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Progressive interstitial collagen deposition in Coxsackievirus B3-induced murine myocarditis
K O Leslie1, J Schwarz, K Simpson
1Department of Pathology, University of Vermont, Burlington 05405.
Abstract:
Myocardial fibrosis can be produced in certain inbred strains of mice after coxsackievirus B subtype 3 (CVB3) infection. The mechanism responsible for this interstitial matrix alteration is unknown. The presumption is that fibrosis occurs in areas of myocyte damage and inflammation associated with viral infection, analogous to scar formation after cell injury in other organ systems. To test this hypothesis, we examined the hearts of A/J strain mice infected with three CVB3 variants (Crowell [CVB3-CR], Woodruff [CVB3-WD], and Lerner [CVB3-LR]), each known to cause different degrees of acute myocardial injury. With these three variants, virus was present in the heart until day 28 after inoculation but was absent thereafter. Fourteen days after inoculation, inflammation with myocyte necrosis was seen in discrete foci throughout the myocardium with all three variants. Collapse and disorganization of the usually delicate connective tissue matrix identifiable by silver impregnation was seen in these areas of myocyte injury. Persistent, diffuse lymphocytic infiltration of the myocardium was seen 55 days after inoculation with CVB3-WD and CVB3-LR, but hearts initially infected with CVB3-CR showed only rare interstitial lymphocytes comparable to uninfected control hearts. The focal scars produced by myocyte necrosis 14 days after inoculation were accentuated and heavily collagenized 55 days after inoculation with CVB3-WD and CVB3-LR; however, these foci were indistinct 55 days after inoculation with CVB3-CR. Furthermore, the usually delicate network of interstitial collagen fibers surrounding individual myocytes became thickened throughout the heart 55 days after inoculation with CVB3-WD and CVB3-LR, away from visibly scarred areas produced early after infection with these variants. This diffuse reticulin thickening was not seen after infection with the Crowell variant. Only the virus variants associated with persistent interstitial inflammation at day 55 developed major collagen matrix alterations and interstitial fibrosis. We conclude that this persistent interstitial lymphocytic infiltration reflects altered immune function related to specific virus variants in this animal strain. We postulate that these lymphocytes are part of a delayed immunopathogenic response uncoupled from the original viral injury and inflammatory damage. Potential mechanisms by which this interstitial lymphocytic infiltration results in fibrosis are discussed.
Insights
Coxsackievirus B3 infection can cause myocardial fibrosis in mice. Persistent inflammation, not direct viral damage, drives this fibrosis, suggesting a delayed immune response contributes to heart scarring.
Area of Science:
- Cardiology
- Virology
- Immunology
Background:
- Myocardial fibrosis, an alteration of the heart's interstitial matrix, can follow Coxsackievirus B3 (CVB3) infection in mice.
- The precise mechanism driving this fibrosis, particularly the role of interstitial matrix alteration, remains unclear.
- It is presumed that fibrosis arises in areas of myocyte damage and inflammation, similar to scar formation in other tissues.
Purpose of the Study:
- To investigate the mechanism of interstitial matrix alteration and myocardial fibrosis following CVB3 infection.
- To compare the effects of different CVB3 variants on myocardial injury, inflammation, and subsequent fibrosis.
- To determine the relationship between viral persistence, inflammatory response, and collagen matrix remodeling.
Main Methods:
- A/J strain mice were infected with three distinct CVB3 variants (CVB3-CR, CVB3-WD, CVB3-LR) known for varying degrees of acute myocardial injury.
- Hearts were examined at 14 and 55 days post-inoculation to assess viral presence, myocyte necrosis, inflammation, and connective tissue matrix changes.
- Silver impregnation was used to visualize the connective tissue matrix, and interstitial collagen fiber thickness was evaluated.
Main Results:
- All three CVB3 variants caused myocyte necrosis and inflammation at 14 days post-inoculation, with associated matrix disorganization.
- Persistent, diffuse lymphocytic infiltration was observed at 55 days in mice infected with CVB3-WD and CVB3-LR, but not CVB3-CR.
- Major collagen matrix alterations and interstitial fibrosis at 55 days were associated only with CVB3 variants causing persistent inflammation, not with the degree of initial myocyte injury.
Conclusions:
- Persistent interstitial lymphocytic infiltration, rather than direct viral injury, is the key factor leading to significant myocardial fibrosis in this model.
- The observed fibrosis appears to be driven by a delayed immunopathogenic response, distinct from the initial viral infection and inflammatory damage.
- Specific CVB3 variants can elicit altered immune responses in susceptible mouse strains, leading to chronic cardiac remodeling and fibrosis.