238-13

Cited by 20 publications

(11 citation statements)

References 32 publications

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“…There has been a report of R. japonica infection focused on inflammatory cytokines. In R. japonica infection, IL-6, IFN-γ, TNF-α, IL-8, MCP-1a, and MIP-1β levels were elevated according to the previous report [ 7 ].…”

Section: Discussionmentioning

confidence: 61%

Transition of Serum Cytokine Concentration in Rickettsia japonica Infection

Kondo

Matsushima

Mizutani

et al. 2020

Infectious Disease Reports

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(1) Background. Rickettsia japonica (R. japonica) infection induces severe inflammation, and the disappearance of eosinophil in the acute stage is one of the phenomena. (2) Materials and Methods. In the current study, we measured the serum concentrations of Th1, Th2, and Th17 cytokines in the acute and recovery stages. (3) Results. In the acute phase, IL-6 and IFN-γ levels were elevated and we speculated that they played a role as a defense mechanism against R. japonica. The high concentration of IFN-γ suppressed the differentiation of eosinophil and induced apoptosis of eosinophil, leading to the disappearance of eosinophil. On day 7, IL-6 and IFN-γ concentrations were decreased, and Th2 cytokines such as IL-5 and IL-9 were slightly increased. On day 14, eosinophil count recovered to the normal level. The transition of serum cytokine concentration in R. japonica infection was presented. (4) Conclusions. IL-6 and IFN-γ seem to be critical cytokines as defense mechanism against R. japonica in the acute phase, and this may deeply connect to the decrease of eosinophil.

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Section: Discussionmentioning

confidence: 61%

Transition of Serum Cytokine Concentration in Rickettsia japonica Infection

Kondo

Matsushima

Mizutani

et al. 2020

Infectious Disease Reports

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“…Rickettsiae invade and proliferate within vascular endothelial cells and cause a vasculitis-like systemic disease ( 30 ). In a study by Tai et al, cytokine and chemokine levels were higher in patients with JSF than in patients with ST, but no significant association was observed between cytokine levels and the clinical severity of disease ( 17 ). Although previous human and animal model studies have revealed the pathogenic mechanisms of severe rickettsial infections ( 31 , 32 ), the mechanisms of severe JSF remain not fully understood.…”

Section: Discussionmentioning

confidence: 97%

“…For a few patients with JSF and ST, severe conditions develop ( 14 – 17 ). However, clinical information regarding JSF has been limited by lack of an appropriate case definition, lack of in-depth information, and studies involving small sample sizes ( 14 , 16 ).…”

mentioning

confidence: 99%

Distinguishing Japanese Spotted Fever and Scrub Typhus, Central Japan, 2004– 2015

Sando¹,

Suzuki²,

Katoh³

et al. 2018

Emerg. Infect. Dis.

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Japanese spotted fever (JSF) and scrub typhus (ST) are endemic to Japan and share similar clinical features. To document the clinical and epidemiologic characteristics that distinguish these 2 rickettsial diseases, during 2004–2015 we recruited 31 JSF patients, 188 ST patients, and 97 nonrickettsial disease patients from the southern Boso Peninsula of Japan. JSF occurred during April–October and ST during November–December. Patients with JSF and ST were significantly older and more likely to reside in wooded areas than were patients with nonrickettsial diseases. Spatial analyses revealed that JSF and ST clusters rarely overlapped. Clinical findings more frequently observed in JSF than in ST patients were purpura, palmar/plantar rash, hyponatremia, organ damage, and delayed defervescence after treatment. Although their clinical features are similar, JSF and ST differ in seasonality, geographic distribution, physical signs, and severity. Because a considerable percentage of patients did not notice rash and eschar, many rickettsial diseases might be underdiagnosed in Japan.

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“…O . tsutsugamushi lacks LPS, but induces TNFα expression during infection of human patients, experimentally infected mice, primary cells, and cultivated host cells [ 34 , 38 , 41 , 68 – 72 ]. We therefore utilized TNFα as an external stimulus for NF-κB.…”

Section: Discussionmentioning

confidence: 99%

Orientia tsutsugamushi uses two Ank effectors to modulate NF-κB p65 nuclear transport and inhibit NF-κB transcriptional activation

Evans¹,

Rodino²,

Adcox³

et al. 2018

PLoS Pathog

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Orientia tsutsugamushi causes scrub typhus, a potentially fatal infection that threatens over one billion people. Nuclear translocation of the transcription factor, NF-κB, is the central initiating cellular event in the antimicrobial response. Here, we report that NF-κB p65 nuclear accumulation and NF-κB-dependent transcription are inhibited in O. tsutsugamushi infected HeLa cells and/or primary macrophages, even in the presence of TNFα. The bacterium modulates p65 subcellular localization by neither degrading it nor inhibiting IκBα degradation. Rather, it exploits host exportin 1 to mediate p65 nuclear export, as this phenomenon is leptomycin B-sensitive. O. tsutsugamushi antagonizes NF-κB-activated transcription even when exportin 1 is inhibited and NF-κB consequently remains in the nucleus. Two ankyrin repeat-containing effectors (Anks), Ank1 and Ank6, each of which possess a C-terminal F-box and exhibit 58.5% amino acid identity, are linked to the pathogen’s ability to modulate NF-κB. When ectopically expressed, both translocate to the nucleus, abrogate NF-κB-activated transcription in an exportin 1-independent manner, and pronouncedly reduce TNFα-induced p65 nuclear levels by exportin 1-dependent means. Flag-tagged Ank 1 and Ank6 co-immunoprecipitate p65 and exportin 1. Both also bind importin β1, a host protein that is essential for the classical nuclear import pathway. Importazole, which blocks importin β1 activity, abrogates Ank1 and Ank6 nuclear translocation. The Ank1 and Ank6 regions that bind importin β1 also mediate their transport into the nucleus. Yet, these regions are distinct from those that bind p65/exportin 1. The Ank1 and Ank6 F-box and the region that lies between it and the ankyrin repeat domain are essential for blocking p65 nuclear accumulation. These data reveal a novel mechanism by which O. tsutsugamushi modulates the activity and nuclear transport of NF-κB p65 and identify the first microbial proteins that co-opt both importin β1 and exportin 1 to antagonize a critical arm of the antimicrobial response.

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Significantly Higher Cytokine and Chemokine Levels in Patients with Japanese Spotted Fever than in Those with Tsutsugamushi Disease

Cited by 20 publications

References 32 publications

Transition of Serum Cytokine Concentration in Rickettsia japonica Infection

Transition of Serum Cytokine Concentration in Rickettsia japonica Infection

Distinguishing Japanese Spotted Fever and Scrub Typhus, Central Japan, 2004– 2015

Orientia tsutsugamushi uses two Ank effectors to modulate NF-κB p65 nuclear transport and inhibit NF-κB transcriptional activation

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