Host Tolerance/Resilience
The antagonistic interactions between a pathogen and its host are complex, likely reflecting the co-evolution and fine tuning of bacterial virulence mechanisms and host immune responses. Bacterial quorum sensing (QS) is governed by population density and coordinates the expression of multiple virulence genes by the production of low-molecular-weight signal molecules, termed infochemicals. QS regulated small molecules can impact human health by affecting host immunity. While immune-driven resistance mechanisms are the prevailing host defense strategy against infection and thus extensively studied, our understanding on another type of defense, tolerance/resilience is still rudimentary. The opportunistic ESKAPE pathogen Pseudomonas aeruginosa (PA) QS regulated small volatile molecule 2-aminoacetophenone (2-AA) has been proposed as a biomarker for PA colonization in chronically infected tissues. The silencing of PA acute virulence functions by 2-AA serves to render the PA cell less detectable by the host’s immune system not only to support the pathogen’s own survival, but also that of the host. We have discovered that 2-AA modulates immune responses in a manner that increases the host’s ability to live with the pathogen, yielding resilience/tolerance to infection and bacterial persistence. The clinical importance of persistent infections is reflected by the many cases in which antibiotics fail to clear infections despite the absence of drug-resistant bacteria, and clinical reports suggest that the contribution of persistent infections to treatment failure and mortality can be as significant as the contribution of antibiotic resistance. Thus, there is an urgent need to understand the mechanistic aspects of host tolerance to persistent infections. Here, we have used 2-AA molecule paradigmatically to uncover the mechanism by which bacterial molecules may “train” the host to become tolerant to high bacterial burden, while having a positive effect on host fitness.