Immune-mediated cytokine storm and its role in severe dengue

Abstract

Dengue remains one of the most important mosquito-borne diseases worldwide. Infection with one of the serologically related dengue viruses (DENVs) can lead to a wide range of clinical manifestations and severity. Severe dengue is characterized by plasma leakage and abnormal bleeding that can lead to shock and death. There is currently no specific treatment for severe dengue due to gaps in understanding of the underlying mechanisms. The transient period of vascular leakage is usually followed by a rapid recovery and is suggestive of the effects of short-lived biological mediators. Both the innate and the adaptive immune systems are activated in severe dengue and contribute to the cytokine production. We discuss the immunological events elicited during a DENV infection and identify candidate cytokines that may play a key role in the severe manifestations of dengue and possible interventions.

Keywords: Adaptive immunity; Cytokines; Dengue; Dengue hemorrhagic fever; Innate immunity; Plasma leakage.

Fig 1

Clinical course of dengue hemorrhagic fever. Clinical events and laboratory findings during phases of illness from the febrile phase through the critical phase and into the recovery phase is shown. Hemoconcentration (an increase in hematocrit) occurs during the critical phase and is an indication of plasma leakage. Platelet counts decline during the illness reaching the lowest point around the time when plasma leakage occurs. Shaded areas represent the normal ranges for temperature, hematocrit, and platelet count.

Fig 2

Immunological events in DENV infection. DENV is introduced through mosquito bites and infects local immune cells including resident dendritic cells, mast cells, and blood-derived dendritic cells. Cytokines produced by these local immune cells regulate viral replication and further recruit immune cells to the site of infection. Infected cells migrate to local lymph nodes where DENV further replicates and activates B and T cells leading to differentiation of these cells into effector cells. DENV disseminates through the circulation and further amplified the innate and the adaptive immune responses. The cytokines produced by these immune cells activate endothelial cells resulting in the perturbation of vascular integrity and coagulopathy. NS1 protein may act directly on endothelial cells to enhance vascular permeability. These cytokines may affect other cell types including hepatocytes leading to liver injury.