Janelle S. Ayres
Tolerance Mechanisms in Host-Pathogen Interactions
What enables a host to defend against pathogenic microbes while accommodating its essential interactions with beneficial microbes? The defense response against microbes is most often assumed to be dependent on the immune system, the primary function of which is thought of as the execution of resistance killing mechanisms. If we confine ourselves to pathogenic interactions, then this assumption may make sense. However, our interactions with microbes are not limited to those of a pathogenic nature. For example, the lower intestines of mammals harbor a complex microbial community composed of trillions of microbes that have co-evolved with the host to achieve a mutually beneficial relationship. As pathogens do not differ intrinsically from beneficial microbes in terms of their ability to activate an immune response, it does not make sense to describe host defense mechanisms solely in terms of killing mechanisms. We and others have described a distinct defense response in animals called tolerance that is crucial for survival of microbial interactions. Tolerance defenses protect the host by limiting the negative impact of microbial interactions on host health without directly impacting microbial levels. We propose that if hosts have evolved mechanisms that would allow them to tolerate microbes as opposed to killing them, then rather than an escalating evolutionary battle of attack by the host and evasion by the microbe, a situation would evolve of mutual cooperative benefit. Thus, the concept of tolerance defenses has enormous repercussions for our understanding of host-microbiota interactions. To begin to define the mechanistic basis of this important defense strategy, we are using symbiotic host-microbial systems with a focus on the mammalian intestine. We are particularly interested in understanding how we can leverage our beneficial interactions with the intestinal microbiota to manipulate tolerance defenses to treat infectious diseases.