Immunocompetent Mice Infected by Two Lineages of Dengue Virus Type 2: Observations on the Pathology of the Lung, Heart and Skeletal Muscle

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.

Primary infection of BALB/c mice with a dengue virus type 4 strain leads to kidney injury

“…These are associated to several biochemical imbalances, such as the increase of blood urea nitrogen and blood creatinine levels, both in BALB/c mice and in humans. 6 , 27 , 41 , 62 …”

Murine diabetic models for dengue virus infection

“…The organs were processed and sectioned before staining with hematoxylin and eosin (H&E) and examined microscopically for histopathological changes 12 . These organs were also harvested for immunohistochemical analyses using 4G2 antibody (tagged E protein of DENV‐3) 41 …”

“…12 These organs were also harvested for immunohistochemical analyses using 4G2 antibody (tagged E protein of DENV-3). 41…”

Mechanism of autophagy induced by activation of the AMPK/ERK/mTOR signaling pathway after TRIM22-mediated DENV-2 infection of HUVECs

“…DENV infection causes several self-limiting febrile diseases including dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). DHF and DSS are fatal syndromes with clinical manifestations of increased vascular permeability and plasma leakage [6], and further result in multiple organ damage and circulatory system failure, which endangers life [7][8][9]. Pathogenesis is associated with the dysfunction of vascular endothelial cells and autophagy.…”