In vivo characterization of cytokine profiles and viral load during murine cytomegalovirus-induced acute myocarditis

Ritter, Jethro Trees; Tang-Feldman, Yajarayma J.; Lochhead, G. Raymond; Estrada, Marko; Lochhead, Stephanie; Yu, Cindy; Ashton-Sager, Amanda; Tuteja, Dipika; Leutenegger, Christian; Pomeroy, Claire

doi:10.1016/j.carpath.2008.12.001

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Volume 19, Issue 2 , Pages 83-93, March 2010

In vivo characterization of cytokine profiles and viral load during murine cytomegalovirus-induced acute myocarditis

Jethro Trees Ritter
- Department of Internal Medicine, University of California, Davis Health System, Sacramento, CA, USA
Yajarayma J. Tang-Feldman
- Department of Internal Medicine, University of California, Davis Health System, Sacramento, CA, USA
- Corresponding author. University of California, Davis Health System, 4610 X Street, Suite 3101, Sacramento, CA 95817, USA. Tel.: +1 530 754 6650; fax: +1 530 754 6652.
G. Raymond Lochhead
- Department of Internal Medicine, University of California, Davis Health System, Sacramento, CA, USA
Marko Estrada
- School of Veterinary Medicine, University of California, Davis, Davis, CA, USA
Stephanie Lochhead
- Department of Internal Medicine, University of California, Davis Health System, Sacramento, CA, USA
Cindy Yu
- Department of Pathology, University of California, Davis Health System, Sacramento, CA, USA
Amanda Ashton-Sager
- Department of Pathology, University of California, Davis Health System, Sacramento, CA, USA
Dipika Tuteja
- Department of Internal Medicine, University of California, Davis Health System, Sacramento, CA, USA
Christian Leutenegger
- School of Veterinary Medicine, University of California, Davis, Davis, CA, USA
Claire Pomeroy
- Department of Internal Medicine, University of California, Davis Health System, Sacramento, CA, USA
- Corresponding author. University of California, Davis Health System, 4610 X Street, Suite 3101, Sacramento, CA 95817, USA. Tel.: +1 530 754 6650; fax: +1 530 754 6652.

Received 15 January 2008; received in revised form 17 June 2008; accepted 3 December 2008. published online 17 February 2009.

Abstract

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)-α, interleukin (IL)-6, and interferon (IFN)-γ, 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-γ 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.

Keywords: Myocarditis, MCMV, Cytokines, Calcification, Inflammation, T cells