Mycobacterium tuberculosis (Mtb) regulates lung macrophage activation and function, including the balance of pro-inflammatory and anti-inflammatory mechanisms that affect pulmonary immune responses and the outcome of infection. We propose that optimum host response and containment of infection requires proper regulation of the inflammatory balance. Better understanding of this balance and how it is regulated will advance our understanding of how Mtb evades host immunity and the problems of latent infection and disease progression. We propose that factors downstream of Toll-like receptor 2 (TLR2) contribute to regulation of this balance;among these are Tpl2, ERK and KLF4, which we propose promote expression of IL-10, induce other anti- inflammatory mechanisms, and contribute to inhibition of macrophage MHC-II antigen presentation, thereby regulating both innate and adaptive immunity to Mtb. We will study markers of lung macrophage inflammatory state and function;a central paradigm will be the balance of IL-10 and IL-12, which are anti-inflammatory and pro-inflammatory mediators, respectively. We will use knockout and floxed gene models (for cell lineage- specific knockout) to focus studies on lung macrophages, as well as pharmacologic tools, to test the role of Tpl2, ERK and other molecules in regulating the inflammatory balance of lung macrophages during infection with Mtb. We will use both human and mouse models to study regulation of lung or alveolar macrophages.
Aim 1 will determine the roles of TLR2 and other receptors pathways in regulating the ERK pathway and the inflammatory balance of lung macrophages during responses to Mtb.
Aim 2 will determine the roles Tpl2, ERK and downstream mechanisms (e.g. KLF4) in regulating the inflammatory balance of lung macrophages during responses to Mtb.
Aim 3 will determine the roles of Tpl2, ERK1/2 and KLF4 in regulation of macrophages and host immunity in vivo.

Public Health Relevance

These studies will reveal molecules and signaling pathways that control the balance of pro- vs. anti-inflammatory responses during tuberculosis (TB) infection in the lung. Control of the inflammatory balance is critical to the outcome of TB infection and either too much or too little inflammatory response is detrimental. Understanding of these mechanisms will clarify critical control points in immune responses, potential mechanisms for immune suppression and immune evasion, potential novel pathways for immunotherapeutic intervention for Mtb infection, and strategies to manipulate responses to TB vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI034343-19A1
Application #
8757891
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Palker, Thomas J
Project Start
1994-09-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
19
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Sande, Obondo J; Karim, Ahmad F; Li, Qing et al. (2016) Mannose-Capped Lipoarabinomannan from Mycobacterium tuberculosis Induces CD4+ T Cell Anergy via GRAIL. J Immunol 196:691-702
Shameli, Afshin; Xiao, Wenbin; Zheng, Yan et al. (2016) A critical role for alpha-synuclein in development and function of T lymphocytes. Immunobiology 221:333-40
Richardson, Edward T; Shukla, Supriya; Sweet, David R et al. (2015) Toll-like receptor 2-dependent extracellular signal-regulated kinase signaling in Mycobacterium tuberculosis-infected macrophages drives anti-inflammatory responses and inhibits Th1 polarization of responding T cells. Infect Immun 83:2242-54
Nguyen, Thao P; Bazdar, Doug A; Mudd, Joseph C et al. (2015) Interferon-α inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling. J Leukoc Biol 97:1139-46
Richardson, Edward T; Shukla, Supriya; Nagy, Nancy et al. (2015) ERK Signaling Is Essential for Macrophage Development. PLoS One 10:e0140064
Athman, Jaffre J; Wang, Ying; McDonald, David J et al. (2015) Bacterial Membrane Vesicles Mediate the Release of Mycobacterium tuberculosis Lipoglycans and Lipoproteins from Infected Macrophages. J Immunol 195:1044-53
Xiao, Wenbin; Shameli, Afshin; Harding, Clifford V et al. (2014) Late stages of hematopoiesis and B cell lymphopoiesis are regulated by α-synuclein, a key player in Parkinson's disease. Immunobiology 219:836-44
Shukla, Supriya; Richardson, Edward T; Athman, Jaffre J et al. (2014) Mycobacterium tuberculosis lipoprotein LprG binds lipoarabinomannan and determines its cell envelope localization to control phagolysosomal fusion. PLoS Pathog 10:e1004471
Reba, Scott M; Li, Qing; Onwuzulike, Sophia et al. (2014) TLR2 engagement on CD4(+) T cells enhances effector functions and protective responses to Mycobacterium tuberculosis. Eur J Immunol 44:1410-21
Zhang, Lumin; Luo, Zhenwu; Sieg, Scott F et al. (2014) Plasmacytoid dendritic cells mediate synergistic effects of HIV and lipopolysaccharide on CD27+ IgD- memory B cell apoptosis. J Virol 88:11430-41

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