Inflammation is a normal part of the host response to bacterial infection. Activation of pathogen recognition receptors leads to cytokine release and the influx of immune cells. Eradicating microbes via inflammation can result in collateral damage: healthy tissues can be damaged by the immune response, but at least the microbial infection is also eliminated. Right?
New findings published in Infection and Immunity this week shift this framework. In fact, some bacteria use a strategy of immune activation to increase their survival. In their recent paper, Qiuchan Deng and Yi Wang, working in the lab of Minhao Wu, show that Pseudomonas aeruginosa trigger immune cell signaling in order to escape intracellular killing.
Macrophage cells (the hungry hungry hippos of the immune system) will engulf pathogens (and other foreign objects) in a process called phagocytosis, when properly activated. Once engulfed, the microbes are killed using oxygen-dependent or –independent mechanisms. The new study shows that one bacterium, Pseudomonas aeruginosa, is able to avoid being killed by the macrophage after it’s been “eaten” – using a previously unseen method.
The researchers first noticed that phagocytosis of Pseudomonas lead to secretion of Caspase-1 and the cytokine IL-1β. This was due to activation of an inflammasome (a cluster of proteins that initiate innate inflammation activities) called NLRP3. In addition to cytokine secretion, the researchers found that NLRP3 activation also induced LC3 to initiate autophagy. Autophagy, or self-eating, has previously been correlated with bacterial clearance - by digesting part of its own cellular makeup, the macrophage can also digest the intracellular microbe. However, the increased autophagy observed during P. aeruginosa infection was correlated with a suppression of bacterial killing – despite the macrophage making normal amounts of its bacterial killing weaponry, such as antimicrobial peptides and reactive oxygen and nitrogen species.
P. aeruginosa infection is a growing threat worldwide and a major hospital-acquired infectious agent. By adding extra IL-1β to P. aeruginosa-infected macrophage cells, the scientists observed an increase in macrophage autophagy and a concurrent decrease in bacterial killing. Could the opposite be true – would elimination of IL-1β make the macrophage cells more efficient bacteria killers?
The authors tested this by silencing Caspase-1, which cleaves IL-1β into its active form – and they observed improved bacterial clearance in the absence of active IL-1β. They also applied rapamycin, which promotes autophagy, and saw less bacterial killing. What remains to be seen is if blocking IL-1β signaling – using an already-approved IL-1β neutralizing antibody – would have the same effect. If so, this research may demonstrate how changing the cytokine microenvironment at the site of infection may shift the microbe-immune system battle in favor of the immune system.
This isn’t the first research on the role of autophagy in Pseudomonas infection. Previous studies have found autophagy to be initiated but (in contrast to the current study) required for bacterial clearance during P. aeruginosa infection. The authors of the current study will have to carefully test in vivo models before drawing strong conclusions and moving forward with the research. The first step forward will be to move their findings from the petri dish to a more complicated environment of the infected host.
-- Julie Wolf