In vivo characterization of cytokine profiles and viral load during murine cytomegalovirus-induced acute myocarditis.
BACKGROUND
Murine cytomegalovirus (MCMV) is an etiologic agent of acute and chronic myocarditis in BALB/c mice. Immunologic host responses appear to play a key role in pathogenesis but have been incompletely defined.


METHODS
BALB/c mice were infected with a sublethal dose of MCMV. Cytokine transcription and viral load (measured by quantitative real-time polymerase chain reaction) and histopathological analyses were performed at specified time points.


RESULTS
Increased tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and interferon (IFN)-gamma, as well as IL-10 mRNA transcripts, were detected in the hearts of infected mice starting at Day 1 post-infection (p.i.), with peak levels occurring at Day 8 p.i. (7-fold, 14-fold, 41-fold, and 16-fold higher than background, respectively). Peak cytokine transcription significantly correlated with a 10-fold increase in viral load (P<.001) at Day 8 p.i. Myocarditis-related pathological changes, measured by infiltration foci, were greatest at Day 8 p.i., corresponding with peak cytokine transcription and significantly correlated with IFN-gamma levels (P<.0001). Infiltration foci were predominantly composed of CD3(+) T cells. Cardiac calcification was observed in most infected mice predominantly over the right ventricle. Histological analysis of heart sections from mice infected with recombinant enhanced green fluorescence protein-MCMV revealed a localized and sporadic pattern of virus throughout all heart layers.


CONCLUSIONS
MCMV-induced myocarditis in BALB/c mice is characterized by in vivo production of proinflammatory cytokines in a pattern correlating with MCMV viral load. The infection pattern and inflammatory response is highly localized, sporadic, and involves endocardium, epicardium, as well as the myocardium, with greatest amounts of virus detected in areas of pathologic calcification.
Ritter
Jethro Trees
JT
Department of Internal Medicine, University of California, Davis Health System, Sacramento, CA 95817, USA.
Tang-Feldman
Yajarayma J
YJ
Lochhead
G Raymond
GR
Estrada
Marko
M
Lochhead
Stephanie
S
Yu
Cindy
C
Ashton-Sager
Amanda
A
Tuteja
Dipika
D
Leutenegger
Christian
C
Pomeroy
Claire
C
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D002114:Calcinosis / Q000276:immunology / Q000473:pathology / Q000821:virology; D016207:Cytokines / Q000032:analysis* / Q000235:genetics; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D042282:Microdissection; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000821:virology*; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000276:immunology / Q000473:pathology / Q000821:virology; D012333:RNA, Messenger / Q000378:metabolism; D019562:Viral Load
D016207:Cytokines; D012333:RNA, Messenger