The assessment of genetically determined predispositions to clinical diseases is a theme central to the vision of a personalized health care. Rare deleterious germline mutations have been found to cause up to 150 different primary immunodeficiencies. In most instances, there is predisposition to multiple infectious diseases. However, it is now becoming apparent that rare mutations in some genes can result in more subtle/narrow clinical phenotypes. This study aims at establishing an ex-vivo genome-wide transcriptome assay to measure leukocyte responses to host- and pathogen-derived immune activators in such patients. Specifically, we are first proposing to characterize blood leukocyte responsiveness in control subjects.
This aim will use whole genome expression microarrays to assess responsiveness in whole blood of 12 healthy subjects exposed to Toll-like and Interleukin 1 receptor family ligands. Secondly, we will identify specific alterations in patterns of blood leukocyte responsiveness in the blood of patients with known inborn errors of TLR immunity.
This aim will assess responsiveness of 18 subjects with increased susceptibility to invasive pneumococcal disease attributed to a defect in function of two key signaling molecules: IRAK4 and MYD88. Altogether this project will serve as a foundation for the development of novel tools to screen for and characterize primary immune deficiencies.

Public Health Relevance

Constitutes a basis for the development of novel genome-wide transcriptome profiling strategy for the detection and identification of primary immunodeficiencies. This assay may be used for determining susceptibility to recurrent, life threatening infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21AI085523-02
Application #
8150074
Study Section
Special Emphasis Panel (ZRG1-IMM-C (52))
Program Officer
Johnson, David R
Project Start
2010-03-12
Project End
2012-02-28
Budget Start
2010-07-13
Budget End
2011-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$170,790
Indirect Cost
Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
076647908
City
Seattle
State
WA
Country
United States
Zip Code
98101
Alsina, Laia; Israelsson, Elisabeth; Altman, Matthew C et al. (2014) A narrow repertoire of transcriptional modules responsive to pyogenic bacteria is impaired in patients carrying loss-of-function mutations in MYD88 or IRAK4. Nat Immunol 15:1134-42
Boisson, Bertrand; Laplantine, Emmanuel; Prando, Carolina et al. (2012) Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol 13:1178-86
Guo, Yiqi; Audry, Magali; Ciancanelli, Michael et al. (2011) Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med 208:2083-98