“Bacteria often only do harm at certain concentrations,” Stefan Kaufmann told BioWorld.   

In fact, bacteria have evolved an entire communication system, so-called quorum sensing, to monitor how many of their colleagues are in the vicinity, and then switch from growth to virulence only at high densities.  

In the Dec. 20, 2019, issue of Science, Kaufmann, who is the founding director of the Max Planck Institute for Infection Biology, and his colleagues report that the immune system could calibrate its response to Pseudomonas aeruginosa by monitoring the bacterial quorum sensing chatter.   

Pseudomonas aeruginosa. Credit: Volker Brinkmann, MPIIB

The aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, could be activated by several of the molecules that P. aeruginosa uses for its interbacterial communication.  

And such eavesdropping did not inevitably activate the immune response. Under some circumstances, quorum sensing signals used by Pseudomonas aeruginosa could inhibit the AhR.  

“The real surprise was [to] see something that inhibits the receptor,” Kaufmann said.  

While receptors like the Toll-like receptors that sense pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) always activate the immune system, the system that Kaufmann and his team have identified allows for a more nuanced response.  

Such a nuanced response makes sense for many pathogens.  

P. aeruginosa infections are a dangerous complication of several diseases, most notably cystic fibrosis. But at the same time, “you have contact with Pseudomonas every day, because they are everywhere,” Kaufmann said.   

A Defcon 1-level response to every Pseudomonas encounter would be a colossal waste of energy.  

In previous work, Kaufmann, co-corresponding author Pedro Moura-Alves, and their colleagues had shown that the AhR was able to activate the immune system when it sensed phenazines, which are one type of quorum sensing molecule used by P. aeruginosa.  

In the work now published in Science, they showed that under some circumstances, “the quorum sensing [signals] were not simply ignored by the aryl receptor, but they actively inhibited the aryl receptor,” he said. “It allows the host to activate the immune response only when it is really needed.”  

First author Pedro Moura-Alves, a group leader at Oxford University’s Ludwig Institute for Cancer Research, told BioWorld that the work “shows that we need to understand more about infection dynamics to better design therapies. Targeting a specific pathway might render the therapy beneficial or detrimental, depending on the infection status. An infection is like an arms race, where both sides of the war adapt to the new scenarios posed by the responses elicited by the pathogen and/or the host. Consequently, when studying host pathogen interactions, we should evaluate both sides of this war simultaneously.”   

The same, he added, is true for targeting the AhR.   

“There are plenty of reports showing both pro-tumorigenic and tumor suppression roles of the AhR, which is a target of biopharma efforts in both oncology and autoimmunity 

“Once again, we need to understand more about this pathway, its modulation and elicited effects in order to be able to draw bigger conclusions.”  

Kaufmann elaborated that “if you target a receptor that is so ubiquitous and broadly distributed, you may stimulate or inhibit the immune response.”   

One of his team’s ongoing research projects is “to really nail down the receptor – what does it see.”  

The AhR is “not only complex because it sees so many different molecules, but also because it is expressed in so many host cells,” where it can set off different gene expression programs. In the liver, for example, AhR activation plays a role in the degradation of toxins, while in epithelial cells it is part of the first line of host defense.  

Given that complexity, Kaufmann said, “inhibition and activation needs to be fine-balanced” – by the body itself, and by attempts to harness the receptors pharmaceutical potential.  

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