Differential susceptibility to hepatic inflammation and proliferation in AXB recombinant inbred mice chronically infected with Helicobacter hepaticus.

Helicobacter hepaticus is a naturally occurring pathogen of mice and has been used to develop models of chronic hepatitis, liver cancer, and, more recently, inflammatory bowel disease, in selected mouse strains. A/JCr mice are particularly susceptible to H. hepaticus-induced hepatitis and subsequent development of liver neoplasms, whereas C57BL/6 mice are resistant. In this study, we inoculated nine AXB recombinant inbred (RI) mouse strains, derived from A/J and C57BL/6 mice, with H. hepaticus to determine the genetic basis of resistance to Helicobacter-induced liver disease. Mice were surveyed 14 months after inoculation by culture and PCR for H. hepaticus colonization of the liver and cecum, and microscopic morphometric evaluations of the liver were performed to quantify and correlate the severity of inflammation, apoptosis, and proliferation. Analysis of variance of hepatic inflammation demonstrated significant variation among the RI strains (P < 0.0001), and the strain distribution pattern suggested a multigenic basis of disease resistance. Quantitative trait analysis using linear regression suggested possible linkage to loci on mouse chromosome 19. Hepatocellular and biliary epithelial apoptosis and proliferation indices, including proliferation of oval cells, were markedly increased and correlated with severity of inflammation. Prevalence of hepatic neoplasia was also increased in susceptible RI strains. These findings demonstrate a genetic basis for susceptibility to Helicobacter-induced disease and provide insight into its pathogenesis.

Low-virulent mouse hepatitis viruses exhibiting various tropisms in macrophages, T and B cell subpopulations, and thymic stromal cells.

Functional or cellular immunodeficiencies have been reported to result from various pathogenic mouse hepatitis virus (MHV) strains. Moreover, low-virulent MHV strains can reduce the ability of mice to seroconvert to other antigens or viruses. To determine the importance of low-virulent MHV strain tropism in immune cells, as a mechanism involved in the induction of immunodeficiencies, peritoneal exudate cells, T and B cell subpopulations, and thymic stromal cells were infected with low-virulent MHV-D, MHV-K, and MHV-N and pathogenic MHV-3 viral strains. Cell viability, percentages of viral protein-expressing cells, and virus titers have been analyzed. On the basis of our findings, low-virulent MHV viral strains exhibit various tropisms in macrophages, B lymphocyte subpopulations, or thymic stromal cells when compared with the more virulent MHV-3 serotype. All MHV strains tested have replicated in peritoneal exudate cells of C57BL/6 or A/J mice. Low-virulent MHV-N and pathogenic MHV-3 strains showed higher tropism for peritoneal exudate cells than low-virulent MHV-K and MHV-D strains. Likewise, MHV-N and -3 serotypes expressed higher tropism than MHV-D or -K serotypes for thymic stromal cells and B lymphoid cells. No tropism for T lymphocytes, however, was detected with MHV except when in contact with previously infected thymic stromal cells. These results raise the problem of immunologic disorders resulting from viral replication in immune cells in mouse colonies subclinically infected with low-virulent MHV strains.

Interaction between mouse hepatitis viruses and primary cultures of Kupffer and endothelial liver cells from resistant and susceptible inbred mouse strains.

Infection with mouse hepatitis virus type 3 (MHV 3) of primary cultures of Kupffer and endothelial cells from the livers of resistant (A/J) and susceptible (BALB/c) mice was followed by the appearance of typical syncytia and comparable yields of virus. Using cells from A/J mice there was a delay of about 24 to 36 h in the appearance of the first particles detected by electron microscopy, the maximum viral titre and the number and size of syncytia. The partial resistance to MHV 3 multiplication expressed by cells from A/J mice was also observed when they infected with a strain of low virulence (JHM strain). The delay in MHV multiplication found in the sinusoidal liver cells, mainly in the endothelial cells, may be an important factor in their resistance, by allowing time for the local and systemic responses to clear the infective particles as well as in determining their degree of hepatotropism.

Radioimmunoassay for intact Gross mouse leukemia virus.

A radioimmunoassay for intact Gross leukemia virus has been developed using 125I-labeled Gross virus grown in tissue culture and guinea pig antisera to Gross virus grown either in tissue culture or harvested from leukemic C3H(f) mice. Separation of bound from free labeled virus was effected using the double antibody method. The assay can detect fewer than 10(8) virus particles and has been used to measure the viral content of individual organs from inoculated leukemic C3H(f) mice and from Ak mice with spontaneous leukemia. Organs from noninoculated healthy C3H(f) mice crossreacted poorly in the system, virus generally being detectable only in the thymus and spleen and at low concentration. In some of the inoculated C3H(f) leukemic mice the viral content of as little as 0.5 mul of plasma is measurable. That this assay is for intact virus and not for soluble antigens of the viral envelope was proven by the observation that the immunoreactive material of plasma and extracts from thymus and liver of leukemic mice has a buoyant denisty in sucrose of 1.17-1.18 g/ml, corresponding to that of intact virus grown in tissue culture. With this sensitivity it may now be possible to quantitate viral concentrations in tissue and body fluids from the time of inoculation through the development of obvious pathology.