Mechanism(S) of Coxsackievirus-Induced Acute Myocarditis in the Mouse

Gauntt, Charles J.; Godeny, Elmer K.; Lutton, C. William; Arizpe, H. M.; Crapman, Nora M.; Tracy, Steven; Revtyak, George; Valente, Anthony J.; Rozek, Marius M.

doi:10.1007/978-1-4899-0891-9_10

Cited by 9 publications

(3 citation statements)

References 47 publications

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“…Both cardiovirulent (able to induce disease) and noncardiovirulent strains of CVB3 replicate well in hearts of experimentally infected mice. Only cardiovirulent CVB3 strains, however, cause the significant cardiomyocyte destruction with subsequent cardiac inflammation which is characteristic of acute myocarditis (13,24,48,81). Noncardiovirulent CVB3 is cleared from the experimentally infected murine heart within 7 to 10 days postinfection (dpi), while infectious cardiovirulent CVB3 remains detectable in hearts for at least 2 weeks postinfection (41,49,81).…”

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“…Noncardiovirulent CVB3 is cleared from the experimentally infected murine heart within 7 to 10 days postinfection (dpi), while infectious cardiovirulent CVB3 remains detectable in hearts for at least 2 weeks postinfection (41,49,81). The fall in murine cardiac CVB3 titer is coincident with the rise in anti-CVB3 neutralizing antibody titers and the ability of T cells to recognize CVB3 antigens (6,24,48). In addition to direct in situ hybridization evidence for enterovirus replication in human heart myocytes (38,80,89) and for cardiovirulent CVB3 replication in murine heart myocytes (41,42,62,80,81), CVB3 infects a variety of cultured cardiac cell types, including murine (30,33,94) and human (37) cardiomyocytes, murine fetal heart fibroblasts (MFHF) (30), and cardiac endothelial cells (32).…”

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The cardiovirulent phenotype of coxsackievirus B3 is determined at a single site in the genomic 5' nontranslated region

Chapman

Hufnagel

et al. 1995

J Virol

129

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We report the construction of chimeric coxsackievirus B3 (CVB3) strains in which sequences of an infectious cDNA copy of a noncardiovirulent CVB3 genome were replaced by the homologous sequences from a cardiovirulent CVB3 genome to identify which of 10 predicted genetic sites determine cardiovirulence. Cardiovirulent phenotype expression was consistently linked to nucleotide 234 (U in cardiovirulent CVB3 and C in avirulent CVB3) in the 5 nontranslated region. Reconstructions of the parental noncardiovirulent CVB3 genome from chimeras restored the noncardiovirulent phenotype when tested in mice. Inoculation of severe combined immunodeficient (scid) mice with the noncardiovirulent CVB3 strain resulted in massive cardiomyocyte necrosis in all animals. Sequence analysis of viral genomes isolated from twelve scid mouse hearts showed that only nucleotide position 234 was different (a C3U transition) from that in the input parental noncardiovirulent CVB3 genome. Higher-order RNA structures predicted by two different algorithms did not demonstrate an obvious local effect caused by the C3U change at nucleotide 234. Initial studies of parental and chimeric CVB3 replication in primary cultures of fetal murine heart fibroblasts and in adult murine cardiac myocytes demonstrated that viral RNA transcriptional efficiency is approximately 10-fold lower for noncardiovirulent CVB3 than for cardiovirulent CVB3. CVB3 did not shut off protein synthesis in murine cardiac fibroblasts, nor were levels of viral protein synthesis significantly different as a function of viral phenotype. Taken together, these data support a significant role for determination of the CVB3 cardiovirulence phenotype by nucleotide 234 in the 5 nontranslated region, possibly via a transcriptional mechanism.

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confidence: 99%

The cardiovirulent phenotype of coxsackievirus B3 is determined at a single site in the genomic 5' nontranslated region

Chapman

Hufnagel

et al. 1995

J Virol

129

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“…At present numerous reports point to a variety of pathogenetic mechanisms contributing to lesions induced by these viruses both during the natural course of infection in humans and during experimental infection in mice. Cell-mediated immunity factors are among the leading ones in the pathogenesis of coxsackievirus infection [1,5,6]. A nonspecific inflammatory exudate in the abdominal cavity may be easily induced by intraperitoneal injection of any stimulant.…”

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Time course of the content of cellular elements in the peritoneal exudate of BALB/c mice infected with coxsackievirus A13

1995

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Coxsackievirus A13 is shown to suppress macrophage exudation into the peritoneal cavity of adult male BALB/c mice. The influence of the infection on the counts of lymphocytes and polymorphonuclear leukocytes is less expressed. The detected changes are regarded as a manifestation of the immunomodulating action of coxsackievirus A13 infection. Key Words: coxsackievirus A13; BALB/c mice; peritoneal exudate; cell compositionCoxsackieviruses play an important role in human pathology [7]. At present numerous reports point to a variety of pathogenetic mechanisms contributing to lesions induced by these viruses both during the natural course of infection in humans and during experimental infection in mice. Cell-mediated immunity factors are among the leading ones in the pathogenesis of coxsackievirus infection [1,5,6]. A nonspecific inflammatory exudate in the abdominal cavity may be easily induced by intraperitoneal injection of any stimulant. After 3 days the exudate consists mainly of mononuelear cells, with macrophages predominating. Intraperitoneal injection of a specific antigen at this time causes a rapid reduction in the number of macrophages in the exudate. Some scientists believe [4] that the reaction of the disappearance of peritoneal exudate cells is similar to the macrophage migration inhibition test in vitro. It may therefore be used for the assessment of cellular immunity.This work was aimed at investigating the influence of coxsackievirus A13 on the time course of the content of cellular elements in the peritoneal exudate of BALB/c mice. MATERIALS AND METHODSThe studies were carried out on 150 male BALB/ c mice aged 4 months from the Stolbovaya breeding center, Russian Academy of Medical Sciences. The prototype coxsackievirus strain A13 (Flores strain) was used, obtained from the Research Institute of Viral Preparations, Russian Academy of Medical Sciences (Moscow). The virus was replicated and titered in a monolayer culture of primary trypsin-treated human embryo fibroblasts by routine methods.Four percent potato starch was used as a reagent stimulating the release of cellular elements into the abdominal cavity. The necessary amount of starch was brewed in distilled water, brought to the boil, autoclaved at 0.5 arm for 20 min, and frozen. Before use, the gel was thawed at room temperature. The resultant suspension was homogenized in a sterile glass homogenizer. One ml (40 nag) of this suspension was intraperitoneally injected to mice.The animals were sacrificed by cervical dislocation. Peritoneal exudate cells were obtained by washing the peritoneal cavity with 8 ml of Hanks ~ solution with 5 units/nil heparin. The total content of nucleus-containing cells and their differentiated numbers were counted in the exudate. For this purpose, the cells were sedimented by centrifu-

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