Each year, 9 million people are newly infected with Mycobacterium tuberculosis (MTb) and approximately 2 million die from MTb worldwide. MTb is particularly devastating in children, where dissemination and meningitis occur much more readily than in adults. Aside from frank immunodeficiency, the factors that cause mycobacterial disease progression in some or allow latency in others are still unclear. One explanation for these pathogens'global success may be common, immunologically subtle variation in host defense genes. We and others have begun to investigate whether variation in innate immune genes might account for the variable natural history of infection in different hosts. The Toll-like receptor (TLR) pathway is central to the innate immune response to infectious pathogens, including MTb. TLR 2 and TLR 1 join as a heterodimer to recognize mycobacteria. We recently discovered that TLR1 deficiency is common in humans and is regulated by a high frequency single nucleotide polymorphism (SNP), T1805G (I602S), which controls the immune response to MTb extracts and tri-acylated lipopeptide, a cell wall component of many bacteria. We hypothesize that T1805G is critical to the human innate immune response to MTb and regulates the adaptive immune response to MTb.
The aims of this proposal are to investigate the molecular and cellular mechanism of the 1805G signaling defect by: determining where in the TLR pathway theTLR1_1805G signaling defect occurs;investigating the effects of TLR1 deficiency on the innate immune responses in human dendritic cells and macrophages;and evaluating the adaptive immune response to MTb peptides in TLR1-deficient mice.

Public Health Relevance

Determining the consequences of a common TLR1 variant on the immune function of dendritic cells and macrophages will further our understanding of how this pathway controls host defenses against MTb;such insights might support the use of TLR1 ligands as adjuvants in future MTb vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
3K08AI076604-01A2S1
Application #
7919658
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Program Officer
Jacobs, Gail G
Project Start
2009-09-12
Project End
2010-08-31
Budget Start
2009-09-12
Budget End
2010-08-31
Support Year
1
Fiscal Year
2009
Total Cost
$50,000
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195