The aryl hydrocarbon receptor elicits protection against toxic environmental molecules. New data show that the receptor also supports the immune system by recognizing bacterially encoded virulence factors. See Article p.387
All animals, including humans, are exposed daily to a variety of chemicals in the air, water and food. Some of these carry valuable information about the host's environment, such as the presence of food, predators, members of the opposite sex or, in the case of hyenas, members of the clan to which they belong1. But others are toxic and must be eliminated. Among several mechanisms for detecting and responding to these environmental cues is the aryl hydrocarbon receptor (AhR) protein, which can facilitate the biotransformation and elimination of toxic compounds encountered in the environment. On page 387 of this issue, Moura-Alves et al.2 report that bacterial compounds known as phenazines also act as potential AhR ligands, and that recognition of these virulence factors by AhR contributes to host defence against invading microbial pathogens.
AhR is widely expressed in the mammalian body and is bound by a broad range of ligands that are mostly aromatic and hydrophobic compounds of endogenous or synthetic origin3. The unbound receptor is retained in an inactive form in the cellular cytoplasm but moves to the nucleus following ligand binding. Once in the nucleus, AhR has several functions, including marking sex-steroid receptors for destruction (by ubiquitination)4 and inducing the transcription of a battery of target genes involved in the regulation of cellular stress and metabolism5.
AhR has also been implicated in cross-talk with the immune system, particularly in promoting the differentiation of Th17 cells4. This suggests that the receptor may have a broad range of functions in addition to clearing unwanted chemical substances. Because the neutralization of microbial infections is one of the key functions of the mammalian immune system, Moura-Alves and colleagues used a molecular-modelling approach to test whether AhR senses ligands of bacterial origin. They found that pigmented virulence factors from pulmonary pathogens such as Pseudomonas aeruginosa and Mycobacterium tuberculosis can bind to the ligand-binding domain of the receptor. They also provide evidence that this new class of ligand, namely phenazines from P. aeruginosa and phthiocol from M. tuberculosis, activate AhR in a dose-dependent manner, leading to the elimination of these virulence factors, possibly through an AhR-controlled metabolic circuit (Fig. 1).
Phenazines and phthiocol are versatile secondary metabolites synthesized by bacteria and are known to influence bacterial interactions with their hosts. Most of these compounds have antibiotic properties and play a key part in regulating cellular redox states and the generation of reactive oxygen species, thus enhancing the virulence of their manufacturer6. In plants, phenazines influence growth by eliciting 'induced systemic resistance' and protection against plant pathogens6,7. Thus, it seems that phenazine-producing bacteria display an interesting species-specific dichotomy, acting as symbionts in plants and as pathogens in animals. Although phenazine-producing bacteria are often soil or plant-dwellers, they are also found in the normal human microbiota8. For instance, Nocardia species are a part of our oral microbiota and reside in our healthy oral cavity, and Methanocercina mazei is a component of our gut microbiome6.
The idea that microbial metabolites activate AhR is not new, as it has long been known that indoles, a group of AhR ligands, are generated by bacterial metabolism of the amino acid tryptophan9. Lactobacilli, found among our gut microbes, produce indole-3-aldehyde as a tryptophan metabolite, and this seems to act as an AhR ligand, promoting host resistance to fungal pathogens10. This suggests that phenazine-dependent activation of AhR may execute other functions in host responses to bacteria in addition to the clearance of virulence factors.
To validate their findings in vivo, Moura-Alves et al. studied mice lacking the gene encoding AhR, and found that infection with phenazine-producing P. aeruginosa induced more-aggressive disease characteristics and increased bacterial load compared to mice with AhR. They also identified two classes of cell — myeloid and parenchymal cells — as the major contributors to this AhR-mediated host defence. An additional twist to the story comes from their finding that phthiocol sensing by AhR, especially by myeloid cells, increases resistance to M. tuberculosis infection and prevents systemic dissemination of the bacterium in mice.
These findings establish a direct dialogue between AhR functions and invading pathogenic microbes, thereby consolidating the concept that AhR is an integral part of mammalian immunity. This new function of AhR is somewhat surprising, given previous demonstrations that AhR activation impairs immune responses to a variety of pathogens including the influenza virus11 and herpesviruses12. Moreover, because our normal, non-pathogenic microbiome contains phenazine-producing bacteria, there must exist a form of tolerance that allows maintenance of these populations in specific sites, possibly mediated by an AhR-dependent mechanism. Indeed, a recent report portrays a 'disease-tolerance defence pathway' controlled by AhR, in which AhR-dependent tolerance against lipopolysaccharide, a component of the bacterial cell wall, imparts protection against pathogenic invasion13. Collectively, these findings provide evidence for AhR's role in mammalian host defence against phenazine-producing bacterial infections and unfold an exciting chapter in our understanding of AhR functions.
The diverse collection of AhR ligands, including hazardous chemical substances, metabolites from tryptophan, dietary ligands in fruits and cruciferous vegetables, and phenazines, suggest that this elusive 'Scarlet Pimpernel'-like receptor harbours a complex and diverse repertoire of functions that remain to be discovered. Moura-Alves and colleagues' findings spark the fascinating idea of an evolutionarily developed AhR–microbiome connection, through which microbial communities can modulate host functions to reinstate the 'survival of the fittest'.
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Kundu, P., Pettersson, S. Mammalian watchdog targets bacteria. Nature 512, 377–378 (2014). https://doi.org/10.1038/nature13741
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