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The impact of juvenile coxsackievirus infection on cardiac progenitor cells and postnatal heart development.

Sin J, Puccini JM, Huang C, Konstandin MH, Gilbert PE, Sussman MA, Gottlieb RA, Feuer R - PLoS Pathog. (2014)

Bottom Line: Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection.Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice.These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

View Article: PubMed Central - PubMed

Affiliation: Donald P. Shiley BioScience Center, San Diego State University, San Diego, California, United States of America.

ABSTRACT
Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

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Beta-adrenergic stimulation-induced cardiac hypertrophy in adult mice infected with CVB3 at an early age leads to dilated cardiomyopathy.Three day-old mice were infected with eGFP-CVB3 (105 pfu IP) or mock-infected. After 13 weeks, a 10 day treatment with isoproterenol (ISO) was used to induce physiologic hypertrophy in infected (No treatment, n = 6; Vehicle only, n = 4; ISO, n = 4) or mock-infected mice (No treatment, n = 4; Vehicle only, n = 8; ISO, n = 5). Alternatively, swimming exercise was used to induce physiologic hypertrophy in surviving mice. (A) Virus-infected mice showed a significant increase in heart weight to tibia length ratio following ISO treatment compared to mock-infected control mice (*p<0.001; two-way ANOVA). (B), Hearts of infected mice displayed cardiac hypertrophy by H&E staining following ISO treatment. (C) Higher magnification of heart sections stained by Masson trichrome revealed fibrosis (blue) in both infected and mock-infected mice only after ISO-treatment. (D) Little to no T cell infiltration was observed in the heart following ISO treatment in both infected and mock-infected mice. A spleen positive control for CD3 staining and a No Primary antibody control are shown.
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ppat-1004249-g007: Beta-adrenergic stimulation-induced cardiac hypertrophy in adult mice infected with CVB3 at an early age leads to dilated cardiomyopathy.Three day-old mice were infected with eGFP-CVB3 (105 pfu IP) or mock-infected. After 13 weeks, a 10 day treatment with isoproterenol (ISO) was used to induce physiologic hypertrophy in infected (No treatment, n = 6; Vehicle only, n = 4; ISO, n = 4) or mock-infected mice (No treatment, n = 4; Vehicle only, n = 8; ISO, n = 5). Alternatively, swimming exercise was used to induce physiologic hypertrophy in surviving mice. (A) Virus-infected mice showed a significant increase in heart weight to tibia length ratio following ISO treatment compared to mock-infected control mice (*p<0.001; two-way ANOVA). (B), Hearts of infected mice displayed cardiac hypertrophy by H&E staining following ISO treatment. (C) Higher magnification of heart sections stained by Masson trichrome revealed fibrosis (blue) in both infected and mock-infected mice only after ISO-treatment. (D) Little to no T cell infiltration was observed in the heart following ISO treatment in both infected and mock-infected mice. A spleen positive control for CD3 staining and a No Primary antibody control are shown.

Mentions: Despite a reduction in the number of CPCs following CVB3 infection, juvenile-infected mice developed normally and were phenotypically indistinguishable from mock-infected control mice at 77 days PI. We determined if stress elicited pathologic remodeling in juvenile-infected adult mice administered with the beta adrenergic agonist, isoproterenol (ISO) [38]. At 91 days PI, juvenile-infected or mock-infected mice were treated with ISO for 10 days, treated with vehicle only, or given no treatment. Although mock-infected mice showed an increase in heart weight/tibia length ratios (HW/TL) following ISO treatment, juvenile-infected animals showed a significantly greater increase in heart mass than mock-infected mice (Figure 7A; *p<0.001). Transverse cross sections of heart tissue from ISO-treated mice infected at an early age showed enlarged left ventricles with thinning of the muscular wall (Figure 7B). Also, ISO-treated mice (CVB3-infected and mock-infected) developed fibrosis, as shown by Masson's Trichrome staining (Figure 7C). These observations supported our hypothesis that subclinical infection with CVB3 predisposed mice to greater pathologic remodeling in the heart. Of note, no infiltrating T cells were observed in CVB3 or mock-infected heart following ISO treatment (Figure 7D).


The impact of juvenile coxsackievirus infection on cardiac progenitor cells and postnatal heart development.

Sin J, Puccini JM, Huang C, Konstandin MH, Gilbert PE, Sussman MA, Gottlieb RA, Feuer R - PLoS Pathog. (2014)

Beta-adrenergic stimulation-induced cardiac hypertrophy in adult mice infected with CVB3 at an early age leads to dilated cardiomyopathy.Three day-old mice were infected with eGFP-CVB3 (105 pfu IP) or mock-infected. After 13 weeks, a 10 day treatment with isoproterenol (ISO) was used to induce physiologic hypertrophy in infected (No treatment, n = 6; Vehicle only, n = 4; ISO, n = 4) or mock-infected mice (No treatment, n = 4; Vehicle only, n = 8; ISO, n = 5). Alternatively, swimming exercise was used to induce physiologic hypertrophy in surviving mice. (A) Virus-infected mice showed a significant increase in heart weight to tibia length ratio following ISO treatment compared to mock-infected control mice (*p<0.001; two-way ANOVA). (B), Hearts of infected mice displayed cardiac hypertrophy by H&E staining following ISO treatment. (C) Higher magnification of heart sections stained by Masson trichrome revealed fibrosis (blue) in both infected and mock-infected mice only after ISO-treatment. (D) Little to no T cell infiltration was observed in the heart following ISO treatment in both infected and mock-infected mice. A spleen positive control for CD3 staining and a No Primary antibody control are shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4117602&req=5

ppat-1004249-g007: Beta-adrenergic stimulation-induced cardiac hypertrophy in adult mice infected with CVB3 at an early age leads to dilated cardiomyopathy.Three day-old mice were infected with eGFP-CVB3 (105 pfu IP) or mock-infected. After 13 weeks, a 10 day treatment with isoproterenol (ISO) was used to induce physiologic hypertrophy in infected (No treatment, n = 6; Vehicle only, n = 4; ISO, n = 4) or mock-infected mice (No treatment, n = 4; Vehicle only, n = 8; ISO, n = 5). Alternatively, swimming exercise was used to induce physiologic hypertrophy in surviving mice. (A) Virus-infected mice showed a significant increase in heart weight to tibia length ratio following ISO treatment compared to mock-infected control mice (*p<0.001; two-way ANOVA). (B), Hearts of infected mice displayed cardiac hypertrophy by H&E staining following ISO treatment. (C) Higher magnification of heart sections stained by Masson trichrome revealed fibrosis (blue) in both infected and mock-infected mice only after ISO-treatment. (D) Little to no T cell infiltration was observed in the heart following ISO treatment in both infected and mock-infected mice. A spleen positive control for CD3 staining and a No Primary antibody control are shown.
Mentions: Despite a reduction in the number of CPCs following CVB3 infection, juvenile-infected mice developed normally and were phenotypically indistinguishable from mock-infected control mice at 77 days PI. We determined if stress elicited pathologic remodeling in juvenile-infected adult mice administered with the beta adrenergic agonist, isoproterenol (ISO) [38]. At 91 days PI, juvenile-infected or mock-infected mice were treated with ISO for 10 days, treated with vehicle only, or given no treatment. Although mock-infected mice showed an increase in heart weight/tibia length ratios (HW/TL) following ISO treatment, juvenile-infected animals showed a significantly greater increase in heart mass than mock-infected mice (Figure 7A; *p<0.001). Transverse cross sections of heart tissue from ISO-treated mice infected at an early age showed enlarged left ventricles with thinning of the muscular wall (Figure 7B). Also, ISO-treated mice (CVB3-infected and mock-infected) developed fibrosis, as shown by Masson's Trichrome staining (Figure 7C). These observations supported our hypothesis that subclinical infection with CVB3 predisposed mice to greater pathologic remodeling in the heart. Of note, no infiltrating T cells were observed in CVB3 or mock-infected heart following ISO treatment (Figure 7D).

Bottom Line: Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection.Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice.These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

View Article: PubMed Central - PubMed

Affiliation: Donald P. Shiley BioScience Center, San Diego State University, San Diego, California, United States of America.

ABSTRACT
Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

Show MeSH
Related in: MedlinePlus