doi: 10.1161/01.RES.0000239428.01434.e2
© 2006 American Heart Association, Inc.
Editorials |
Integrin-Linked Kinase Plays a Key Role in Coxsackievirus Replication
From the Department of Medicine and Pathology, The Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Charles J. Lowenstein, 950 Ross Building, 720 Rutland Ave, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. E-mail clowenst{at}jhmi.edu
See related article, pages 354–361
Key Words: ILK • Coxsackievirus • Akt signaling • decay accelerating factor • apoptosis
Viral infection may be a major cause of idiopathic dilated cardiomyopathy, but little is known about how viruses enter the cardiac myocyte and damage it. Understanding the pathogenesis of viral myocarditis will lead to new strategies for the treatment and prevention of heart failure. In this issue of Circulation Research, Esfandiareiet al show that the integrin-linked kinase (ILK) plays a key role in the lifecycle of the cardiotropic virus Coxsackievirus.1
More than 100 000 patients in the United States have a nonischemic dilated cardiomyopathy, and this disease accounts for 45% of all heart transplants.2,3 More than 25% of the nonischemic dilated cardiomyopathy cases may be caused by viral infections.4 The virus that most commonly infects the heart is Coxsackievirus, a small RNA virus (picornavirus) spread through the fecal–oral route.5 Coxsackievirus infection causes a viral prodrome of fever and myalgias, followed by diarrhea. Approximately 2 weeks after the onset of infection, direct viral injury of cardiac myocytes in combination with the inflammatory host response cause a cardiomyopathy. The clinical course of viral cardiomyopathy is highly variable, ranging from an acute fulminant disease, with complete recovery, to a smoldering chronic inflammatory state with progressive heart failure and death.
The lifecycle of Coxsackievirus is short and simple. Coxsackievirus binds to 2 receptors, decay accelerating factor (DAF) and the Coxsackievirus adenovirus receptor (CAR), and then enters the cardiac myocyte.6 The virus hijacks the host, forcing it to translate its RNA genome into a single large polyprotein. Viral proteases then cleave this polyprotein into smaller polypeptides, including structural proteins, viral proteases, and an RNA-dependent RNA polymerase. The viral polymerase copies the viral RNA genome directly into RNA strands, the capsid proteins assemble around the viral RNA, and the mature viral particle exits the cell.
Although this outline of the viral lifecycle is simple enough, details of some stages remain elusive. Esfandiarei et al now show that the cellular kinase ILK plays a critical role in viral replication.1 ILK is a unique adaptor that connects cell adhesion molecules to intracellular signaling pathways.7 Extracellular matrix proteins activate integrins, triggering ILK, which in turn activates downstream targets including Akt, glycogen synthase kinase 3 (GSK3), and phosphatase holoenzyme inhibitor 1 (PHI-1). ILK also interacts with a set of actin binding proteins, parvin and paxillin. By connecting integrins to the actin cytoskeleton and cytoplasmic kinases, ILK is thought to transduce extracellular signals into intracellular signals.
In this issue of Circulation Research, McManus and colleagues show that Coxsackievirus infection activates ILK, which then triggers Akt signaling.1 Blocking ILK or Akt decreases viral replication and also enhances host cell viability. These results suggest that ILK plays a key role in the viral lifecycle. How?
ILK might promote viral replication by regulating the actin cytoskeleton. Many pathogens rely on cytoskeletal proteins to travel through the cell to subcellular domains where they can replicate and infect adjacent cells. ILK interacts with paxillin and parvin, which in turn regulate actin polymerization.1 Perhaps rearrangements of the actin cytoskeleton are important to viral replication. An exciting recent report showed that Coxsackievirus interacts with one of its receptors, DAF, which in turn triggers the rearrangement of actin fibers, permitting virus movement to tight junctions where it encounters its second receptor CAR.6 Perhaps ILK mediates the effects of DAF on actin. Another suggestion is that ILK promotes viral replication by triggering downstream kinases such as GSK3, PHI-1, or Akt. For example, CVB3 infection activates GSK3, which is necessary for cytopathic effects of the virus.8
Another intriguing possibility is that ILK promotes viral replication by suppressing host apoptosis. Apoptosis can be an innate immune response to viral infection.9 Coxsackievirus and other picornaviruses convert the host cell into a factory producing viral particles, but apoptosis shuts down viral production. Viruses have evolved various strategies to block apoptosis.9 One viral target within the apoptotic cascade is Akt. The protein kinase Akt is a serine–threonine kinase that regulates a wide array of cellular functions, including cell survival and metabolism.10 Perhaps Coxsackievirus infection activates ILK, which triggers Akt signaling, in turn suppressing apoptotic pathways and boosting virus replication.
The current study in Circulation Research raises interesting questions about cardiotropic viruses. How does viral infection activate ILK—perhaps through either viral receptor, DAF or CAR? What is the role of the actin cytoskeleton during viral replication? How does Akt signaling affect virus replication—by controlling apoptosis or by directly phosphorylating viral enzymes? Are there other targets of ILK that play a role in the viral lifecycle? Finally, can we develop novel drugs that activate apoptosis in selected cell populations and use these compounds to limit viral replication?
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Acknowledgments |
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Sources of Funding
Supported by grants from the NIH (R01 HL078635, R01 HL074061, P01 HL65608, P01 HL56091), the American Heart Association (EIG 0140210N), the Ciccarone Center, and the John and Cora H. Davis Foundation.
Disclosures
C.J.L. receives research support from the NIH and from Pfizer Inc.
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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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Related Article:
Circ. Res. 2006 99: 354-361.
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