Severity of disease induced by a pancreatropic Coxsackie B4 virus correlates with the H-2K q locus of the major histocompatibility complex

Ramsingh, Arlene I.; Slack, Jill K.; Silkworth, Jay B.; Hixson, Angela

doi:10.1016/0168-1702(89)90027-0

Cited by 36 publications

(40 citation statements)

References 15 publications

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“…Our previous studies have shown that CVB4-V infection causes chronic pancreatitis in a variety of mouse strains (31). Disease severity correlates with destruction of the exocrine pancreas.…”

Section: Resultsmentioning

confidence: 99%

“…Although treatment with IL-12 did not alter viral replication in the pancreas, IL-12 was able to protect the pancreas from extensive damage. In untreated mice, widespread damage eventually leads to exocrine pancreatic insufficiency, which is responsible for morbidity and mortality (31,33). In mouse strains (B10, SJL) that survive infection, extensive pancreatic damage leads to chronic pancreatitis.…”

Section: Discussionmentioning

confidence: 99%

“…The virulent CVB4-V variant induces a severe pancreatitis, which can lead to mortality or progress to chronic disease (chronic pancreatitis). We have shown that the severity of CVB4-V-induced chronic disease is influenced by the major histocompatibility complex (31), cytokines (33), and T cells (33). Chronic pancreatitis, in this model, is due to immunopathological mechanisms.…”

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confidence: 99%

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Exogenous Interleukin-12 Protects against Lethal Infection with Coxsackievirus B4

Potvin

Metzger

Lee

et al. 2003

J Virol

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Infections with the group B coxsackieviruses either can be asymptomatic or can lead to debilitating chronic diseases. To elucidate the mechanism by which these viruses cause chronic disease, we developed a mouse model of chronic pancreatitis by using a virulent variant of coxsackievirus B4, CVB4-V. Infection with CVB4-V results in an early, severe pancreatitis, which can lead to mortality or progress to chronic pancreatitis. Chronic pancreatitis, in this model, is due to immunopathological mechanisms. We investigated whether interleukin-12 (IL-12) could modulate the outcome of CVB4-V infection. Eighty-five percent of the infected mice treated with 500 ng of IL-12 survived, whereas all untreated mice succumbed. To understand the mechanism underlying the beneficial effect of IL-12, we investigated the role of gamma interferon (IFN-␥). Three lines of evidence suggest that the protective effect of IL-12 is due to IFN-␥. The group B coxsackieviruses are enteroviruses belonging to the Picornaviridae family. In humans, most infections with the group B viruses are asymptomatic (25, 30). Generally, symptomatic infections result in mild illnesses of the upper respiratory tract, the gastrointestinal tract, and the skin. Occasionally, the group B coxsackieviruses cause chronic inflammatory disease of the pancreas (insulin-dependent type I diabetes mellitus, idiopathic chronic pancreatitis), heart (dilated cardiomyopathy), and central nervous system (7). The mechanism by which the group B viruses cause chronic disease is a topic of ongoing debate. One view is that coxsackieviruses cause chronic disease via viral persistence (18,19,38,40). Viral persistence may be due to the prolonged presence of low levels of infectious virus that continue to cause tissue injury. Alternatively, viral persistence may be due to the prolonged presence of viral RNA in the absence of infectious virus. The implication is that a low level of translation results in the synthesis of viral proteins that continue to stimulate immune responses, which cause prolonged tissue destruction. Another view is that coxsackieviruses cause chronic disease via immunemediated mechanisms directed against self-antigens. In mouse models, extensive evidence indicates that immunopathological mechanisms contribute to coxsackievirus-induced chronic disease (11,15,16,32,35,36).We have developed a mouse model of coxsackievirus B4-induced disease by using two serologically indistinguishable variants of the B4 serotype, CVB4-P and CVB4-V (5). The avirulent CVB4-P variant induces a mild, transient inflammation of the pancreas (pancreatitis) with full recovery of the tissues by 10 days of infection. The virulent CVB4-V variant induces a severe pancreatitis, which can lead to mortality or progress to chronic disease (chronic pancreatitis). We have shown that the severity of CVB4-V-induced chronic disease is influenced by the major histocompatibility complex (31), cytokines (33), and T cells (33). Chronic pancreatitis, in this model, is due to immunopathological mechanisms.Given t...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Exogenous Interleukin-12 Protects against Lethal Infection with Coxsackievirus B4

Potvin

Metzger

Lee

et al. 2003

J Virol

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“…Severity of disease induced depends upon virulence determinants in the genotype of the infecting strain (Ramsingh et al, 1989;Caggana et al, 1993;Ramsingh and Collins, 1995). Molecular studies of one well-characterized strain of coxsackievirus B4 (CVB4) showed that changes in single amino acids in either of two of the four capsid polypeptides of the virion could significantly affect the capacity of the virus for inducing pancreatitis in mice (Caggana et al, 1993;Ramsingh and Collins, 1995).…”

Section: Introductionmentioning

confidence: 99%

“…Increased expression of GAD65 in the islets of CVB4-infected mice has been found during active early virus infection at that site. The genetic background of the murine strain involved in the CVB4-mouse response to infection also plays a major role in determining whether or not pancreatitis/IDDM is induced and severity of disease induced (Lansdown, 1976;Webb and Madge, 1980;Ramsingh et al, 1989;Tisch et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

A glyconutritional mixture (Ambrotose®) provides some amelioration to mice with coxsackievirus-induced pancreatitis

Gauntt

Busbee

Wood

et al. 1999

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Challenge of adolescent male CD-1 mice with a coxsackievirus B3 (CVB3) strain (CVB3,) induces mild to severe destruction of pancreatic acinar cells, but causes no deaths and does not induce hyperglycemia. A weekly parenteral (intraperitoneal) administration of a glyconutritional mixture (Ambrotose | to virus-challenged mice was assessed to determine if there were any benefits to recovery over an eight month period. Virus-challenged mice showed a significant weight loss over the initial five weeks of the experiment, but injection of Ambrotose | to similar virus-challenged mice restored the total body weight to levels found in normal mice. Normal mice given Ambrotose | exhibited a small weight gain. Mice given Ambrotose | showed reduced severity of pancreatitis, as evidenced by significant reductions in percentages of pancreatic acinar cells destroyed and proportion of sections of pancreata with destroyed acinar cells, compared to virus control-mice not injected with Ambrotose | Statistical analyses of the extent of acinar cell pathology in all virus-challenged mice showed that Ambrotose | contributed significantly to recovery of the acinar cell population in virus-inoculated mice. Anti-viral antibody titers were not affected by Ambrotose | injections. One potential mechanism to explain the benefits derived from Ambrotose | injections came from studies of antioxidant levels of glutathione in splenic macrophages/monocytes. Whereas CVB3 challenge of mice reduced glutathione levels in the latter cells, Ambrotose | injections to viruschallenged mice restored glutathione levels to those found in normal mice. In summary, most but not all mice derived benefits from Ambrotose | injections, i.e. a reduction in pathology in the pancreas and restored levels of the antioxidant glutathione in macrophages/monocytes. Higher doses of Ambrotose | could provide greater benefits for more mice, a study for the future.

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Group B coxsackievirus myocarditis and pancreatitis: Connection between viral virulence phenotypes in mice

et al. 2000

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The group B coxsackieviruses (CVB) induce experimental pancreatitis and myocarditis in mice and are established agents of human myocarditis, especially in children. We tested the hypothesis that the development of CVB-induced myocarditis is linked to CVB-induced pancreatitis by studying the replication of different CVB strains in mice. Eight of nine genotypically different type 3 CVB (CVB3) strains induced acute pancreatitis in mice; of these, three viruses also induced acute myocarditis. One CVB3 strain was avirulent for both organs. Myocarditis was not observed in the absence of pancreatitis. The results obtained by inoculation of mice with strains of other CVB serotypes were consistent with these data. Infectious virus titers were measured in serum, pancreas, and heart as a function of time after inoculation of mice with three CVB3 strains. Each strain was representative of one of the three viral virulence phenotypes: avirulent, pancreovirulent only, and cardiovirulent. All strains replicated well and persisted in the pancreas through 8 days post-inoculation, but the cardiovirulent CVB3 strain tended to replicate to higher titer earlier and persist longer in sera, pancreatic, and cardiac tissues than the noncardiovirulent strains. Replication of the CVB3 strains were studied in two human pancreatic tumor lines and in primary human endothelial cell cultures derived from cardiac artery. Cardiovirulent strains, both individually and as a group, tended to replicate to titers as high as, or higher than, noncardiovirulent strains did in cell culture. The data are consistent with the possibility of an etiologic link between CVB-induced pancreatic and heart disease.

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Severity of disease induced by a pancreatropic Coxsackie B4 virus correlates with the H-2K q locus of the major histocompatibility complex

Cited by 36 publications

References 15 publications

Exogenous Interleukin-12 Protects against Lethal Infection with Coxsackievirus B4

Exogenous Interleukin-12 Protects against Lethal Infection with Coxsackievirus B4

A glyconutritional mixture (Ambrotose®) provides some amelioration to mice with coxsackievirus-induced pancreatitis

Group B coxsackievirus myocarditis and pancreatitis: Connection between viral virulence phenotypes in mice

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