The microbiomes of humans and other animals are complex and poorly understood, but there is growing appreciation that they affect health in a wide variety of ways. Most potential invading pathogens interact extensively with a complex ecosystem of resident microbes before they can even contact host tissues. These interactions are clearly important, but have been very difficult to study for lack of tractable experimental systems. Our innovative recent work has established an experimental system in which the resident microbiome can protect against invasion by some species of bordetellae but not others that are very closely related. We further made the complementary finding that other bordetellae can displace the resident microbiota from the respiratory tract, including long-term chronic colonizers. Our extensive experience with the comparative biology and genomics of these closely related species has revealed candidate genes involved and our reverse genetics has allowed us to begin to identify roles for some of these, as described in our preliminary results. These data are beginning to reveal the complex interactions with resident microbiota as a critical aspect of an invading pathogen's initial colonization of the mammalian respiratory tract. This proposal will determine the ecological mechanisms involved in this competition, and identify molecular mechanisms (genes), in the context of naturally occurring interactions with resident microbiota that determine susceptibility/resistance to invading pathogens.
The importance of the resident host microbiome in resistance to invading pathogens is intuitive, and demonstrated in several unnatural perturbations, such as during the use of broad spectrum antibiotics. But there are few experimental systems in which to study the details of the natural competitive interactions between invading pathogens and resident microbiota that can determine the outcome of exposure to infectious disease. We have recently shown that Bordetella pertussis, which causes whooping cough in humans, poorly colonizes the respiratory tracts of mice because of competition with resident microbiota, while the closely related B. bronchiseptica is able to efficiently colonize mice, displacing the resident microbiota in the process. This proposal seeks to understand the ecological mechanisms behind how resident microorganisms can inhibit B. pertussis colonization and the molecular mechanisms by which B. bronchiseptica eliminates chronic colonizers of the respiratory tract.
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