Dysregulated immune cell responses in severe dengue pathogenesis

Abstract

Life-threatening severe dengue (SD) develops in a small subset of patients suffering from dengue fever (DF), a febrile disease that develops following infection with dengue virus (DENV). DENV is a mosquito-borne positive -sense RNA virus. The rapid spread of DENV vectors, which was exacerbated by climate change and inadequate control measures, has led to outbreaks affecting millions worldwide. There is no specific treatment for DF, and the recently introduced vaccines are ineffective in containing the current outbreaks. Like many other viral diseases, the immune system plays a key role in dengue pathogenesis. The lack of models replicating the disease's immunopathological features has hampered the understanding of the immune system's role in developing this disease. Recent advances, such as single-cell approaches, provide better systems and methodologies to study the role of different immune cells in SD, closing this gap and providing a better mechanistic understanding of disease pathogenesis and promoting the identification of targets for therapeutic interventions. Here, we summarize recent advances in SD research, focusing on immune cell interactions and their role in disease severity.

Keywords: cytokine production; dengue fever; dengue virus; immune dysfunction; immunopathogenesis; severe dengue.

Figure 1

Early immune cell interactions during DENV infection. An infected mosquito transmits the virus into the skin during a blood meal. Langerhans cells, moDCs, and monocytes are the first to encounter the virus, serving as primary replication sites. These infected cells further disseminate the virus by interacting with other immune cells at the site of infection, including other DC subsets, macrophages, and mast cells. The virus reaches microcapillaries directly during the bite or via infected cells that reach the bloodstream. Infected DCs reach peripheral lymph nodes where they attempt to activate T cells by presenting viral antigens. However, their impaired maturation and altered cytokine production (increased IL-10, reduced IL-12 and type I IFN) may lead to a suboptimal and potentially skewed T cell response. Monocytes, including intermediate subsets, also migrate to the lymph nodes and can modulate B cell responses. These interactions activate and shape the adaptive immune response (Created with BioRender.com).

Figure 2

Immune cell contribution to SD progression. Initial infection of immune cells in the skin leads to viral dissemination to the bloodstream and lymph nodes. Mechanisms such as ADE during secondary infection, where non-neutralizing antibodies bind the virus and Fc receptors on monocytes/macrophages, contribute to an increase in viral load. The infection affects multiple immune cell types, leading to altered differentiation patterns and dysregulated cytokine production, impairing viral clearance and causing a further increase in viral load. Excess cytokine production, NETosis, dysregulated vasoactive mediators’ secretion, and additional mechanisms compromise endothelial integrity, contributing to capillary leak and culminating in the development of SD (Created with BioRender.com).