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J Virol. 2017 Aug 24;91(18). pii: e00617-17. doi: 10.1128/JVI.00617-17. Print 2017 Sep 15.

Transcriptional Profiling Confirms the Therapeutic Effects of Mast Cell Stabilization in a Dengue Disease Model.

Author information

1
Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, New York, USA jmm2105@cumc.columbia.edu ashley.st.john@duke-nus.edu.sg.
2
Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore.
3
Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.
4
Department of Microbiology, University of Washington, Seattle, Washington, USA.
5
Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore jmm2105@cumc.columbia.edu ashley.st.john@duke-nus.edu.sg.
6
Department of Microbiology and Immunology, Young Loo Lin School of Medicine, National University of Singapore, Singapore.

Abstract

There are no approved therapeutics for the treatment of dengue disease despite the global prevalence of dengue virus (DENV) and its mosquito vectors. DENV infections can lead to vascular complications, hemorrhage, and shock due to the ability of DENV to infect a variety of immune and nonimmune cell populations. Increasingly, studies have implicated the host response as a major contributor to severe disease. Inflammatory products of various cell types, including responding T cells, mast cells (MCs), and infected monocytes, can contribute to immune pathology. In this study, we show that the host response to DENV infection in immunocompetent mice recapitulates transcriptional changes that have been described in human studies. We found that DENV infection strongly induced metabolic dysregulation, complement signaling, and inflammation. DENV also affected the immune cell content of the spleen and liver, enhancing NK, NKT, and CD8+ T cell activation. The MC-stabilizing drug ketotifen reversed many of these responses without suppressing memory T cell formation and induced additional changes in the transcriptome and immune cell composition of the spleen, consistent with reduced inflammation. This study provides a global transcriptional map of immune activation in DENV target organs of an immunocompetent host and supports the further development of targeted immunomodulatory strategies to treat DENV disease.IMPORTANCE Dengue virus (DENV), which causes febrile illness, is transmitted by mosquito vectors throughout tropical and subtropical regions of the world. Symptoms of DENV infection involve damage to blood vessels and, in rare cases, hemorrhage and shock. Currently, there are no targeted therapies to treat DENV infection, but it is thought that drugs that target the host immune response may be effective in limiting symptoms that result from excessive inflammation. In this study, we measured the host transcriptional response to infection in multiple DENV target organs using a mouse model of disease. We found that DENV infection induced metabolic dysregulation and inflammatory responses and affected the immune cell content of the spleen and liver. The use of the mast cell stabilization drug ketotifen reversed many of these responses and induced additional changes in the transcriptome and immune cell repertoire that contribute to decreased dengue disease.

KEYWORDS:

dengue fever; dengue virus; interferons; mast cell; transcriptional regulation

PMID:
28659489
PMCID:
PMC5571258
DOI:
10.1128/JVI.00617-17
[Indexed for MEDLINE]
Free PMC Article

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