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Chronic active hepatitis in mice caused by Helicobacter hepaticus
J M Ward1, M R Anver, D C Haines
1Veterinary and Tumor-Pathology Section, National Cancer Institute, NCI-Frederick Cancer Research, Maryland 21702-1201.
Abstract:
Helicobacter infections cause chronic gastroenteritis in humans and several animal species. We recently discovered a new Helicobacter (H. hepaticus) that is the etiological agent of a unique chronic active hepatitis in mice. Natural infection appeared to be acquired early in life in enzootically infected colonies. Liver lesions arose as focal necrosis and focal nonsuppurative inflammation by 1 to 4 months of age in susceptible mouse strains. By 6 to 8 months, extensive liver involvement included hepatocytomegaly, bile ductular (oval cell) hyperplasia, and cholangitis. There was an age-related increase in proliferating cell nuclear antigen hepatocyte nuclear labeling index. The bacteria were usually found within bile canaliculi as determined by ultrastructural evaluation of liver lesions, the Steiner modification of the Warthin-Starry stain and immunohistochemistry with a rabbit antibody to Helicobacter pylori. Naturally infected mice showed an age-related increase in serum IgG antibodies to Helicobacter hepaticus proteins. The disease was experimentally reproduced by intraperitoneal injection of liver suspensions from affected livers or bacteria cultivated in vitro. The earliest lesions of the experimental disease appeared 4 weeks after injection. The course of spontaneous and experimental infection was slow and insidious and resulted in high titers of antibodies to bacterial proteins. This chronic bacterial infection represents a new model of chronic liver disease.
Insights
A newly discovered Helicobacter (H. hepaticus) causes chronic active hepatitis in mice. This bacterial infection, acquired early in life, provides a new model for studying chronic liver disease.
Area of Science:
- Hepatology
- Microbiology
- Veterinary Pathology
Background:
- Helicobacter infections are known causes of chronic gastroenteritis.
- A novel Helicobacter species, H. hepaticus, has been identified as the cause of a distinct hepatitis in mice.
Purpose of the Study:
- To characterize the etiology and pathogenesis of H. hepaticus-induced chronic active hepatitis in mice.
- To establish H. hepaticus infection as a model for chronic liver disease research.
Main Methods:
- Histopathological examination of liver tissues from naturally and experimentally infected mice.
- Ultrastructural evaluation, Steiner modification of Warthin-Starry stain, and immunohistochemistry to detect bacteria.
- Serological analysis to assess antibody responses to H. hepaticus proteins.
- Experimental reproduction of the disease via inoculation with infected liver homogenates or cultured bacteria.
Main Results:
- H. hepaticus infection led to progressive liver lesions including necrosis, inflammation, hepatocytomegaly, bile ductular hyperplasia, and cholangitis.
- Bacteria were localized within bile canaliculi.
- An age-related increase in hepatocyte proliferation and serum IgG antibodies to H. hepaticus was observed.
- The disease course was slow and insidious in both spontaneous and experimental infections.
Conclusions:
- H. hepaticus is the etiological agent of a unique chronic active hepatitis in mice.
- This infection serves as a valuable new model for investigating the mechanisms of chronic liver disease development and progression.