Characteristics of dengue virus‐infected peripheral blood mononuclear cell death that correlates with the severity of illness

Abstract

The pathogenic mechanism of the severe form of dengue is complicated. Recent reports indicate that apoptotic death of various tissues or organs may be associated with vascular leakage, and ultimately leads to the death of DENV-infected patients. In the present study, we provide additional evidence supporting the detrimental role of apoptosis in DENV infection. A comparison of the rate of apoptosis in PBMCs isolated from patients suffering DF, a mild form of the disease, and the rate in patients with DHF, a life-threatening disease, revealed that PBMCs from DHF patients underwent apoptosis at a significantly higher rate than those suffering from DF alone. This suggests that the severity of natural DENV infection correlates with PBMC apoptosis. In addition, this cell death was induced not only by DENV itself, but also by the apoptotic activities of pro-inflammatory cytokines, such as TNF-α, and IL-1β, that were upregulated in DHF patients. The death of these mononuclear cells that function in an innate immune system may explain the higher viral load in DHF patients than in DF patients. Interestingly, a gene expression profile pattern elucidated that apoptosis occurring during natural DENV infection involved mainly the extrinsic apoptosis pathway, which is mediated via both caspase-dependent and caspaseindependent mechanisms. In conclusion, our data highlight the adverse effect of apoptosis induced by DENV and by pro-inflammatory cytokines during natural DENV infection.Key words apoptosis, cDNA microarray analysis, dengue hemorrhagic fever/dengue shock syndrome, dengue virus, receptor-mediated death.Dengue fever and DHF/DSS, the world's most significant arthropod-borne viral diseases, are caused by DENV. DENV, a member of the Flavivirus genus, has caused lifethreatening epidemics in more than 100 countries in tropical and subtropical areas (1). Each year, 50-100 million people are estimated to be infected by DENV (2-4). While

Viability and Functionality of Cryopreserved Peripheral Blood Mononuclear Cells in Pediatric Dengue

“…This mechanism modulates immune cell activation against the virus, ensuring homeostasis (37). PBMC death in acute DV infection has been linked to disease severity (11,12). In our study, this association was not found (Fig.…”

“…A high frequency of apoptotic PBMCs, particularly CD8 ϩ T lymphocytes (TLs), circulate during the acute phase (11). In some cases, the magnitude of cellular death has been associated with clinically severe forms of disease (12). Although apoptosis induction in PBMCs in the context of dengue infection is a mechanism to control viral replication (13), the elevated frequencies of cells in different stages of cellular death may affect the efficiency with which these cells are cryopreserved.…”

Dengue NS1 antigen as a marker of severe clinical disease

“…Since in this study the NS1 antigen levels significantly and inversely correlate with lymphocyte counts (p < 0.0001, R = -0.48), it appears that dengue viraemia could be possibly leading to lymphopenia. Massive T cell apoptosis has been shown to occur in dengue infection, which has been associated with more severe disease [20],[30]. Although the cause of massive T cell death is not clear it has been thought that T cells undergo apoptosis due to massive proliferation and activation induced cell death [31].…”

Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation

“…5,[9][10][11] This cytokine has been linked to increased endothelial permeability, 5,11 thrombosis, and dysregulated hemostasis in dengue. 9 IL-1b is synthesized as a larger precursor protein that is cleaved into the active cytokine by inflammasomes, intracellular multimolecular complexes that control caspase-1 activity in the innate immune system.…”