Abstract
Dengue virus (DENV) infection by one of the four serotypes (DENV-1 to 4) may result in a wide spectrum of clinical manifestations, with unpredictable evolution and organ involvement. Due to its association with severe epidemics and clinical manifestations, DENV-2 has been substantially investigated. In fact, the first emergence of a new lineage of the DENV-2 Asian/American genotype in Brazil (Lineage II) in 2008 was associated with severe cases and increased mortality related to organ involvement. A major challenge for dengue pathogenesis studies has been a suitable animal model, but the use of immune-competent mice, although sometimes controversial, has proven to be useful, as histological observations in infected animals reveal tissue alterations consistent to those observed in dengue human cases. Here, we aimed to investigate the outcomes caused by two distinct lineages of the DENV-2 Asian/American genotype in the lung, heart and skeletal muscle tissues of infected BALB/c mice. Tissues were submitted to histopathology, immunohistochemistry, histomorphometry and transmission electron microscopy (TEM) analysis. The viral genome was detected in heart and skeletal muscle samples. The viral antigen was detected in cardiomyocytes and endothelial cells of heart tissue. Heart and lung tissue samples presented morphological alterations comparable to those seen in dengue human cases. Creatine kinase serum levels were higher in mice infected with both lineages of DENV-2. Additionally, statistically significant differences, concerning alveolar septa thickening and heart weight, were observed between BALB/c mice infected with both DENV-2 lineages, which was demonstrated to be an appropriate experimental model for dengue pathogenesis studies on lung, heart and skeletal muscle tissues.
Highlights
The incidence of dengue has grown dramatically around the world in recent decades, and currently, more than half of the global population lives in areas with a risk of Dengue virus (DENV) transmission [1,2]
Lineage I was observed when compared to noninfected mice at 72 hpi and 7 dpi; the mean value decreased at 14 dpi (0.199 g)
When analyzing mice infected with Lineage I, we observed that, on average, the ratio between lung weight and body weight was slightly higher at 7 dpi
Summary
The incidence of dengue has grown dramatically around the world in recent decades, and currently, more than half of the global population lives in areas with a risk of DENV transmission [1,2]. Infection by any of the four serotypes may result in a wide spectrum of clinical manifestations with unpredictable evolution and outcome, varying from selflimited flu-like illnesses to a severe form of the disease, characterized by thrombocytopenia, coagulopathy, increased vascular permeability that may lead to multiple organ impairment, Microorganisms 2021, 9, 2536. A study has suggested that pulmonary involvement during DENV infection is mild to moderate and is more likely to be observed in patients presenting more severe symptoms [10]. The disruption of skeletal muscle integrity leads to the release of intracellular muscle components, such as CK into the bloodstream and extracellular space [21], and a study showed an increase in the levels of this protein in dengue patient sera [22]. Some studies have reported muscle alterations in human samples [22,23,24,25,26,27]
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