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A human secretome library screen reveals a role for Peptidoglycan Recognition Protein 1 in Lyme borreliosis

A. Gupta, G. Arora, CE. Rosen, Z. Kloos, Y. Cao, J. Cerny, A. Sajid, D. Hoornstra, M. Golovchenko, N. Rudenko, U. Munderloh, JW. Hovius, CJ. Booth, C. Jacobs-Wagner, NW. Palm, AM. Ring, E. Fikrig

. 2020 ; 16 (11) : e1009030. [pub] 20201111

Language English Country United States

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc21011881

Grant support
Howard Hughes Medical Institute - United States

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.

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$a Lyme disease, the most common vector-borne illness in North America, is caused by the spirochete Borrelia burgdorferi. Infection begins in the skin following a tick bite and can spread to the hearts, joints, nervous system, and other organs. Diverse host responses influence the level of B. burgdorferi infection in mice and humans. Using a systems biology approach, we examined potential molecular interactions between human extracellular and secreted proteins and B. burgdorferi. A yeast display library expressing 1031 human extracellular proteins was probed against 36 isolates of B. burgdorferi sensu lato. We found that human Peptidoglycan Recognition Protein 1 (PGLYRP1) interacted with the vast majority of B. burgdorferi isolates. In subsequent experiments, we demonstrated that recombinant PGLYRP1 interacts with purified B. burgdorferi peptidoglycan and exhibits borreliacidal activity, suggesting that vertebrate hosts may use PGLYRP1 to identify B. burgdorferi. We examined B. burgdorferi infection in mice lacking PGLYRP1 and observed an increased spirochete burden in the heart and joints, along with splenomegaly. Mice lacking PGLYRP1 also showed signs of immune dysregulation, including lower serum IgG levels and higher levels of IFNγ, CXCL9, and CXCL10.Taken together, our findings suggest that PGLYRP1 plays a role in the host's response to B. burgdorferi and further demonstrate the utility of expansive yeast display screening in capturing biologically relevant interactions between spirochetes and their hosts.
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$a Arora, Gunjan $u Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
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$a Cao, Yongguo $u Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America $u Department of Clinical Veterinary Medicine, and Key Laboratory for Zoonosis Research, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun, China
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$a Cerny, Jiri $u Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America $u Faculty of Tropical AgriSciences, Czech University of Life Sciences in Prague, Prague, Czech Republic
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$a Sajid, Andaleeb $u Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
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$a Hoornstra, Dieuwertje $u Amsterdam UMC, University of Amsterdam, Center for Experimental and Molecular Medicine, Amsterdam Infection and Immunity, Amsterdam, Netherlands
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$a Golovchenko, Maryna $u Biology Centre, Institute of Parasitology Czech Academy of Sciences, Buweiss, Czech Republic
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$a Rudenko, Natalie $u Biology Centre, Institute of Parasitology Czech Academy of Sciences, Buweiss, Czech Republic
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$a Munderloh, Ulrike $u Department of Entomology, University of Minnesota, St. Paul, Minnesota, United States of America
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$a Hovius, Joppe W $u Amsterdam UMC, University of Amsterdam, Center for Experimental and Molecular Medicine, Amsterdam Infection and Immunity, Amsterdam, Netherlands
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$a Booth, Carmen J $u Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
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$a Jacobs-Wagner, Christine $u Department of Biology, Stanford University, Stanford, California, United States of America $u ChEM-H Institute, Stanford University, Stanford, California, United States of America $u Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America
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$a Palm, Noah W $u Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
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$a Ring, Aaron M $u Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America
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