Dengue virus (DENV) is the cause of the acute febrile and debilitating diseases dengue fever and dengue hemorrhagic fever (DHF). These diseases affect an estimated 50 million individuals each year, making a licensed dengue vaccine a global health priority. Four serotypes of DENV, a single stranded RNA virus, infect human populations worldwide but there is currently no effective DENV vaccine. While primary infections of each serotype typically result in a quickly contained illness, a second challenge with a different serotype can lead to lethal complications, in part, due to the presence of harmful cross-reactive antibodies. These issues highlight the imperative of optimizing any vaccine formulation to promote a protective adaptive immune response to all serotypes, avoiding harmful side effects. Mast cells (MC) are present in tissues at the host- environment interface, such as the skin, where DENV-infected mosquitoes deposit virus, and are distributed systemically throughout connective tissues. Although the role of MCs in promoting optimal immunity during bacterial infection is well characterized, MCs are also known for detrimental contributions to certain inflammatory conditions. Few studies have examined interactions of MCs with viral infections and DENV infection, specifically. Our previous work and preliminary data reveal that MCs strongly react to DENV and can limit the spread of DENV infection when localized in the skin. However, preliminary data also suggest that when DENV virus particles are present in large numbers, systemically, MCs can contribute to vascular leakage, particularly when MCs are sensitized with heterologous anti-DENV antibodies during secondary infection. Here, we propose to extend these observations to investigate the role of MCs in mobilizing protective immunity against DENV to primary or homologous secondary challenges and to examine their contribution, if any, to complications of secondary challenge with a different serotype. Furthermore, by capitalizing on the capacity of MCs to offer early protection from DENV, we may prevent the establishment of systemic infection. MC activators, when incorporated in vaccines, can serve as potent adjuvants by evoking a powerful immune response. Therefore, finally, we propose to develop a novel vaccine strategy that selectively harnesses the MCs capacity to amplify and augment protective adaptive immune responses to generate high affinity antibodies and productive cellular immunity simultaneously against all DENV serotypes.

Public Health Relevance

Dengue infections represent a global health problem. Identifying critical immune cells involved in modulating the beneficial immune responses as well as the pathological sequellae of dengue fever could lead to novel strategies for preventing and treating these infections. We have recently discovered that mast cells play a beneficial role at the early stages of infection but potentially play a very harmful role during certain secondary infections. This proposal is directed at investigating the dual role of mast cells in dengue infections and of developing effective strategies to modulate mast cell properties for therapeutic purposes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL112921-02
Application #
8680362
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Sarkar, Rita
Project Start
2013-07-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$379,455
Indirect Cost
$134,455
Name
Duke University
Department
Pathology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705