Heart and skeletal muscle are targets of dengue virus infection

Abstract

Background: Dengue fever is one of the most significant re-emerging tropical diseases, despite our expanding knowledge of the disease, viral tropism is still not known to target heart tissues or muscle.

Methods: A prospective pediatric clinical cohort of 102 dengue hemorrhagic fever patients from Colombia, South America, was followed for 1 year. Clinical diagnosis of myocarditis was routinely performed. Electrocardiograph and echocardiograph analysis were performed to confirm those cases. Immunohistochemistry for detection of dengue virus and inflammatory markers was performed on autopsied heart tissue. In vitro studies of human striated skeletal fibers (myotubes) infected with dengue virus were used as a model for myocyte infection. Measurements of intracellular Ca2+ concentration as well as immunodetection of dengue virus and inflammation markers in infected myotubes were performed.

Results: Eleven children with dengue hemorrhagic fever presented with symptoms of myocarditis. Widespread viral infection of the heart, myocardial endothelium, and cardiomyocytes, accompanied by inflammation was observed in 1 fatal case. Immunofluorescence confocal microscopy showed that myotubes were infected by dengue virus and had increased expression of the inflammatory genes and protein IP-10. The infected myotubes also had increases in intracellular Ca2+ concentration.

Conclusions: Vigorous infection of heart tissues in vivo and striated skeletal cells in vitro are demonstrated. Derangements of Ca2+ storage in the infected cells may directly contribute to the presentation of myocarditis in pediatric patients.

FIGURE 1

Immunohistochemistry of heart tissue from a fatal DHF case show dengue infection of myocardium. (A) H&E stained sections of myocardium appeared morphologically normal. (B, C) Immunohistochemistry performed with monoclonal anti-DENV antibody MAB8705 revealed intracytoplasmic granular deposits within some cardiomyocytes often in a perinuclear location (arrow, B) and multifocally within interstitial and endothelial cells (C). (D) Immunohistochemistry performed with a monoclonal anti-DENV antibody MAB8705 on non-infected control myocardium tissue was negative for viral antigen. (E) Infected myocardium tissue did not stain with an isotype matched irrelevant antibody.