Malaria remains a number one killer disease in the world with more than 200 million people infected, and half a million deaths every year. This is no effective vaccine and the emergence of drug resistance prevents efficient malaria control. Further investigations are needed and of high priority to better understand this important parasitic disease and its severe forms in order to improve clinical outcomes. Data from human and mouse studies suggests that the immunomodulatory cytokine type I IFN and its signaling is associated with malaria disease outcome. Type I IFN exhibits very broad immunomodulatory properties and profound effects on innate and adaptive immune cell activation and programming. Plasmacytoid dendritic cells (pDCs) are the most specialized cell subset in producing type IFN, and can secrete up to a 1,000 times more abundant levels of type I IFN than any other cell type. Using the Plasmodium yoelii surrogate mouse model of lethal malaria infection that recapitulates many features of human severe malaria, we have established type I IFN as an essential early mediator of immune cell activation that can modulate disease outcomes. We discovered that BM macrophages through functional and physical interactions control pDC activation. In this proposal, we seek to understand the molecular mechanisms underlying this interaction.

Public Health Relevance

relevant statement This project investigates specific aspects of the immune response associated with malaria infections, a leading cause of morbidity and mortality worldwide. We will examine the role of type I interferon and a subset of leukocyte that produce this powerful immunomodulatory molecule released during infection as reported in infected humans but also in mouse models. We will use a mouse model of severe blood stage malaria as surrogate to precisely investigate how this blood parasite is detected by the host immune system. These studies will inform of immunity to malaria is initiated, but also vaccine and adjunctive therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI128735-01
Application #
9234441
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Pesce, John T
Project Start
2016-12-08
Project End
2018-11-30
Budget Start
2016-12-08
Budget End
2017-11-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine, Inc
Department
Type
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461