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.
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.
|Ang, W X Gladys; Church, Alison M; Kulis, Mike et al. (2016) Mast cell desensitization inhibits calcium flux and aberrantly remodels actin. J Clin Invest 126:4103-4118|
|Choi, Hae Woong; Abraham, Soman N (2015) Mast cell mediator responses and their suppression by pathogenic and commensal microorganisms. Mol Immunol 63:74-9|
|Miao, Yuxuan; Li, Guojie; Zhang, Xiaoli et al. (2015) A TRP Channel Senses Lysosome Neutralization by Pathogens to Trigger Their Expulsion. Cell 161:1306-19|
|Chan, Cheryl Y; St John, Ashley L; Abraham, Soman N (2013) Mast cell interleukin-10 drives localized tolerance in chronic bladder infection. Immunity 38:349-59|
|Choi, Hae Woong; Brooking-Dixon, Rhea; Neupane, Subham et al. (2013) Salmonella typhimurium impedes innate immunity with a mast-cell-suppressing protein tyrosine phosphatase, SptP. Immunity 39:1108-20|
|Gwinn, William M; Johnson, Brandi T; Kirwan, Shaun M et al. (2013) A comparison of non-toxin vaccine adjuvants for their ability to enhance the immunogenicity of nasally-administered anthrax recombinant protective antigen. Vaccine 31:1480-9|
|Bowen, Samantha E; Watt, Christine L; Murawski, Inga J et al. (2013) Interplay between vesicoureteric reflux and kidney infection in the development of reflux nephropathy in mice. Dis Model Mech 6:934-41|
|St John, Ashley L; Abraham, Soman N (2013) Innate immunity and its regulation by mast cells. J Immunol 190:4458-63|
|Staats, Herman F; Kirwan, Shaun M; Choi, Hae Woong et al. (2013) A Mast Cell Degranulation Screening Assay for the Identification of Novel Mast Cell Activating Agents. Medchemcomm 4:|