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.
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.
|Tashkandi, Hammad; Shameli, Afshin; Harding, Clifford V et al. (2018) Ultrastructural changes in peripheral blood leukocytes in ?-synuclein knockout mice. Blood Cells Mol Dis 73:33-37|
|Stefaniuk, Catherine M; Hong, Hong; Harding, Clifford V et al. (2018) ?-Synuclein concentration increases over time in plasma supernatant of single donor platelets. Eur J Haematol :|
|Shukla, Supriya; Richardson, Edward T; Drage, Michael G et al. (2018) Mycobacterium tuberculosis Lipoprotein and Lipoglycan Binding to Toll-Like Receptor 2 Correlates with Agonist Activity and Functional Outcomes. Infect Immun 86:|
|Athman, Jaffre J; Sande, Obondo J; Groft, Sarah G et al. (2017) Mycobacterium tuberculosis Membrane Vesicles Inhibit T Cell Activation. J Immunol 198:2028-2037|
|Karim, Ahmad F; Sande, Obondo J; Tomechko, Sara E et al. (2017) Proteomics and Network Analyses Reveal Inhibition of Akt-mTOR Signaling in CD4+ T Cells by Mycobacterium tuberculosis Mannose-Capped Lipoarabinomannan. Proteomics 17:|
|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|
|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|
|Nguyen, Thao P; Bazdar, Doug A; Mudd, Joseph C et al. (2015) Interferon-? inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling. J Leukoc Biol 97:1139-46|
|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|
|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|
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