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From the Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California
Viral myocarditis is remarkably common, being detected in
approximately 1% of unselected asymptomatic individuals. Many cases
are attributable to enteroviral infection, and in particular to
coxsackievirus B3. The underlying pathogenesis is
controversial, but most studies admit the important
immunopathological role of infiltrating CD8+ (cytotoxic) T
lymphocytes (CTLs). We have previously shown that CTLs play conflicting
roles in coxsackievirus B (CVB) myocarditis; they assist in controlling
virus replication, but also are instrumental in causing the
extensive inflammatory disease, which often results in severe
myocardial scarring. A role for perforin, the major CTL
cytolytic protein, in CVB myocarditis has been
suggested, but never proven. In the present study we use
perforin knockout (PKO) mice to show that perforin plays a major role
in CVB infection; in broad terms, perforin is important in
immunopathology, but not in CVB clearance. For example,
PKO mice are better able to withstand a normally lethal dose of CVB
(100% survival of PKO mice compared with 90% death in +/+
littermates). In addition, PKO mice given a nonlethal dose of
CVB develop only a mild myocarditis, whereas their
perforin+ littermates have extensive myocardial lesions.
The myocarditis in PKO mice resolves more quickly, and these
mice show minimal histological sequelae; in contrast, late in
disease the perforin+ mice develop severe myocardial
fibrosis. PKO mice, despite lacking this major CTL effector
function, can control the infection and eradicate the virus;
growth kinetics and peak CVB titers are indistinguishable in PKO and
perforin+ mice. Therefore, the immunopathological
and antiviral effects of CTLs can be uncoupled by ablation of perforin;
this offers a promising target for therapy of myocarditis.
Furthermore, we evaluate the possible roles of
apoptosis, and of chemokine expression, in CVB
infection. In perforin+ mice, apoptotic cells are
detected within the inflammatory infiltrate, whereas in their
PKO counterparts, apoptotic myocyte nuclei are seen. Chemokine
expression in both PKO and perforin+ mice precedes and
parallels the course of myocarditis. Several chemokines are detectable
earlier in PKO mice than in perforin+ mice, but PKO
mice show reduced peak levels, and chemokine expression decays
sooner. In particular, MIP-1
expression is barely detectable
at any time point in PKO mice, but it is readily identified in
perforin+ animals, peaking just before the time of
maximal myocarditis; this is particularly interesting, given
that MIP-1 knockout mice are resistant to CVB myocarditis,
but remain able to control viral infection. Thus, the chemokine
pathway offers a second route of intervention to diminish myocarditis
and its sequelae, while permitting the host to eradicate the
virus.
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|
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