Our goal is to study how infection with Mycobacterium tuberculosis (MTB) regulates antigen (Ag) presenting cells (APCs, e.g.macrophages and dendritic cells). MTB is an important human pathogen that evades host defenses to maintain chronic infection. Dendritic cells must present MTB Ags to prime CD4 T cell responses, and CD4 effector T cells must recognize infected macrophages presenting MTB Ags to provide effector functions, including production of IFN-g, which is essential to host resistance. Regulation of macrophage ARC function by MTB is important to tuberculosis pathogenesis but remains poorly understood. We propose that Toll-like receptor (TLR) signaling by MTB pathogen-associated molecular patterns (PAMPs) produces both immune- activating effects (e.g.induction of pro-inflammatory cytokines by macrophages or maturation of dendritic cells) and late phase downregulatory effects (e.g.inhibition of MHC-II expression and Ag processing by macrophages that are chronically infected with MTB). We will investigate the ability of MTB PAMPs to signal via TLRs to modulate dendritic cell and macrophage APC function. We will focus on three major lipoprotein PAMPs of MTB that were identified in our previous studies, namely LpqH (19-kDa lipoprotein), LprG and LprA. We will study the ability of LpqH, LprG and LprA to signal via TLR2, TLR2/1 or TLR2/6, induce macrophage expression of pro-inflammatory cytokines, act as adjuvants to influence Th1/Th2 differentiation of T cell responses, promote dendritic cell maturation and cause late phase downregulation of macrophage MHC-II expression and Ag processing (including signaling and chromatin remodeling studies). Approaches will include production of recombinant His-tagged PAMPs and engineered variants for structure-function studies, generation of PAMP knockout MTB and M. bovis BCG and investigation of APC regulation by RFP-tagged mycobacteria in vivo with a mouse model of tuberculosis. Overall, these studies will enhance our understanding of tuberculosis pathogenesis and contribute to optimization of vaccine strategies for tuberculosis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Gondre-Lewis, Timothy A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
Simmons, Daimon P; Wearsch, Pamela A; Canaday, David H et al. (2012) Type I IFN drives a distinctive dendritic cell maturation phenotype that allows continued class II MHC synthesis and antigen processing. J Immunol 188:3116-26
Liu, Yi C; Simmons, Daimon P; Li, Xiaoxia et al. (2012) TLR2 signaling depletes IRAK1 and inhibits induction of type I IFN by TLR7/9. J Immunol 188:1019-26
Mahon, Robert N; Sande, Obondo J; Rojas, Roxana E et al. (2012) Mycobacterium tuberculosis ManLAM inhibits T-cell-receptor signaling by interference with ZAP-70, Lck and LAT phosphorylation. Cell Immunol 275:98-105
Li, Qing; Ding, Xuedong; Thomas, Jeremy J et al. (2012) Rv2468c, a novel Mycobacterium tuberculosis protein that costimulates human CD4+ T cells through VLA-5. J Leukoc Biol 91:311-20
Lancioni, Christina L; Li, Qing; Thomas, Jeremy J et al. (2011) Mycobacterium tuberculosis lipoproteins directly regulate human memory CD4(+) T cell activation via Toll-like receptors 1 and 2. Infect Immun 79:663-73
Drage, Michael G; Tsai, Han-Chun; Pecora, Nicole D et al. (2010) Mycobacterium tuberculosis lipoprotein LprG (Rv1411c) binds triacylated glycolipid agonists of Toll-like receptor 2. Nat Struct Mol Biol 17:1088-95
Ramachandra, Lakshmi; Qu, Yan; Wang, Ying et al. (2010) Mycobacterium tuberculosis synergizes with ATP to induce release of microvesicles and exosomes containing major histocompatibility complex class II molecules capable of antigen presentation. Infect Immun 78:5116-25
Simmons, Daimon P; Canaday, David H; Liu, Yi et al. (2010) Mycobacterium tuberculosis and TLR2 agonists inhibit induction of type I IFN and class I MHC antigen cross processing by TLR9. J Immunol 185:2405-15
Reuter, Morgan A; Pecora, Nicole D; Harding, Clifford V et al. (2010) Mycobacterium tuberculosis promotes HIV trans-infection and suppresses major histocompatibility complex class II antigen processing by dendritic cells. J Virol 84:8549-60
Harding, Clifford V; Boom, W Henry (2010) Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors. Nat Rev Microbiol 8:296-307

Showing the most recent 10 out of 70 publications