Inflammasome Fuels Dengue Severity

Abstract

Dengue is an acute febrile disease triggered by dengue virus. Dengue is the widespread and rapidly transmitted mosquito-borne viral disease of humans. Diverse symptoms and diseases due to Dengue virus (DENV) infection ranges from dengue fever, dengue hemorrhagic fever (life-threatening) and dengue shock syndrome characterized by shock, endothelial dysfunction and vascular leakage. Several studies have linked the severity of dengue with the induction of inflammasome. DENV activates the NLRP3-specific inflammasome in DENV infected human patients, mice; specifically, mouse bone marrow derived macrophages (BMDMs), dendritic cells, endothelial cells, human peripheral blood mononuclear cells (PBMCs), keratinocytes, monocyte-differentiated macrophages (THP-1), and platelets. Dengue virus mediated inflammasome initiates the maturation of IL-1β and IL-18, which are critical for dengue pathology and inflammatory response. Several studies have reported the molecular mechanism through which (host and viral factors) dengue induces inflammasome, unravels the possible mechanisms of DENV pathogenesis and sets up the stage for the advancement of DENV therapeutics. In this perspective article, we discuss the potential implications and our understanding of inflammasome mechanisms of dengue virus and highlight research areas that have potential to inhibit the pathogenesis of viral diseases, specifically for dengue.

Dengue Virus Envelope Protein Domain III Induces Nlrp3 Inflammasome-Dependent NETosis-Mediated Inflammation in Mice

“…Inflammasomes, cellular molecular sensors for PAMPs and DAMPs, are multimeric protein complexes comprising of NLRs [nucleotide-binding domain (NBD) and leucine-rich-repeat-(LRR)-containing], the absent in melanoma-2 (AIM2)-like receptors (ALRs), an adaptor molecule ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1 ( 14 , 25 , 69 , 70 ). Activation of inflammasomes leads to protein-cleavage processes, turning pro-caspase 1 into active form caspase 1, which converts pro-IL-1β and pro-IL-18 into respective active forms (IL-1β and IL-18) ( 69 ).…”

“…In addition to EIII, DENV membrane protein (M) and non-structural proteins NS2A, NS2B were also shown to induce inflammasome activation ( 14 , 97 , 98 ), and NS1 was demonstrated to enhance inflammation through a toll-like receptor 4 ( 99 , 100 ). NS2A, NS2B have shown to serve as viroporins to increase cell-membrane permeability and activate inflammasome ( 14 , 101 , 102 ).…”

“…Pathogenic roles of NETosis have been found in non-infectious diseases, such as autoimmunity, coagulation, acute injuries and cancer ( 19 ). In addition, NETosis has been reported associating with cytokine storm in various infectious diseases, including dengue ( 14 , 20 , 21 ). Interleukin (IL)-1β, a potent proinflammatory cytokine released by DENV-infected leukocytes, has been considered as a critical component in cytokine storm ( 22 – 24 ).…”

“…Interleukin (IL)-1β, a potent proinflammatory cytokine released by DENV-infected leukocytes, has been considered as a critical component in cytokine storm ( 22 – 24 ). Inflammasomes, cellular sensors for pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs), are critical for IL-1 activation ( 14 , 25 ), and the cell death process pyroptosis ( 26 ). Reports revealed that the elevated levels of circulating IL-1β and gene expression in DHF patients suggesting the involvement of IL-1β in the disease severity ( 27 , 28 ).…”

“…Reports revealed that the elevated levels of circulating IL-1β and gene expression in DHF patients suggesting the involvement of IL-1β in the disease severity ( 27 , 28 ). IL-1β enhances the vascular permeability, particularly in association with other proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon in clinical profiles of DF and DHF ( 14 , 29 – 31 ).…”