Dendritic cells and dengue virus infection in the skin: immune response and the role of mosquito saliva
Final Report Abstract
The skin and its immune cells, such as dendritic cells (DCs) and macrophages, are an important barrier against invading pathogens. Dengue is a major public health problem worldwide, with an estimated 390 million infections and 100 million cases per year and no specific therapeutic or vaccine available. Aedes mosquitoes transmit dengue virus (DENV) to humans via the skin when taking a blood meal. Previous studies have examined DENV infection only in the epidermis, the upper-most layer of the skin, but no information existed about DENV infection in the dermis, the layer below that contains blood vessels. This project aimed to establish the initial targets for DENV replication in the skin, the immune response, and the impact of mosquito saliva on early DENV infection and pathogenesis. To address these questions, we established a model of intradermal DENV infection in the skin of mouse ears, as biopsies from naturally-infected human skin are unavailable. The steady-state dermis already contains classical DCs and macrophages, which we found to be the initial targets of DENV infection (1). Monocytes that circulate in the blood were then recruited to the dermis and differentiated to monocyte-derived DCs. These newly-recruited monocytes and monocyte-derived DCs became DENV-infected in a second wave and then were the major targets for DENV replication 48-72 hours post-infection (1). We thus demonstrated how DENV exploits the immune response by infecting cells that are recruited to the skin as part of antiviral defense. These results should help future research to develop new strategies for vaccination and therapeutics against dengue. Because saliva from the Aedes aegypti mosquito vector contains hemostatic and immunomodulatory components, we examined the role of mosquito saliva in DENV infection and development of disease. We found that the presence of mosquito salivary gland extracts (SGE) in the intradermal DENV inoculum reduced disease severity in naïve mice but exacerbated disease and induced lethality during secondary, antibody-enhanced infection (manuscript in preparation). Flow cytometry of the skin revealed greater DENV infection of dermal DCs and macrophages in the presence of mosquito SGE that was more pronounced during antibody-dependent enhancement compared to naïve infection conditions. These results highlight mosquito-derived factors in augmenting dengue pathogenesis under conditions when humans are at higher risk of severe disease. These studies should stimulate the further investigation of mechanism, saliva components, and potential use of mosquito-derived components as adjuvants during intradermal vaccination. Yet, many questions remain, which we summarized in a review article (2). DENV infects the same cells (DCs, monocytes, and macrophages) that are essential for inducing and maintaining optimal innate and adaptive immune responses (2). This tropism of DENV appears to impair DC function, which may undermine the priming of DENV-specific memory responses (2). Dissecting the dual role of DCs in DENV infection—as targets of virus replication and mediators of immunity—will be crucial for understanding the early events in dengue pathogenesis and is the subject of my current research. Further, additional studies on the immunomodulatory effects of mosquito saliva on early DENV infection in the skin and their impact on disease severity are ongoing.
Publications
- Dendritic cells in dengue virus infection: Targets of virus replication & mediators of immunity. 2014 (Review) Front Immunol 5:647
Schmid MA, Diamond MS, and Harris E
(See online at https://doi.org/10.3389/fimmu.2014.00647) - Monocyte recruitment to the dermis and differentiation to dendritic cells increases the targets for dengue virus replication. 2014 PLoS Pathog 10(12): e1004541
Schmid MA and Harris E
(See online at https://doi.org/10.1371/journal.ppat.1004541) - Mosquito Saliva Increases Endothelial Permeability in the Skin, Immune Cell Migration, and Dengue Pathogenesis during Antibody-Dependent Enhancement. PLoS Pathog 12(6): e1005676, 2016
Schmid MA, Glasner DR, Shah S, Michlmayr D, Kramer L, and Harris E
(See online at https://doi.org/10.1371/journal.ppat.1005676)
