Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice

Wen, Jie; Xiao, Yongtao; Wang, Jun; Pan, Weihua; Zhou, Ying; Zhang, Xiaoling; Guan, Wei; Chen, Yingwei; Zhou, Kejun; Wang, Yan; Shi, Bisheng; Zhou, Xiaohui; Cai, Wei

doi:10.1038/labinvest.2014.148

Cited by 17 publications

(9 citation statements)

References 35 publications

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“…The second important finding is the correlation between locoregional HHV-6 (and possibly CMV in the later course) detection and severe liver allograft complications. We further hypothesize that routine CMV prophylaxis with valganciclovir is not sufficient to prevent HHV-6 (and HHV-7) infection, which raises important questions for clinical practice [33, 34].…”

Section: Discussionmentioning

confidence: 99%

Prevalence of human herpesviruses in biliary fluid and their association with biliary complications after liver transplantation

et al. 2019

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Background Beta-herpesviruses are common opportunistic pathogens that cause morbidity after liver transplantation (LT). Methods Objective of the study was to evaluate the prevalence and correlation of herpesviruses in bile, blood and liver tissue and to investigate their association with biliary complications and retransplantation (re-LT) free survival after LT. The study design is a single-center case-control study. We performed quantative polymerase chain reaction (qPCR) for herpesvirus 1–8 DNA in bile, blood and liver tissue of 73 patients after first LT and analyzed their clinical courses retrospectively. Results The median follow-up was 48 months (range 2–102), during which a total of 16 patients underwent re-LT and 11 patients died. Of the patients, 46.5% received valganciclovir prophylaxis at the time of bile sample acquisition. Cytomegalovirus (CMV) (18.3%), human herpesvirus 6 (HHV-6) (34.2%), human herpesvirus 7 (HHV-7) (20.5%) and Epstein-Barr virus (EBV) (16.4%) were highly prevalent in bile after LT, while herpes simpex virus 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV) and human herpesvirus 8 (HHV-8) were not or rarely detected in bile. Valganciclovir prophylaxis did not reduce the prevalence of HHV-6 and HHV-7 in bile, but it did reduce the presence of CMV and EBV. The presence of HHV-6 in bile was associated with non-anastomotic biliary strictures (NAS) and acute cellular rejection (ACR). Conclusions CMV, EBV, HHV-6 and HHV-7 are more prevalent in biliary fluid than in liver biopsy or blood serum after LT. HHV-6 and HHV-7 might be associated with biliary complications after LT. Biliary fluids might be an attractive target for routine herpesvirus detection.

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Section: Discussionmentioning

confidence: 99%

Prevalence of human herpesviruses in biliary fluid and their association with biliary complications after liver transplantation

et al. 2019

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“…Cytomegalovirus (CMV) has also been used to recapitulate BA in animal models (55). For instance, a regulatory T cell (Treg)-depleted neonatal mouse, when infected with low-dose CMV (LD-CMV) to study BA, induced extensive inflammation, atresia of intrahepatic bile ducts and partial obstruction of the extrahepatic bile ducts.…”

Section: Other Virus Induced Modelsmentioning

confidence: 99%

Innate Immunity and Pathogenesis of Biliary Atresia

et al. 2020

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Biliary atresia (BA) is a devastating fibro-inflammatory disease characterized by the obstruction of extrahepatic and intrahepatic bile ducts in infants that can have fatal consequences, when not treated in a timely manner. It is the most common indication of pediatric liver transplantation worldwide and the development of new therapies, to alleviate the need of surgical intervention, has been hindered due to its complexity and lack of understanding of the disease pathogenesis. For that reason, significant efforts have been made toward the development of experimental models and strategies to understand the etiology and disease mechanisms and to identify novel therapeutic targets. The only characterized model of BA, using a Rhesus Rotavirus Type A infection of newborn BALB/c mice, has enabled the identification of key cellular and molecular targets involved in epithelial injury and duct obstruction. However, the establishment of an unleashed chronic inflammation followed by a progressive pathological wound healing process remains poorly understood. Like T cells, macrophages can adopt different functional programs [pro-inflammatory (M1) and resolutive (M2) macrophages] and influence the surrounding cytokine environment and the cell response to injury. In this review, we provide an overview of the immunopathogenesis of BA, discuss the implication of innate immunity in the disease pathogenesis and highlight their suitability as therapeutic targets.

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“…Ten infants in our study had positive or high positive TNF-α, of whom 88.8% had positive liver CMV PCR, and 9 had low positive levels of TNF-α, of whom 7 were liver CMV PCR positive. Increase in Th1-related genes TNF-α, caspase-1, and STAT-1 in mice from the low dose CMV group compared to the control groups were observed by Wen et al [14]. Orange et al…”

Section: Discussionmentioning

confidence: 77%

Hepatic interferon γ and tumor necrosis factor a expression in infants with neonatal cholestasis and cytomegalovirus infection

Meshram¹,

Velhal²,

Padwal³

et al. 2020

ceh

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Aim of the study:To determine the hepatic interferon γ (IFN-γ) and tumor necrosis factor a (TNF-a) levels in infants with neonatal cholestasis (NC) and associated cytomegalovirus (CMV) infection. Material and methods: This study was conducted in 21 infants with NC over a period of 6 months from June 2017 to December 2017 to determine the hepatic IFN-γ and TNF-a levels in infants with NC and associated CMV infection. Results: IFN-γ levels were positive in 16 (80%), low positive in 3 (16%) and negative in 1 (5%) patients. High positive and positive TNF-a levels were seen in 9 (56.3%) patients with positive liver CMV PCR and low positive levels were seen in 7 (43.7%) patients with positive liver CMV PCR (odds ratio [OR] = 2.6). Positive IFN-γ was present in 13 (81.3%) patients with positive liver CMV PCR and low positive or negative IFN-γ was seen in 3 (18.7%) patients with positive liver CMV PCR (OR = 2.2). Six (60%) patients with positive or high positive TNF-a levels in liver tissue had biliary atresia (BA) whereas 7 (77.7%) with low positive TNF-a levels had non-BA neonatal hepatitis (OR = 5.25). Six (37.5%) patients with positive IFN-γ had BA whereas 2 (50%) patients with low positive or negative IFN-γ had BA (OR = 0.6). Conclusions: There is high prevalence of CMV in liver tissues in patients with NC and elevated TNF-a and IFN-γ levels are seen in these patients. Elevated TNF-a is also seen in patients with BA. The association of elevated TNF-a, BA and CMV infection needs to be evaluated further.

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Low doses of CMV induce autoimmune-mediated and inflammatory responses in bile duct epithelia of regulatory T cell-depleted neonatal mice

Cited by 17 publications

References 35 publications

Prevalence of human herpesviruses in biliary fluid and their association with biliary complications after liver transplantation

Prevalence of human herpesviruses in biliary fluid and their association with biliary complications after liver transplantation

Innate Immunity and Pathogenesis of Biliary Atresia

Hepatic interferon γ and tumor necrosis factor a expression in infants with neonatal cholestasis and cytomegalovirus infection

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