During the initial stages of infection, circulating Plasmodium falciparum parasites initiate a cascade of events that trigger antigen presenting cells and natural killer (NK) cells to secrete both pro-inflammatory and anti-inflammatory cytokines. The characteristics of these innate immune responses appear to be a critical step in determining control of parasitemia, severity of infection, and the effectiveness of ensuing adaptive responses. In Burkina Faso, the two main ethnic groups, the Fulani and Mossi, have a differential ability to control parasitemia which appears to be mediated by differences in early IFN-( associated responses. Through a whole genome transcriptional approach, we aim to understand critical gene expression patterns which account for the effective early IFN-( responses in the Fulani. We will extend these studies by defining the role of critical cellular subsets, notably NK cells and T cells, in mediating these robust IFN-( responses. Lastly, we will determine the role of enhanced detection of blood stage parasite through TLRs in mediating the differential downstream IFN-( responses in the Fulani. With growing evidence of what appears to be a "hard-wired" resistance to malaria associated with robust IFN-( responses, the ethnic groups in Burkina Faso offers a unique opportunity to delineate the mechanisms underlying these protective early IFN-( responses. Understanding the key genes/pathways and cell populations that account for these effective early responses to malaria is vital to supporting ongoing vaccine efforts and the development of novel immunomodulatory aimed at harnessing these responses.

Public Health Relevance

Malaria remains the single greatest cause of morbidity and mortality in children in Africa. It is likely that the earliest immune responses to this pathogen are key determinants of disease outcome. Through the study of early antimalarial transcriptional and functional responses in two ethnic groups with differing susceptibility to malaria, we will identify the key innate pathways which underlie this differential ability to control parasitemia, information that will lead to improved vaccine and therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI097695-03
Application #
8479313
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Rao, Malla R
Project Start
2012-06-05
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$159,682
Indirect Cost
$49,612
Name
Yale University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520