A molecular and serologic evaluation of enteroviral involvement in human myocarditis

doi:10.1016/0022-2828(90)91476-N

Journal of Molecular and Cellular Cardiology

Volume 22, Issue 4, April 1990, Pages 403-414

https://doi.org/10.1016/0022-2828(90)91476-N Get rights and content

Abstract

Murine coxsackie B virus infection models of myocarditis and numerous human serologic studies associating elevated enterovirus-specific IgM titers with the clinical diagnosis of myocarditis have been used to support an etiologic role for enteroviruses in human myocarditis. Of the human enteroviruses, coxsackie B viruses (CVB) are the enterovirus group most commonly associated with the human disease. While hybridization probes exist to detect most, if not all, human enteroviruses, no probe capable of specifically detecting an enteroviral group (such as the CVB) to the exclusion of all others has been described to date. Thus, to test the hypothesis that enteroviral involvement in human myocarditis is commonplace, we examined a case series of human myocarditic heart tissues for enteroviruses by in situ hybridization using a generic enterovirus probe. These results were then compared with CVB-specific IgM levels in the cognate satient sera. Comparison of the hybridization data with the CVB-specific IgM levels in the cognate sera yielded no valid correlation between the detection of enterovirus RNA and specificity of CVB identification in any patient. The data are consistent with common enterovirus infections in humans and a possible etiologic role in myocarditis but do not support a specific etiologic role for CVB in this study group.

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Myocarditis, inflammation of the muscular portion of the heart, encompasses a number of different diseases with diverse etiologies and variable clinical presentations. This chapter reviews the definition of myocarditis as per traditional criteria and briefly discusses newer criteria being applied. The roles of clinical history, laboratory diagnostics, electrocardiography, echocardiography, radiology, and biopsy in making a diagnosis of myocarditis are discussed. Each of the common histologic presentations of myocarditis is discussed with respect to the appearance under the microscope and with respect to clinical etiology. These etiologies are then discussed in terms of pathophysiology and the most common presentations observed. The chapter closes with a brief discussion on treatment of myocarditis.
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Myocarditis, inflammation of the muscular portion of the heart, encompasses a number of different diseases with diverse etiologies and variable clinical presentations. This chapter reviews the definition of myocarditis as per traditional criteria and briefly discusses some of the newer criteria being applied. The roles of clinical history, laboratory diagnostics, electrocardiogram, echocardiography, radiology, and biopsy in making a diagnosis of myocarditis are discussed. Each of the common histologic presentations of myocarditis is discussed with respect to the appearance under the microscope and with respect to clinical etiology. These etiologies are then discussed in terms of pathophysiology and the most common presentations observed. The chapter closes with a brief discussion on treatment of myocarditis.
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Severe health consequences have been associated with outbreaks of coxsackievirus infection (Cui et al., 2010a; Verma et al., 2009; Wong et al., 2011). Moreover, group B coxsackievirus (CVB) infection has been implicated in the development of myocarditis and dilated cardiomyopathy (Bowles et al., 1986; Jin et al., 1990; Knowlton, 2008; Martin et al., 1994; Tracy et al., 1990). In spite of this, there is presently no specific and effective therapy available for CVB infection.
Coxsackievirus B type 3 (CVB3) is one of the major pathogens associated with human heart disease. miRNAs are a class of short, noncoding RNA that can post-transcriptionally modulate gene expression. By comparing the CVB3 genome and miR-342-5p sequences, we found there were potential miR-342-5p targets in the CVB3 genome. To verify the effect of miR-342-5p on CVB3 biosynthesis, HeLa cells were infected with a Renilla luciferase (RLuc)-expressing CVB3 variant (RLuc-CVB3). We observed that miR-342-5p could significantly inhibit the expression of RLuc in infected cells. In HeLa cells infected with an enhanced green fluorescence protein (EGFP)-expressing CVB3 variant (EGFP-CVB3), EGFP expression was also significantly inhibited by miR-342-5p. The inhibitory effect of miR-342-5p on EGFP expression in EGFP-CVB3-infected cells could be reversed by transfection with anti-miR-342-5p oligonucleotide (AMO-miR-342-5p). Moreover, RNA and protein biosynthesis in wild-type CVB3 was significantly inhibited by miR-342-5p. By mutating the putative targets of miR-342-5p in the 2C-coding region, a sequence, nt4989–nt5015, was identified as the miR-342-5p target. The conserved nt4989–nt5015 sequences of CVB type 1–5 suggest miR-342-5p may exert its inhibitory effect in other types of coxsackievirus besides CVB3. Western blotting indicated that miR-342-5p could indeed suppress protein expression in CVB type 1 and 5. There was a moderate abundance of miR-342-5p in the gut, heart, and brain of Balb/c mice, suggesting that miR-342-5p may interact with CVB3 in vivo. Taken together, these results indicate that miR-342-5p can inhibit CVB3 biosynthesis by targeting its 2C-coding region and therefore may be a potential therapeutic agent in the treatment of CVB3 infection.
Patchy myocardial pattern of virus sequence persistence in heart transplant recipients - Possible role of sampling error in the etiology
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Citation Excerpt :
Kühl et al11 showed that adenovirus persistence worsened the prognosis of idiopathic left ventricle failure. Recent results have shown that virus eradication with interferon may attenuate the clinical consequences of DCM due to an entero- or adenovirus etiology.7–9 The effects of interferon therapy in acute myocarditis-related end stage heart failure, however remain controversial.19
The pathway from viral myocarditis to end-stage heart failure is commonly accepted, but diagnosis of virus-mediated myocardial injury remains challenging. Virus persistency in the myocardium may accelerate ventricular failure; thus, a precise diagnosis of virus persistency may prevent the development of end-stage heart failure.
We performed a systematic investigation on the sampling error of viral diagnostics in heart transplant recipients: Transmural samples from 5 regions of the explanted hearts from recipients during heart transplantation were amplified using entero-, adeno-, and herpesvirus sequences and histologic examinations performed.
We examined 175 myocardial samples from dilated cardiomyopathy and 100 samples from 20 forensic medicine patients. Seven patients were positive for the examined viruses: 10 positive regions for adenovirus, and 1 positive region for herpes virus DNA, but none for enterovirus. A focal myocardial pattern was detected for adenovirus.
Our results with the patchy myocardial viral persistence may explain possible false-negative results related to virus-mediated etiology among end-stage dilated cardiomyopathy patients. Therefore, repeated endomyocardal biopsies, and multiple cardiac samples are recommended to be obtained to evaluate the etiology of heart failure, thus reducing the occurrence of end-stage heart failure and decreasing the number of patients requiring heart transplantation.
Coxsackievirus B<inf>3</inf> affects endothelial tight junctions: Possible relationship to ZO-1 and F-actin, as well as p38 MAPK activity
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Group B coxsackievirus (CVB) consists of six serotypes, of which CVB3 in particular is considered to be the most frequent cause of human viral heart disease as well as other related disorders (Tracy et al., 1990; Baboonian et al., 1997; Pallansch, 1997).
Tight junction (TJ) plays a pivotal role in preventing the invasion of pathogens from the blood to extracellular environment. However, the mechanisms by which Group B coxsackievirus 3 (CVB₃) can get through TJ from the apical surface still remain obscure. In the present study, the human umbilical vein endothelial cell (HUVEC) was utilized to investigate the alterations in F-actin and ZO-1 status, permeability as well as p38 mitogen-activated protein kinase (MAPK) activity in response to CVB₃ by means of fluorescence labeling, flow cytometry, and macromolecule permeability assay. We found that CVB₃ was able to induce reorganization of F-actin and redistribution of ZO-1, increase the level of F-actin, and elevate the permeability of FITC-albumin. Moreover, CVB₃-mediated the above effects involve in P38 MAPK activation. Our preliminary study indicates that CVB₃-induced alteration in permeability may be attributed to disruption of F-actin and ZO-1 organizations and that SB203580, a specific P38 MAPK inhibitor, can reverse these effects. The precise mechanisms underlying the CVB₃-mediated effects on HUVECs need to be studied further.
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Reovirus-induced murine myocarditis provides an excellent model for the human disease. Previously, we showed that reovirus induction of and sensitivity to interferon-β (IFN-β) are important determinants of protection against cardiac damage. IFN-β induces a number of genes with antiviral activities, including the dsRNA-activated protein kinase, PKR. Once bound to viral dsRNA, PKR becomes activated and phosphorylates eukaryotic initiation factor-2α (eIF2α) leading to the cessation of host cell translation. Additionally, activated PKR can exert its antiviral effects by inducing phosphorylation of IκB, leading to the activation of the transcription factor NFκB and subsequent induction of IFN-β. Thus, activated PKR can both induce and be induced by IFN-β. Recently, numerous reports have shown PKR to be dispensable for both induction of IFN as well as protection against disease. However, both PKR's role in the heart in response to viral infection and its ability to prevent cardiac damage have gone largely unexplored. Here, we demonstrate PKR to be critical for viral induction of IFN-β in primary cardiac myocyte cultures. Additionally, we show that loss of PKR leads to an increase in virulence for both myocarditic and nonmyocarditic reoviruses. Finally, we demonstrate PKR to be critical for protection against reovirus-induced viral myocarditis.

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Original articleA molecular and serologic evaluation of enteroviral involvement in human myocarditis

Abstract

Lancet

J Am Coll Cardiol

Dev Biol

J Virol Meto

Anal Biochem

J Virol Meth

J Pediatrics

Lancet

Prog Cardiovasc Dis

Cell

Lancet

Detection of persistent coxsackie B virus RNA in dilated cardiomyopathy and myocarditis

European Heart J

Myocarditis—an histopathologic definition and classification

Am J Cardiovasc Pathol

A study of coxsackie B virus infections, 1972–1983

J Hyg Camb

Mu-antibody capture ELISA for the rapid diagnosis of enterovirus infections in patients with asceptic meningitis

J Med Virol

Interactions with the Immune System

Detection of viral sequences of low reiteration frequency by in situ hybridization

Identification of coxsackie B viruses and enteroviruses in general using nucleic acid hybridization

European Heart J

Enteroviruses

Immunohistochemical study of the myocardium in murine coxsackie B3 virus myocarditis using monoclonal antibodies—significance of Lyt-l antigen-bearing lymphocytes in cell-mediated immunity

Jap Circ J

The Evolution and Management of Human Viral Infections

The detection of coxsackievirus RNA in cardiac tissue by in situ hybridization

J Gen Virol

Properties of coxsackievirus B3 variants which are amyocarditic or myocarditic for mice

J Med Virol

Temperature-sensitive mutant of coxsackievirus B3 establishes resistance in neonatal mice that protects them during adolescence against coxsackievirus B3-induced myocarditis

Infect Immunol

Acetylation of chromosome squaches of Drosophila melanogaster decreases the background in autoradiographs from hybridization with (125I)-labeled RNA

J Histochem Cytochem

Representativity of endomyocardial biopsies: A theoretical approach based on quantitative light microscopy

Cardiology

Original article
A molecular and serologic evaluation of enteroviral involvement in human myocarditis

Acetylation of chromosome squaches of Drosophila melanogaster decreases the background in autoradiographs from hybridization with (¹²⁵I)-labeled RNA