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© 2000 American Heart Association, Inc.
Editorials |
Viral Myocarditis
Receptors That Bridge the Cardiovascular With the Immune System?
From the Heart & Stroke/Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada.
Correspondence to Dr Peter Liu, Heart & Stroke/Lewar Centre of Excellence, EN12-324, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4. E-mail peter.liu{at}utoronto.ca
Key Words: receptors • adenovirus • cardiomyocytes
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Introduction |
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 Top Introduction Role of the Receptors...How Are the Receptors...Could the Immune-Cardiovascular...References |
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Viral myocarditis exhibits different clinical phenotypes depending on the age of the patient. In pediatric patients, viral myocarditis can present as acute heart failure and cardiogenic shock, and in older patients, it often presents as chronic, slowly progressive heart failure and dilated cardiomyopathy. The severity of viral myocarditis is determined by a delicate balance between the viral infection and the inflammatory response that is engendered in the host.
The commonest viral causes of human myocarditis include coxsackievirus B group and adenovirus. It is no accident that these two viruses emerged as the commonest etiological agent of myocarditis. Recent elegant work by Bergelson et al1 demonstrated that both of these viruses share a common cell surface receptor—coxsackie-adenoviral receptor (CAR).
CAR is a 46-kDa member of the immunoglobulin (Ig) superfamily, featuring the Ig loops maintained by disulphide bonds between appropriately positioned cysteines. The extracellular domain is the key functional component for coxsackievirus internalization.2 CAR also serves as an attachment receptor for adenovirus. However, the natural function and regulation of CAR are still relatively unknown.
The efficiency in targeting the host cell by coxsackievirus and
adenovirus depends on their distinct coreceptors. Coxsackievirus B
(CVB) uses the complement deflecting protein decay accelerating factor
(DAF, CD55) as its coreceptor,3 whereas adenovirus uses
integrin 
vß3 and
vß5 as its
coreceptors.4 DAF as a coreceptor serves an important
function by significantly increasing the binding efficiency of
coxsackievirus onto the DAF-CAR receptor complex to facilitate
internalization by CAR.5
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Role of the Receptors in Viral Myocarditis |
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TopIntroductionRole of the Receptors...How Are the Receptors...Could the Immune-Cardiovascular...References |
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Myocarditis is both a viral and inflammatory disease. The virus uses the T and B lymphocytes as part of its trafficking in the host, increasing viral load in the heart (a classic Trojan Horse scenario). The localization of the virus in the heart determines the subsequent development of the inflammatory foci in the heart, as the immune system is activated trying to clear the virus.6 Therefore, the ability for the virus to enter the target cells such as the myocyte will very much influence the subsequent course of the disease. Hence, information on the receptor repertoire in the myocytes, as studied by Ito et al7 and reported in this issue of Circulation Research, contributes significantly to our understanding of the pathogenesis of the disease and the corresponding clinical phenotype.
In the case of coxsackieviral myocarditis, the internalization receptor
(CAR) collaborates with the attachment coreceptor (DAF), probably
through a stereochemical interaction (Figure
). DAF facilitates the
binding of the virus onto the receptor-coreceptor complex, and CAR is
responsible for the internalization of the virus to permit subsequent
viral replication. As noted by Ito et al,7 DAF and CAR are
part of an immune family of receptors, suggesting an interaction
between cardiovascular development and immune signaling
pathways. Paradoxically, these immune molecules such as CAR when
expressed in the cardiovascular system are used by an
external infectious agent as portal of entry into the myocyte.
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How Are the Receptors Regulated? |
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TopIntroductionRole of the Receptors...How Are the Receptors...Could the Immune-Cardiovascular...References |
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How receptors such as CAR are regulated will be important in understanding the kinetics of the disease. It is of interest that CAR is expressed in higher quantities in younger hearts than older hearts, suggesting a developmental role. In addition, it may also explain the higher propensity of coxsackieviral infections in newborns and young children with a more clinically acute disease. The most interesting aspect of the present study suggested that the CAR receptor can be induced under immunological activation. In the present study, this was generated through an autoimmune mechanism by immunizing with myosin. The myosin autoimmune murine model is a good general noninfectious model to study the inflammatory component of myocarditis.
Thus, immune stimulation increases expression of the CAR receptor, making the target organ even more susceptible to further uptake of the virus. As suggested by Ito et al,7 CAR may in addition play a role in cell-cell communication and may further enhance the inflammatory interaction between immune cells and the myocyte and the subsequent repair process.
Because the immune system is often activated by cytokine signaling pathways, CAR may also be regulated through this mechanism. It is therefore of interest that when the immune system is specifically inhibited through targeted knockout strategy, such as with CD4-/-/CD8-/- null transgenics8 or through knockout of the tyrosine kinases such as p56lck-/--associated signal amplification pathways,9 coxsackieviral myocarditis is dramatically reduced in severity, without an increase in viral titers. This may be facilitated by a decreased upregulation of CAR, significantly impairing the kinetics of replication of the etiological viral agent.
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Could the Immune-Cardiovascular Linkage Have a Happy Ending? |
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TopIntroductionRole of the Receptors...How Are the Receptors...Could the Immune-Cardiovascular...References |
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Insights into the virus-receptor interaction and its regulation by the immune system, as elucidated by the present study, further enhance our understanding of myocarditis. Inflammation can lead to increased expression of CAR, which in turn may lead to an increase in viral infection and amplify the inflammatory process. This positive feedback loop may point toward novel therapeutic strategies. Specific peptide or nonpeptide blockers that interfere with the interaction of the virus with its receptor is one approach. Reduction of specific elements of the inflammatory response may secondarily decrease CAR receptor expression and, in turn, protect the host from viral myocarditis. CAR provides the first example of a unique linkage between the cardiovascular and immune system. It also opens the door to fully explore its scientific implications and develop novel therapeutic opportunities.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionRole of the Receptors...How Are the Receptors...Could the Immune-Cardiovascular...References |
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1. Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science. 1997;275:1320–1323.
2.
Wang X, Bergelson JM. Coxsackievirus and adenovirus
receptor cytoplasmic and transmembrane domains are not essential for
coxsackievirus and adenovirus infection. J Virol. 1998;73:2559–2562.
3. Shafren DR, Bates RC, Agrez MV, Herd RL, Burns GF, Barry RD. Coxsackievirus B1, B3 and B5 use decay accelerating factor as a receptor for cell attachment. J Virol. 1995;69:3873–3877.[Abstract]
4.
Roelvink PW, Lizonova A, Lee JGM, Li Y, Bergelson JM,
Finberg RW, Brough DE, Kovesdi I, Wickham TJ. The
coxsackievirus-adenovirus receptor protein can function as a cellular
attachment protein for adenovirus serotypes from subgroups A, C, D, E,
and F. J Virol. 1998;72:7909–7915.
5. Martino TA, Petric M, Brown M, Aitken K, Gauntt CJ, Richardson CD, Chow LH, Liu PP. Cardiovirulent coxsackieviruses and the decay-accelerating factor (CD55) receptor. Virology. 1998;244:302–314.[Medline] [Order article via Infotrieve]
6.
Klingel K, Hohenadl C, Canu A, Albrecht M, Seemann M,
Mall G, Kandolf R. Ongoing enterovirus-induced myocarditis is
associated with persistent heart muscle infection: quantitative
analysis of virus replication, tissue damage, and inflammation.
Proc Natl Acad Sci U S A. 1992;89:314–318.
7.
Ito M, Kodama M, Masuko M, Yamaura M, Fuse K, Uesugi
Y, Hirono S, Okura Y, Kato K, Hotta Y, Honda T, Kuwano R, Aizawa Y.
Expression of coxsackievirus and adenovirus receptor in hearts of rats
with experimental autoimmune myocarditis. Circ Res. 2000;86:275–280.
8.
Opavsky MA, Penninger J, Aitken K, Wen WH, Dawood F,
Mak T, Liu P. Susceptibility to myocarditis is dependent on the
response of ß T lymphocytes to coxsackieviral infection.
Circ Res. 1999;85:551–558.
9. Liu P, Aitken K, Kong YY, Martino T, Dawood F, Wen WH, Opavsky MA, Kozieradzki I, Bachmaier K, Straus D, Mak T, Penninger J. Essential role for the tyrosine kinase p56lck in coxsackievirus B3 mediated heart disease. Nat Med. In press.
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