Lyme disease, the most common vector-borne illness in North America, is caused by the spirochete Borrelia burgdorferi. Infection begins in the skin following a tick bite and can spread to the hearts, joints, nervous system, and other organs. Diverse host responses influence the level of B. burgdorferi infection in mice and humans. Using a systems biology approach, we examined potential molecular interactions between human extracellular and secreted proteins and B. burgdorferi. A yeast display library expressing 1031 human extracellular proteins was probed against 36 isolates of B. burgdorferi sensu lato. We found that human Peptidoglycan Recognition Protein 1 (PGLYRP1) interacted with the vast majority of B. burgdorferi isolates. In subsequent experiments, we demonstrated that recombinant PGLYRP1 interacts with purified B. burgdorferi peptidoglycan and exhibits borreliacidal activity, suggesting that vertebrate hosts may use PGLYRP1 to identify B. burgdorferi. We examined B. burgdorferi infection in mice lacking PGLYRP1 and observed an increased spirochete burden in the heart and joints, along with splenomegaly. Mice lacking PGLYRP1 also showed signs of immune dysregulation, including lower serum IgG levels and higher levels of IFNγ, CXCL9, and CXCL10.Taken together, our findings suggest that PGLYRP1 plays a role in the host's response to B. burgdorferi and further demonstrate the utility of expansive yeast display screening in capturing biologically relevant interactions between spirochetes and their hosts.

Amsterdam UMC University of Amsterdam Center for Experimental and Molecular Medicine Amsterdam Infection and Immunity Amsterdam Netherlands

Biology Centre Institute of Parasitology Czech Academy of Sciences Buweiss Czech Republic

ChEM H Institute Stanford University Stanford California United States of America

Department of Biology Stanford University Stanford California United States of America

Department of Clinical Veterinary Medicine and Key Laboratory for Zoonosis Research Ministry of Education College of Veterinary Medicine Jilin University Changchun China

Department of Comparative Medicine Yale University School of Medicine New Haven Connecticut United States of America

Department of Entomology University of Minnesota St Paul Minnesota United States of America

Department of Immunobiology Yale University School of Medicine New Haven Connecticut United States of America

Faculty of Tropical AgriSciences Czech University of Life Sciences Prague Prague Czech Republic

Howard Hughes Medical Institute Chevy Chase Maryland United States of America

Microbiology Program Yale School of Medicine New Haven Connecticut United States of America

Section of Infectious Diseases Department of Internal Medicine Yale University School of Medicine New Haven Connecticut United States of America

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