Diabetes acceleration or prevention by a coxsackievirus B4 infection: critical requirements for both interleukin-4 and gamma interferon.

Type 1 diabetes acceleration in nonobese diabetic (NOD) mice through coxsackievirus B4 (CVB4) infection requires a preexisting critical mass of autoreactive T cells in pancreatic islets, and in the absence of this insulitic threshold, CVB4 infection leads to long-term disease protection. To understand this acceleration and protection process, we challenged 8- and 12-week-old NOD mice containing a disruption in interleukin-4 (IL-4) or gamma interferon (IFN-gamma) genes (NOD IL-4-/- and NOD IFN-gamma-/-, respectively) with a diabetogenic, pancreatropic Edwards strain of CVB4. The elimination of IL-4 did not alter the rate of insulitis or diabetes development in NOD mice, while the elimination of IFN-gamma delayed these events several weeks. CVB4 infection in 8-week-old mice only significantly accelerated the onset of diabetes in a subset of standard, but not IL-4- or IFN-gamma-deficient, NOD mice. Long-term diabetes protection was established in standard NOD mice as well as in the NOD IFN-gamma-/- mice that did not rapidly develop disease following CVB4 infection at 8 weeks of age. When mice were infected at 12 weeks of age, the onset of diabetes was accelerated in NOD IL-4-/- mice, while neither acceleration nor long-term protection was elicited in NOD IFN-gamma-/- mice. No differences were observed in the kinetics of CVB4 clearance in pancreases from NOD, NOD IL-4-/-, and NOD IFN-gamma-/- mice. Collectively, these results suggest that at the insulitis threshold at which CVB4 infection can first accelerate the onset of diabetes in NOD mice, IL-4 as well as IFN-gamma contributes to this pathogenic process. The protective mechanism against diabetes elicited in NOD mice infected with CVB4 prior to the development of a critical threshold level of insulitis requires neither IL-4 nor IFN-gamma.

Coxsackievirus experimental heart diseases.

Many microorganisms, particularly viruses, can cause myocarditis, an inflammatory disease of the heart. The frequency of and major factors that contribute to this disease, including a pronounced gender (male) bias, age and genetic background parameters are discussed, along with signs and symptoms of disease in infants to adults. Individuals with acute disease generally recover without sequelae; the chronic form can develop into idiopathic dilated cardiomyopathy and death can follow. Among viruses most frequently associated with cases in the U.S., the coxsackieviruses group B (CVB) are major etiologic agents. The association between the CVB and disease is based on detection of viral RNA in heart biopsy specimens by polymerase chain reaction assays. Excellent CVB-, particularly coxsackievirus B3 (CVB3)-, mouse models of the disease have identified mechanisms of induction and establishment of chronic myocarditis. CVB3-murine models share many biologic parameters of the acute and chronic diseases in humans, and show that cardiopathologic alterations result from virus-induced and immunologic reactions in heart tissues. Several immune responses to a CVB3 infection that become cardiopathogenic, instead of protective, are discussed in an attempt to explain why immunosuppressive treatments are not effective. Bed rest and supportive therapy are the current treatment for patients with myocarditis.

Evaluation of coxsackievirus infection in children with human immunodeficiency virus type 1-associated cardiomyopathy.

In a matched case-control study of the association between coxsackieviruses and cardiac impairment, 24 human immunodeficiency virus (HIV) type 1-infected children with cardiac impairment were compared with 24 HIV-1-infected control subjects. Serologic evidence of coxsackievirus infection was present in all children, with no significant difference in geometric mean antibody titers between case patients and control subjects. Conditional logistic regression to test for an association between coxsackievirus antibody titer and the presence or absence of cardiac impairment, by any indicator, showed an odds ratio of 1.11 (95% confidence interval, 0.58-2.10; P=.75), indicating no association between coxsackievirus infection and cardiac impairment. Coxsackievirus antibody titers correlated positively with total IgG levels in nonrapid progressors but not in rapid progressors. Paired serum samples taken before and after diagnosis of cardiac impairment in 5 patients showed no evidence of intervening coxsackievirus infection. These results do not identify a causal role for coxsackieviruses for cardiomyopathy in HIV-1-infected children.