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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM113681-04
Application #
9413351
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Reddy, Michael K
Project Start
2015-02-01
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Georgia
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
Taylor-Mulneix, Dawn L; Bendor, Liron; Linz, Bodo et al. (2017) Bordetella bronchiseptica exploits the complex life cycle of Dictyostelium discoideum as an amplifying transmission vector. PLoS Biol 15:e2000420
Hamidou Soumana, Illiassou; Linz, Bodo; Harvill, Eric T (2017) Environmental Origin of the Genus Bordetella. Front Microbiol 8:28
Dewan, Kalyan K; Taylor-Mulneix, Dawn L; Hilburger, Lindsay J et al. (2017) An Extracellular Polysaccharide Locus Required for Transmission of Bordetella bronchiseptica. J Infect Dis 216:899-906
Taylor-Mulneix, Dawn L; Hamidou Soumana, Illiassou; Linz, Bodo et al. (2017) Evolution of Bordetellae from Environmental Microbes to Human Respiratory Pathogens: Amoebae as a Missing Link. Front Cell Infect Microbiol 7:510
Gorgojo, Juan; Scharrig, Emilia; Gómez, Ricardo M et al. (2017) Bordetella parapertussis Circumvents Neutrophil Extracellular Bactericidal Mechanisms. PLoS One 12:e0169936
Freyberg, Zachary; Harvill, Eric T (2017) Pathogen manipulation of host metabolism: A common strategy for immune evasion. PLoS Pathog 13:e1006669
Ivanov, Yury V; Linz, Bodo; Register, Karen B et al. (2016) Identification and taxonomic characterization of Bordetella pseudohinzii sp. nov. isolated from laboratory-raised mice. Int J Syst Evol Microbiol 66:5452-5459
Bendor, Liron; Weyrich, Laura S; Linz, Bodo et al. (2015) Type Six Secretion System of Bordetella bronchiseptica and Adaptive Immune Components Limit Intracellular Survival During Infection. PLoS One 10:e0140743
Ivanov, Yury V; Shariat, Nikki; Register, Karen B et al. (2015) A newly discovered Bordetella species carries a transcriptionally active CRISPR-Cas with a small Cas9 endonuclease. BMC Genomics 16:863
Register, Karen B; Ivanov, Yury V; Harvill, Eric T et al. (2015) Novel, host-restricted genotypes of Bordetella bronchiseptica associated with phocine respiratory tract isolates. Microbiology 161:580-92

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