Enteroviral infection of mice with severe combined immunodeficiency. Evidence for direct viral pathogenesis of myocardial injury.
Inbred mice with genetically determined severe combined immunodeficiency (SCID) lack mature T and B lymphocyte functions. To distinguish direct viral effects in the pathogenesis of myocarditis from those mediated by antigen-specific and histocompatibility-complex-restricted host immunity, we inoculated coxsackievirus B3 into homozygous young adult SCID mice. We found that infected SCID mice invariably developed extensive myocarditis between 7 and 14 days postinoculation with high subsequent mortality. Histopathologic examination of the infected SCID myocardium indicated multiple foci of cardiomyocyte necrosis and a delayed pleomorphic inflammatory infiltrate. Immunohistochemically, the coxsackievirus B3-infected SCID heart contained frequent clusters of macrophages (Mac-1+) as well as other cells that may represent nonspecific phagocytic or cytolytic effectors. In situ hybridization with radiolabeled cDNA probes for enteroviral genome indicated a significant excess of positive-strand genome in the SCID myocardium compared with that in similarly infected non-SCID controls, with hybridization signals localized primarily to cardiomyocytes. In vitro culture confirmed persistent viremia and a vast excess of infective virus in the SCID myocardium relative to infected non-SCID controls. Thus, direct viral mechanisms in the production of cardiomyocyte injury in coxsackievirus B3-infected mice appear to be more important than previously recognized, particularly in the setting of unrestricted viral proliferation.
Chow
L H
LH
John P. Robarts Research Institute, University of Western Ontario, London, Canada.
Beisel
K W
KW
McManus
B M
BM
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D009202:Cardiomyopathies / Q000209:etiology* / Q000276:immunology / Q000382:microbiology; D003384:Coxsackievirus Infections / Q000150:complications; D004279:DNA, Viral / Q000032:analysis; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000276:immunology / Q000302:isolation & purification; D004769:Enterovirus Infections / Q000150:complications* / Q000276:immunology; D006321:Heart / Q000382:microbiology; D007150:Immunohistochemistry; D016130:Immunophenotyping; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID / Q000382:microbiology*; D009205:Myocarditis / Q000209:etiology / Q000276:immunology / Q000382:microbiology; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D009693:Nucleic Acid Hybridization; D016511:Severe Combined Immunodeficiency / Q000150:complications* / Q000276:immunology; D014779:Virus Replication
D000956:Antigens, Viral; D004279:DNA, Viral