Mechanisms and consequences of enterovirus persistence in cardiac myocytes and cells of the immune system.
In humans and experimental murine models enteroviruses, and in particular coxsackieviruses of group B (CVB), may induce chronic myocarditis associated with a persistent type of heart muscle infection. Persistent myocardial infection has been characterized by restricted viral replication and gene expression, which is capable of sustaining chronic inflammation. Altered replication and transcription of the virus, in addition to an immune response insufficient to recognize and clear infected cells entirely, are essential mechanisms for initiation and maintenance of persistent heart muscle infection. Viral cytotoxicity was found to be crucial for organ pathology both during acute and persistent infection, indicating that enterovirus myocarditis is a virus-induced rather than an immune-mediated disease. Notably, resistance to the development of persistent heart muscle infection is not linked to the H-2 haplotype of the host. In addition to persistently infected myocytes, detection of the replicative minus-strand RNA intermediate provided evidence for virus replication in lymphoid cells of the spleen, predominantly in splenic B lymphocytes, during the course of the disease. Whereas viral RNA was also detected in certain CD4+ helper T cells and Mac1+ macrophages, no enteroviral genomes were identified in CD8+ T cells. Detection of infected activated B lymphocytes both in heart tissue of CVB3-infected immunocompetent mice and syngenic SCID mice receiving splenocytes from CVB3-infected donors support the concept that B cell traffic may contribute to maintenance of chronic disease. Dissection of the diversity of viral and host-specific determinants in susceptible and resistant hosts will allow us to define the protective mechanisms that mediate resistance to the development of life-threatening acute and chronic enterovirus myocarditis.
Kandolf
R
R
Department of Molecular Pathology, Institute for Pathology, University Hospital of Tübingen, Germany. reinhard.kandolf@med.uni-tuebingen.de
Sauter
M
M
Aepinus
C
C
Schnorr
J J
JJ
Selinka
H C
HC
Klingel
K
K
D000818:Animals; D003384:Coxsackievirus Infections / Q000473:pathology / Q000821:virology; D004770:Enterovirus; D029822:Enterovirus B, Human; D004769:Enterovirus Infections / Q000473:pathology / Q000821:virology*; D006321:Heart / Q000821:virology*; D006801:Humans; D007107:Immune System / Q000473:pathology / Q000821:virology*; D051379:Mice; D009205:Myocarditis / Q000473:pathology / Q000821:virology; D013154:Spleen / Q000276:immunology / Q000821:virology