Macrophages have two major physiological functions - host defense and removal of apoptotic cells and other by-products of metazoan physiology. Both of these functions rely on phagocytosis, although the consequences of phagocytic uptake of microbial pathogens and apoptotic cells differ dramatically. Phagocytosis of microorganisms is accompanied by the inflammatory responses, whereas phagocytosis of apoptotic cells and other self material is not. This difference is due to the engagement of Toll-like receptors (TLRs) in the former, but not in the latter case. We investigated the effect of TLR signaling on phagocytic process. Our preliminary data demonstrate that TLR signaling triggers enhanced rate of phagocytic uptake and an inducible mode of phagolysosomal fusion. We found that only the phagosomes that contain TLRs ligands fuse with lysosomes at an induced rate, suggesting the existence of a mechanism of spatial organization of the signaling pathway responsible for the nducible fusion. We further defined the pathway as p38 MAP kinase pathway. Our results :lemonstrate that the fate of phagosomes containing bacteria differs from the fate of phagosomes containing apoptotic cells. The goal of this proposal is 1) to investigate the cellular localization of TLRs and mechanism responsible for differential TLR targeting to specific compartments; 2) to investigatethe role of TLR signaling on vesicular trafficking, specifically, in the phagosome maturation inmacrophages and dendritic cells upon phagocytosis of microbial and apoptotic cells; 3) to investigate the immunological consequences of TLR-induced phagosome maturation in dendritic cells upon phagocytosis of microbial cells and apoptotic cells. We plan to compare the results in mammalian cells to those observed in Drosophila in collaboration with the Ezekowitz Laboratory, Project 1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI044220-06A1
Application #
6788680
Study Section
Special Emphasis Panel (ZAI1-AR-I (J2))
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
6
Fiscal Year
2004
Total Cost
$539,883
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Gendrin, Mathilde; Turlure, Fanny; Rodgers, Faye H et al. (2017) The Peptidoglycan Recognition Proteins PGRPLA and PGRPLB Regulate Anopheles Immunity to Bacteria and Affect Infection by Plasmodium. J Innate Immun 9:333-342
Lombardo, Fabrizio; Christophides, George K (2016) Novel factors of Anopheles gambiae haemocyte immune response to Plasmodium berghei infection. Parasit Vectors 9:78
Lombardo, Fabrizio; Ghani, Yasmeen; Kafatos, Fotis C et al. (2013) Comprehensive genetic dissection of the hemocyte immune response in the malaria mosquito Anopheles gambiae. PLoS Pathog 9:e1003145
Cezairliyan, Brent; Vinayavekhin, Nawaporn; Grenfell-Lee, Daniel et al. (2013) Identification of Pseudomonas aeruginosa phenazines that kill Caenorhabditis elegans. PLoS Pathog 9:e1003101
Feinbaum, Rhonda L; Urbach, Jonathan M; Liberati, Nicole T et al. (2012) Genome-wide identification of Pseudomonas aeruginosa virulence-related genes using a Caenorhabditis elegans infection model. PLoS Pathog 8:e1002813
Chung, Yoon-Suk Alexander; Kocks, Christine (2012) Phagocytosis of bacterial pathogens. Fly (Austin) 6:21-5
Whiteman, Noah K; Gloss, Andrew D; Sackton, Timothy B et al. (2012) Genes involved in the evolution of herbivory by a leaf-mining, Drosophilid fly. Genome Biol Evol 4:900-16
Pukkila-Worley, Read; Ausubel, Frederick M (2012) Immune defense mechanisms in the Caenorhabditis elegans intestinal epithelium. Curr Opin Immunol 24:3-9
Chung, Yoon-Suk Alexander; Kocks, Christine (2011) Recognition of pathogenic microbes by the Drosophila phagocytic pattern recognition receptor Eater. J Biol Chem 286:26524-32
Limmer, Stefanie; Haller, Samantha; Drenkard, Eliana et al. (2011) Pseudomonas aeruginosa RhlR is required to neutralize the cellular immune response in a Drosophila melanogaster oral infection model. Proc Natl Acad Sci U S A 108:17378-83

Showing the most recent 10 out of 88 publications