Saturday, August 30, 2014

Ancient defense mechanism is not color-blind

Here is a very simple paper from Nature. Sometimes simple equals great. Not this time, though. No wonder it took 1.5 year to have it published.

This is a study about Aryl Hydrocarbon receptor (AhR). As I have discussed in earlier posts, AhR senses environmental pollutants and toxins, like p-dioxin. More importantly, however, AhR senses natural, endogenously-generated molecules like amino acid tryptophan degradation products. Upon ligand engagement, AhR activates detoxifying enzymes.

Here (1), the authors tested the hypothesis the AhR can detect pathogen-associated molecules. Using in silico modeling they identify several pigmented virulence factors derived from P. aeruginosa (phenazine) and M. tuberculosis (phthiocol) that could bind AhR.

To verify this finding in vitro the authors used luciferase reporter assay with human macrophage cell line (THP-1) transfected with AhR responsive elements. Indeed, physiological concentration of phenazine or phthiocol could activate AhR

To test this observation in vivo, the authors infected AhR-KO mice with P. aeruginosa. Compared to wild-type control, AhR-KO mice succumbed to infection more rapidly. This was associated with more tissue damage and less neutrophil infiltration. 

Bone marrow chimera experiment indicated that both haematopoietic and non-haematopoietic cell expression of AhR were necessary for resistance to P. aeruginosa infection. 

In addition, the authors showed that resistance to M. tuberculosis (both at low or high dose) was also influenced by absence of AhR signaling. 

In summary, the authors postulate that AhR can sense infection-derived molecules and contributes to host defense.

While this model is very simple, there are few weaknesses in this paper. Since AhR function is quite broad, to show its relevance in infection-derived molecule detection, the authors should have used AhR-ligand deficient P. aeruginosa or M. tuberculosis, for example, mutant strain PA14 phz ½. However, the authors did not used it. In absence of such experiment, however, the authors conclusion regarding pattern-recognition receptor function of AhR is questionable.

No comments:

Post a Comment