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Review
. 2024 May 4;16(5):727.
doi: 10.3390/v16050727.

The Dynamic Relationship between Dengue Virus and the Human Cutaneous Innate Immune Response

Michelle M Martí  1 , Priscila M S Castanha  1   2 , Simon M Barratt-Boyes  1
Affiliations
Review

The Dynamic Relationship between Dengue Virus and the Human Cutaneous Innate Immune Response

Michelle M Martí et al. Viruses. .

Abstract

Dengue virus (DENV) is a continuing global threat that puts half of the world's population at risk for infection. This mosquito-transmitted virus is endemic in over 100 countries. When a mosquito takes a bloodmeal, virus is deposited into the epidermal and dermal layers of human skin, infecting a variety of permissive cells, including keratinocytes, Langerhans cells, macrophages, dermal dendritic cells, fibroblasts, and mast cells. In response to infection, the skin deploys an array of defense mechanisms to inhibit viral replication and prevent dissemination. Antimicrobial peptides, pattern recognition receptors, and cytokines induce a signaling cascade to increase transcription and translation of pro-inflammatory and antiviral genes. Paradoxically, this inflammatory environment recruits skin-resident mononuclear cells that become infected and migrate out of the skin, spreading virus throughout the host. The details of the viral-host interactions in the cutaneous microenvironment remain unclear, partly due to the limited body of research focusing on DENV in human skin. This review will summarize the functional role of human skin, the cutaneous innate immune response to DENV, the contribution of the arthropod vector, and the models used to study DENV interactions in the cutaneous environment.

Keywords: antiviral; cutaneous; dendritic cells; dengue virus; human skin; innate immunity; interferon; keratinocytes; macrophages; skin explants.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic of pattern recognition receptors (PRRs) involved in intracellular viral sensing and downstream signaling. TLR-3/7/8/9, RIG-I, and MDA5 are ds- or ssRNA-sensing proteins, whereas cGAS is a dsDNA-sensing protein. These PRRs culminate in the recruitment and phosphorylation of interferon regulatory factors (IRFs). Activated IRFs translocate to the nucleus and bind IFN-stimulated response elements (ISRE) that induce transcription of type I interferons (IFNs) and select IFN-stimulated genes (ISGs). Released type I IFN binds to IFN-αβ receptors (IFNAR) and induces the JAK-STAT signaling pathway. JAK-Tyk2 kinases dimerize, and the activated form phosphorylates signal transducers and activators of transcription 1 and 2 (STAT). IRF9 is recruited to this complex and nuclearly translocates, inducing the expression of ISGs. These pathways create a positive feedback loop that amplifies the transcription of IFNs and ISGs in the skin, fostering an antiviral environment to combat viral infections. Red circles represent phosphorylation.
Figure 2
Figure 2
Schematic of an ex vivo human skin explant model. (1). Dengue virus (DENV) is inoculated into tissue with a bifurcated needle. (2). DENV infects keratinocytes and nearby Langerhans cells. (3). Infected and bystander keratinocytes produce cytokines and chemokines to activate the immune response and recruit immune cells from surrounding tissue to the site of infection. (4). The virus spreads to the dermis and infects fibroblasts, mast cells, dermal dendritic cells, and macrophages. (5). Infected and bystander dermal cells produce cytokines and chemokines to recruit cells and prevent the spread of infection. (6). Infected Langerhans cells and dermal dendritic cells migrate out of the tissue into the media, mimicking the migration to lymphoid tissue that occurs in humans. * Red = infected cells, blue = uninfected cells. Cells not drawn to scale; lymphocytes and natural killer cells not pictured.
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This research received no external funding.
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