A Role for Human Skin Mast Cells in Dengue Virus Infection and Systemic Spread

Troupin, Andrea; Shirley, Devon L.; Londoño-Rentería, Berlin; Watson, Alan M.; McHale, Cody; Hall, Alex R.; Hartstone‐Rose, Adam; Klimstra, William B.; Gomez, Gregorio; Colpitts, Tonya M.

doi:10.4049/jimmunol.1600846

Cited by 47 publications

(59 citation statements)

References 68 publications

(68 reference statements)

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“…Previous studies have demonstrated a dual role of mast cells in DENV pathophysiology by using mast cell-deficient mice, a role that is either protective by reducing vascular permeability or aggravative by enhancing DENV infectivity and macrophage skin infiltrates at the inoculation site compared to wild-type mice [20,21]. Troupin et al recently confirmed their crucial role in DENV replication and systemic propagation [22]. They demonstrated that human skin mast cells were permissive to DENV following exposure of samples of human skin tissue to infected mosquitoes [22].…”

Section: Figurementioning

confidence: 99%

Skin innate immune response to flaviviral infection

Garcia

Wehbe

Lévêque

et al. 2017

European Cytokine Network

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Skin is a complex organ and the largest interface of the human body exposed to numerous stress and pathogens. Skin is composed of different cell types that together perform essential functions such as pathogen sensing, barrier maintenance and immunity, at once providing the first line of defense against microbial infections and ensuring skin homeostasis. Being inoculated directly through the epidermis and the dermis during a vector blood meal, emerging Dengue, Zika and West Nile mosquito-borne viruses lead to the initiation of the innate immune response in resident skin cells and to the activation of dendritic cells, which migrate to the draining lymph node to elicit an adaptive response. This literature review aims to describe the inflammatory response and the innate immune signalization pathways involved in human skin cells during Dengue, Zika and West Nile virus infections.

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Section: Figurementioning

confidence: 99%

Skin innate immune response to flaviviral infection

Garcia

Wehbe

Lévêque

et al. 2017

European Cytokine Network

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“…Human skin mast cells were isolated and cultured as described previously (37,38). Briefly, mast cells were isolated and purified from fresh surgical specimens of human skin tissues that were purchased from the Cooperative Human Tissue Network (CHTN) of the National Cancer Institute.…”

Section: Cellsmentioning

confidence: 99%

Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions

et al. 2020

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Mast cells are inflammatory immune cells that play an essential role in mediating allergic reactions in humans. It is well-known that mast cell activation is critically regulated by intracellular calcium ion (Ca 2+) concentrations. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed on mast cells that is activated by various ligands, including several FDA approved drugs; consequently, this receptor has been implicated in causing pseudo-allergic reactions in humans. MRGPRX2 activation leads to an increase in intracellular Ca 2+ levels; however, the Ca 2+ mobilizing mechanisms utilized by this receptor are largely unknown. Previous reports showed that store-operated Ca 2+ entry (SOCE) via the calcium sensor, stromal interaction molecule 1 (STIM1), regulates mast cell response induced by the high-affinity IgE receptor (FcεRI). In this study, using complementary pharmacologic and genetic ablation approaches we demonstrate that SOCE through STIM1 promotes MRGPRX2-induced human mast cell response in vitro. Importantly, SOCE also critically modulates MrgprB2 (mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Collectively, our data suggests that MRGPRX2/MrgprB2 activation of mast cells is dependent on SOCE via STIM1, and further characterization of the MRGPRX2-SOCE-STIM1 pathway will lead to the identification of novel targets for the treatment of pseudo-allergic reactions in humans.

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“…The latter activates endothelial cell proliferation and is associated with increased vascular permeability. In addition, it has angiogenic and lymphogenic properties that together with the presence of viral particles in both cytoplasmic granules and granules after their release from mast cells, facilitate the systemic spread of the virus [39].…”

Section: Immune Response and Pathogenesis Of Dengue Virusmentioning

confidence: 99%

Humanized Mice in Dengue Research: A Comparison with Other Mouse Models

et al. 2020

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Dengue virus (DENV) is an arbovirus of the Flaviviridae family and is an enveloped virion containing a positive sense single-stranded RNA genome. DENV causes dengue fever (DF) which is characterized by an undifferentiated syndrome accompanied by fever, fatigue, dizziness, muscle aches, and in severe cases, patients can deteriorate and develop life-threatening vascular leakage, bleeding, and multi-organ failure. DF is the most prevalent mosquito-borne disease affecting more than 390 million people per year with a mortality rate close to 1% in the general population but especially high among children. There is no specific treatment and there is only one licensed vaccine with restricted application. Clinical and experimental evidence advocate the role of the humoral and T-cell responses in protection against DF, as well as a role in the disease pathogenesis. A lot of pro-inflammatory factors induced during the infectious process are involved in increased severity in dengue disease. The advances in DF research have been hampered by the lack of an animal model that recreates all the characteristics of this disease. Experiments in nonhuman primates (NHP) had failed to reproduce all clinical signs of DF disease and during the past decade, humanized mouse models have demonstrated several benefits in the study of viral diseases affecting humans. In DENV studies, some of these models recapitulate specific signs of disease that are useful to test drugs or vaccine candidates. However, there is still a need for a more complete model mimicking the full spectrum of DENV. This review focuses on describing the advances in this area of research.

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A Role for Human Skin Mast Cells in Dengue Virus Infection and Systemic Spread

Cited by 47 publications

References 68 publications

Skin innate immune response to flaviviral infection

Skin innate immune response to flaviviral infection

Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions

Humanized Mice in Dengue Research: A Comparison with Other Mouse Models

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