The Pathology of Severe Dengue in Multiple Organs of Human Fatal Cases: Histopathology, Ultrastructure and Virus Replication

Abstract

Dengue is a public health problem, with several gaps in understanding its pathogenesis. Studies based on human fatal cases are extremely important and may clarify some of these gaps. In this work, we analyzed lesions in different organs of four dengue fatal cases, occurred in Brazil. Tissues were prepared for visualization in optical and electron microscopy, with damages quantification. As expected, we observed in all studied organ lesions characteristic of severe dengue, such as hemorrhage and edema, although other injuries were also detected. Cases presented necrotic areas in the liver and diffuse macro and microsteatosis, which were more accentuated in case 1, who also had obesity. The lung was the most affected organ, with hyaline membrane formation associated with mononuclear infiltrates in patients with pre-existing diseases such as diabetes and obesity (cases 1 and 2, respectively). These cases had also extensive acute tubular necrosis in the kidney. Infection induced destruction of cardiac fibers in most cases, with absence of nucleus and loss of striations, suggesting myocarditis. Spleens revealed significant destruction of the germinal centers and atrophy of lymphoid follicles, which may be associated to decrease of T cell number. Circulatory disturbs were reinforced by the presence of megakaryocytes in alveolar spaces, thrombus formation in glomerular capillaries and loss of endothelium in several tissues. Besides histopathological and ultrastructural observations, virus replication were investigated by detection of dengue antigens, especially the non-structural 3 protein (NS3), and confirmed by the presence of virus RNA negative strand (in situ hybridization), with second staining for identification of some cells. Results showed that dengue had broader tropism comparing to what was described before in literature, replicating in hepatocytes, type II pneumocytes and cardiac fibers, as well as in resident and circulating monocytes/macrophages and endothelial cells.

Development of viable TAP-tagged dengue virus for investigation of host–virus interactions in viral replication

“…DENV infects several organs in humans, altering host homeostasis and counteracting the host response (Aye et al, 2014;Pó voa et al, 2014). These events suggest complex interactions between host and virus where viral proteins play roles in several networks.…”

Lactate based optical screening of dengue virus infection in human sera using Raman spectroscopy

“…The biochemical impact of dengue virus infection on the function of various body organs like liver, kidney, lungs, heart etc. as well as elevated level of lactate is well established and reported [27][28][29][30][31][32][33]. As stated earlier, liver and kidney are the two main organs in the human body which regulate the lactate level.…”

Small G Rac1 is involved in replication cycle of dengue serotype 2 virus in EAhy926 cells via the regulation of actin cytoskeleton

“…Asparasitic pathogens, many viruses depend on the components of the host cell to replicate and complete the steps of their life cycle, including viral entry, transportation to the site of replication or the release of progeny virions to the extracellular environment (Angelini et al, 2013;Bass et al, 1995;Garoff et al, 1998;Kallewaard et al, 2005;Lyman and Enquist, 2009;Monaghan et al, 2005;Ott et al, 1996;Ravkov et al, 1998). A variety of viruses have been found to utilize diverse approaches to regulate actin cytoskeletons to create a suitable microenvironment for effectively establishing infection (Chu et al, 2003;Sun and Whittaker, 2007).…”

“…However, the mechanism underlying the increased vascular permeability induced by DENV infection is currently unclear. Recently, a morphological study identified hemorrhage, edema and swollen vascular endothelial cells (VECs) in several organs in fatal dengue patients, and viral antigens and negative-strand RNA were detected in VECs, hepatocytes and macrophages (Povoa et al, 2014). This finding indicated that increased vascular permeability and morphological changes of VECs are characteristic pathological features of severe dengue.…”