title: Distinct lipid a moieties contribute to pathogen-induced site-specific vascular inflammation.
abstract: Several successful pathogens have evolved mechanisms to evade host defense, resulting in the establishment of persistent and chronic infections. One such pathogen, Porphyromonas gingivalis, induces chronic low-grade inflammation associated with local inflammatory bone loss and systemic inflammation manifested as atherosclerosis. P. gingivalis expresses an atypical lipopolysaccharide (LPS) structure containing heterogeneous lipid A species, that exhibit Toll-like receptor-4 (TLR4) agonist or antagonist activity, or are non-activating at TLR4. In this study, we utilized a series of P. gingivalis lipid A mutants to demonstrate that antagonistic lipid A structures enable the pathogen to evade TLR4-mediated bactericidal activity in macrophages resulting in systemic inflammation. Production of antagonistic lipid A was associated with the induction of low levels of TLR4-dependent proinflammatory mediators, failed activation of the inflammasome and increased bacterial survival in macrophages. Oral infection of ApoE(-/-) mice with the P. gingivalis strain expressing antagonistic lipid A resulted in vascular inflammation, macrophage accumulation and atherosclerosis progression. In contrast, a P. gingivalis strain producing exclusively agonistic lipid A augmented levels of proinflammatory mediators and activated the inflammasome in a caspase-11-dependent manner, resulting in host cell lysis and decreased bacterial survival. ApoE(-/-) mice infected with this strain exhibited diminished vascular inflammation, macrophage accumulation, and atherosclerosis progression. Notably, the ability of P. gingivalis to induce local inflammatory bone loss was independent of lipid A expression, indicative of distinct mechanisms for induction of local versus systemic inflammation by this pathogen. Collectively, our results point to a pivotal role for activation of the non-canonical inflammasome in P. gingivalis infection and demonstrate that P. gingivalis evades immune detection at TLR4 facilitating chronic inflammation in the vasculature. These studies support the emerging concept that pathogen-mediated chronic inflammatory disorders result from specific pathogen-mediated evasion strategies resulting in low-grade chronic inflammation.
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Connie
authors.initials: C
authors.lastname: Slocum
authors.affiliation: Department of Periodontics, School of Dentistry, University of Washington, Seattle, Washington, United States of America.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Coats
authors.affiliation: Department of Biophysics, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Ning
authors.initials: N
authors.lastname: Hua
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Kramer
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Papadopoulos
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Ellen O
authors.initials: EO
authors.lastname: Weinberg
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Cynthia V
authors.initials: CV
authors.lastname: Gudino
authors.affiliation: Department of Biophysics, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: James A
authors.initials: JA
authors.lastname: Hamilton
authors.affiliation: Department of Periodontics, School of Dentistry, University of Washington, Seattle, Washington, United States of America.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Darveau
authors.affiliation: Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, Massachusetts, United States of America; Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Genco
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000276:immunology; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016866:Bacteroidaceae Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008050:Lipid A / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D010024:Osteoporosis / Q000235:genetics / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016966:Porphyromonas gingivalis / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology; D014657:Vasculitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D008050:Lipid A; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4