Neuritis and Gastrointestinal Hemorrhage in Scrub Typhus Patients

Kim, Dong-Min; Yun, Na Ra; Lim, Sung‐Chul

doi:10.4269/ajtmh.14-0478

“…A recent report involving hematoxylin‐eosin staining and immunohistochemical staining of samples from patients with hemorrhagic ulcers caused by scrub typhus confirmed that the main pathogenesis of scrub typhus involves neuritis as well as vasculitis. Moreover, in some cases, hemorrhage was found to aggravate due to neuritis‐induced failure in the nerve defense mechanism . However, in our patients, the prevalence of hemorrhage was significantly lower in the OT‐PU group than in the HP‐PU group (26 of 79, 32.9% vs 8 of 62, 12.9%; P = .007).…”

Section: Discussioncontrasting

confidence: 49%

“…It can be speculated that direct involvement of systemic vasculitis leads to gastrointestinal symptoms and signs . Scrub typhus ulcer is characterized by acute inflammatory cell infiltration and thrombus in small vessel, which is considered characteristic feature of vasculitis . It need more study on comparison of pathogenetic mechanisms and pathology between H. pyroli ulcer and scrub typhus ulcer.…”

Section: Discussionmentioning

confidence: 99%

Endoscopic characteristics of infection‐associated peptic ulcers

Choi

¹

,

Kim

²

,

Lee

³

et al. 2017

Helicobacter

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This is the first study to compare endoscopic features of peptic ulcers caused by H. pylori and O. tsutsugamushi. Peptic ulcers in patients with H. pylori infection occurred predominantly in the antrum/body/lesser curvature and presented with single, round/oval lesions, while ulcers in patients with scrub typhus occurred predominantly in the antrum/greater curvature and presented with multiple, irregular lesions. Scrub typhus should be considered as a cause of duodenal ulcer in scrub typhus-endemic areas.

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“…2E) and may indicate that the upregulation of ALT and AMY might be highly dependent on IFN-γ stimulation. Dehydration may also manifest in severely infected mice, as evidenced by elevated minerals in the blood attributed to gastrointestinal dysfunction, akin to observations in patients[57, 58].…”

Section: Discussionmentioning

confidence: 94%

Lack of the IFN-γ signal leads to lethalOrientia tsutsugamushiinfection in mice with skin eschar lesions

Liang,

Wang,

Sun

et al. 2024

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Scrub typhus is an acute febrile disease due toOrientia tsutsugamushi(Ot) infection and can be life-threatening with organ failure, hemorrhage, and fatality. Yet, little is known as to how the host reacts toOtbacteria at early stages of infection; no reports have addressed the functional roles of type I versus type II interferon (IFN) responses in scrub typhus. In this study, we used comprehensive intradermal (i.d.) inoculation models and two clinically predominantOtstrains (Karp and Gilliam) to uncover early immune events. Karp infection induced sequential expression ofIfnbandIfngin inflamed skin and draining lymph nodes at days 1 and 3 post-infection. Using doubleIfnar1-/-Ifngr1-/-andStat1-/-mice, we found that deficiency in IFN/STAT1 signaling resulted in lethal infection with profound pathology and skin eschar lesions, that resembled to human scrub typhus. Further analyses demonstrated that deficiency in IFN-γ, but not IFN-I, resulted in impaired NK cell and macrophage activation and uncontrolled bacterial growth and dissemination, leading to metabolic dysregulation, excessive inflammatory cell infiltration, and exacerbated tissue damage. NK cells were found to be the major cellular source of early IFN-γ, contributing to the initialOtcontrol. In vitro studies with dendritic cell cultures revealed a superior antibacterial effect offered by IFN-γ than IFN-β. Comparative in vivo studies with Karp- and Gilliam-infection revealed a crucial role of IFN-γ signaling in protection against progression of eschar lesions andOtinfection lethality. Additionally, our i.d. mouse models of lethal infection with eschar lesions are promising tools for immunological study and vaccine development for scrub typhus.SummaryScrub typhus can lead to severe complications and even fatality if not treated properly; however, the early host immune responses toOtbacterium infection remain unclear. This study focused on the functional roles of IFNs in i.d. inoculation mouse models of scrub typhus. We found that mice lacking IFN receptors were highly susceptible toOtinfection, which resulted in severe pathology and skin eschar lesions that resembled to human scrub typhus. Further investigation revealed that the lack of IFN-γ, but not IFN-I, resulted in dysregulated innate immune responses, leading to uncontrolled bacterial burdens and tissue damage. Using IFN-γ reporter mice and neutralizing antibody treatment, we confirmed that NK cells were the major source of early IFN-γ, and thus played a key role in controllingOtdissemination. Moreover, our comparative studies with twoOtstrains revealed bacterium strain- and dose-dependent eschar formation and disease severity. In conclusion, our study highlights the crucial role of IFN-γ signaling in ensuring host protection againstOtinfection. Our mouse models resemble skin eschar lesions and lethal infections observed in human disease, offering potential for future immunological studies on scrub typhus.

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“…This is not consistent with the histological result which shows extensive necrosis in the absence of IFN-γ signaling (Fig 2E ) and may indicate that the upregulation of ALT and AMY might be highly dependent on IFN-γ stimulation. Dehydration may also manifest in severely infected mice, as evidenced by elevated minerals in the blood attributed to gastrointestinal dysfunction, akin to observations in patients [61,62].…”

Section: Plos Pathogensmentioning

confidence: 87%

Lack of the IFN-γ signal leads to lethal Orientia tsutsugamushi infection in mice with skin eschar lesions

Liang,

Wang,

Sun

et al. 2024

PLoS Pathog

0

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Scrub typhus is an acute febrile disease due to Orientia tsutsugamushi (Ot) infection and can be life-threatening with organ failure, hemorrhage, and fatality. Yet, little is known as to how the host reacts to Ot bacteria at early stages of infection; no reports have addressed the functional roles of type I versus type II interferon (IFN) responses in scrub typhus. In this study, we used comprehensive intradermal (i.d.) inoculation models and two clinically predominant Ot strains (Karp and Gilliam) to uncover early immune events. Karp infection induced sequential expression of Ifnb and Ifng in inflamed skin and draining lymph nodes at days 1 and 3 post-infection. Using double Ifnar1-/-Ifngr1-/- and Stat1-/- mice, we found that deficiency in IFN/STAT1 signaling resulted in lethal infection with profound pathology and skin eschar lesions, which resembled to human scrub typhus. Further analyses demonstrated that deficiency in IFN-γ, but not IFN-I, resulted in impaired NK cell and macrophage activation and uncontrolled bacterial growth and dissemination, leading to metabolic dysregulation, excessive inflammatory cell infiltration, and exacerbated tissue damage. NK cells were found to be the major cellular source of innate IFN-γ, contributing to the initial Ot control in the draining lymph nodes. In vitro studies with dendritic cell cultures revealed a superior antibacterial effect offered by IFN-γ than IFN-β. Comparative in vivo studies with Karp- and Gilliam-infection revealed a crucial role of IFN-γ signaling in protection against progression of eschar lesions and Ot infection lethality. Additionally, our i.d. mouse models of lethal infection with eschar lesions are promising tools for immunological study and vaccine development for scrub typhus.

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Neuritis and Gastrointestinal Hemorrhage in Scrub Typhus Patients

Cited by 4 publications

References 8 publications

Endoscopic characteristics of infection‐associated peptic ulcers

Endoscopic characteristics of infection‐associated peptic ulcers

Lack of the IFN-γ signal leads to lethalOrientia tsutsugamushiinfection in mice with skin eschar lesions

Lack of the IFN-γ signal leads to lethal Orientia tsutsugamushi infection in mice with skin eschar lesions

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