Phagosomal degradation increases TLR access to bacterial ligands and enhances macrophage sensitivity to bacteria.
Signaling by innate immune receptors initiates and orchestrates the overall immune responses to infection. Macrophage receptors recognizing pathogens can be broadly grouped into surface receptors and receptors restricted to intracellular compartments, such as phagosomes and the cytoplasm. There is an expectation that ingestion and degradation of microorganisms by phagocytes contributes to activation of intracellular innate receptors, although direct demonstrations of this are rare, and many model ligands are studied in soluble form, outside of their microbial context. By comparing a wild-type strain of Staphylococcus aureus and a lysozyme-sensitive mutant, we have been able directly to address the role of degradation of live bacteria by mouse macrophages in determining the overall innate cellular inflammatory response. Our investigations revealed a biphasic response to S. aureus that consisted of an initial signal resulting from the engagement of surface TLR2, followed by a later, second wave on inflammatory gene induction. This second wave of inflammatory signaling was dependent on and correlated with the timing of bacterial degradation in phagosomes. We found that TLR2 signaling followed by TLR2/TLR9 signaling enhanced sensitivity to small numbers of bacteria. We further found that treating wild-type bacteria with the peptidoglycan synthesis-inhibiting antibiotic vancomycin made S. aureus more susceptible to degradation and resulted in increased inflammatory responses, similar to those observed for mutant degradation-sensitive bacteria.
Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Andrea J
AJ
Wolf
Andrea
A
Arruda
Christopher N
CN
Reyes
Amber T
AT
Kaplan
Takahiro
T
Shimada
Kenichi
K
Shimada
Moshe
M
Arditi
George
G
Liu
David M
DM
Underhill
D000818:Animals; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008024:Ligands; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000276:immunology*; D010588:Phagosomes / Q000276:immunology* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
D008024:Ligands; D051193:Toll-Like Receptors