Interplay between innate immune responses and bacterial interactions.
We have been addressing various aspects of innate immunity, especially in the context of interplay between pathogenic E. coli and Salmonella and host response. Work includes studying how the innate system responds to pathogens, including defining mechanisms of innate immunity.
As well, several studies are underway to determine how the above pathogens alter innate responses to cause a successful infection. Finally, significant work is ongoing on defining ways to enhance the innate resonse as a novel and broad-spectrum method to treat infectious diseases. We have recently received funding from the Bill and Melinda Gates Foundation/Foundation for National Institutes of Health for our program on Novel Therapeutics that Boost Innate Immunity to Treat Infectious Diseases, as well as from Genome Canada for work on The Pathogenomics of Innate Immunity.
Pathogen modification of phagocytosis
Some pathogens such as Pseudomonas, enteropathogenic E. coli, and Yersinia can block phagocytic uptake into macrophages. By translocating specialized type III effector proteins into the macrophage cell, these pathogens interrupt the signal transduction cascades necessary for actin rearrangement, and thereby prevent phagocytosis. Other pathogens that use a type IV secretion system (such as Brucella and Legionella), or type III secretion systems (such as Salmonella, and probably Chlamydia), can induce their own uptake into macrophage cells by
stimulating actin rearrangements proximal to attached bacteria, and then secrete additional effectors into the host cell to modify the trafficking of the invasion vacuole in order to prevent fusion with lysosomes. Vacuoles containing Legionella and Brucella, for example, then acquire markers of the endoplasmic reticulum, thereby creating a protective niche for replication within cells.
Targeting the surveillance systems of innate immunity
The innate immune response relies on surveillance systems to detect foreign microbes. Toll-like receptors (TLR) are pattern-recognition receptors on the surface of a variety of cell types that recognize bacterial and viral proteins and nucleic acids. Currently there are 11 TLR that each have
a distinct ligand specificity, but can homodimerize and heterodimerize to increase the repertoire of possible downstream signaling pathways. NODs on the other hand are cytoplasmic detection systems for peptidoglycan (PG), with NOD2 recognizing PG from both Gram-negative and Gram-positive bacteria and NOD1 having a greater specificity for Gram-negative PG in particular. The NF-?B signaling cascade is essential for proper signaling downstream of both TLR and NOD and its activation serves to invoke a suite of pro-inflammatory mediators such as cytokines, chemokines and cell adhesion receptors. Yersinia secretes a molecule called LcrV into the extracellular
space that can bind directly to TLR2 and modify the downstream response in a way that promotes the secretion of the anti-inflammatory cytokine, IL-10, while preventing the widespread activation of pro-inflammatory cytokines. Two other secreted proteins, AvrA and YopJ, from Salmonella, and Yersinia, respectively, directly interfere with the activation of NF-?B. Bacterial interference with the NOD-PG detection system could be possible through the use of additional secreted bacterial proteins (dotted lines).
Pathogen interference in the innate to adaptive immune transition
Some bacterial pathogens can interfere with the signals downstream of innate immune activation that are required for the generation of an adaptive immune response. Chlamydia, for example, secretes a protein into the cytoplasm of cells called CPAF, which is a protease that degrades transcription factors required for the expression of MHC class I and II molecules. Helicobacter pylori VacA inhibits the activation of helper T cells by blocking the loading of MHC class II molecules and by preventing T cell receptor signaling. Other bacterial secreted effectors (dotted lines) might interfere with the processing and loading of exogenous protein antigens onto MHC class I molecules during a process called cross-presentation, or usurp the function of the host proteasome to their own advantage
* Text and images reprinted from CURRENT BIOLOGY, Vol 14, No 19, 2004, Coombes et al, “Evasive Maneuvers by Secreted Bacterial…”, pp R856-R867 Copyright (2004), with permission from Elsevier