Pyroptosis : an alternative programmed cell death in dengue virus (DENV) infection

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Pyroptosis : an alternative programmed cell death in dengue virus (DENV) infection


Author: Cheung , Ka Tik
Title: Pyroptosis : an alternative programmed cell death in dengue virus (DENV) infection
Degree: Ph.D.
Year: 2016
Subject: Dengue viruses.
Cell death.
Hong Kong Polytechnic University -- Dissertations
Department: Dept. of Health Technology and Informatics
Pages: xxi, 204 pages : color illustrations
Language: English
InnoPac Record:
Abstract: Dengue fever (DF) is a mosquito-borne disease caused by dengue virus (DENV), which is a member of the family Flaviviridae. DENV is categorised into five serotypes (DENV-1, -2, -3, -4 and -5). DF is a self-limiting illness; however, it can also progress to more severe forms, including Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS). DHF and DSS are severe febrile illnesses that can progress to hypovolemic shock with characteristic hemostatic abnormalities and increased capillary leakage. The outcome of DENV infection depends on the interactions between host cells and DENVs. The host cells are thought to respond to viral infection by initiation of cell death or secretion to the host of stimulating factors, like cytokines. It has been reported that host cells undergo cell death in response to DENV infection. Apoptosis is perhaps the most widely recognised process of programmed cell death in DENV infection. However, other types of cell death exist, including autophagy, oncosis and caspase-1-dependent programmed cell death (also known as pyroptosis). These may also contribute to the mechanism of cell death in DENV infection. Given that pyroptosis can promote pathogen clearance by a more aggressive approach than silencing cell death (e.g., apoptosis and autophagy) in response to DENV, which in turn leads to inflammation, the mechanism by which this occurs in DENV is still not completely clear. In addition, one of the major explanations of the vascular leakage that occurs in DHF or DSS is endothelial cell (EC) death induced by DENV. Pyroptosis in DENV-infected ECs could offer an alternative explanation. In this study, macrophages and ECs were used as in-vitro cell models to demonstrate that pyroptosis could be an alternative process of programmed cell death in DENV infection. We hypothesised that both macrophages and ECs would be able to undergo pyroptosis and provide the sources of IL-1β production during DENV-2 infection with the activation of caspase-1. We further hypothesised that pyroptosis in ECs could be induced by DENV-2 infection and increase membrane permeability.
Our results found an increase in expression of NALP3, ASC and caspase-1. It is suggested that DENV triggers activation of caspase-1 through the sensor NALP3 and induces the production of the pro-inflammatory cytokines IL-1β in macrophages and ECs. Finally, elevated LDH activity showed evidence of cell lysis and demonstrated that cell death occurred after DENV infection. Therefore, we can conclude that the activation of pyroptosis in macrophages and ECs could be triggered by DENV infection in-vitro. Further, plasma leakage is the hallmark of DHF, which is associated with a sudden increase in systemic vascular permeability. In the current study, our results indicated that the pyroptosis in ECs induced by DENV-2 infection increased membrane permeability. This is the first evidence that pyroptosis in ECs contributes to the mechanism of vascular leakage during DENV-2 infection. This study also demonstrated that the production of IL-1β and activation of pyroptosis in macrophages and HUVECs during DENV-2 infection were regulated not only by caspase-1 but also by caspase-4 and that caspase-4 was upstream of caspase-1 in the activation pathway. Caspase-4 thus appears to be a key mediator of inflammation and pyroptosis in macrophages during DENV-2 infection. Additional studies are required to elucidate further the molecular mechanisms involved. Further, this study showed that while apoptosis may not be a major type of cell death induced by DENV infection in macrophages and ECs at higher multiplicities of infection, it will be the major type of programmed cell death in both macrophage and ECs when DENV occurs at a lower infectious dose. The fate and amount of DENV-infected macrophages may affect the level of DENV and pro-inflammatory cytokines in patients, in turn affecting severity. From the results of the present study, it can be concluded that both macrophages and ECs are able to undergo pyroptosis and provide sources of IL-1β production during DENV-2 infection with the activation of caspase-1. Caspase-4 was also found to be involved in the activation of caspase-1. In another finding, pyroptosis in ECs can be induced by DENV-2 infection, resulting in increased membrane permeability. These results provide an in-depth understanding of pyroptosis as an alternative process of programmed cell death and of caspase-1 and -4 activations during DENV infection. Our results shed light on the pathogenesis of DENV infection and may also provide new knowledge for the future development of therapeutic targets that could help to develop better management of severe dengue disease.

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