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  • Distinct lipid a moieties contribute to pathogen-induced site-specific vascular inflammation.

Distinct lipid a moieties contribute to pathogen-induced site-specific vascular inflammation.

PLoS pathogens (2014-07-11)
Connie Slocum, Stephen R Coats, Ning Hua, Carolyn Kramer, George Papadopoulos, Ellen O Weinberg, Cynthia V Gudino, James A Hamilton, Richard P Darveau, Caroline A Genco
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.

MATERIALS
Product Number
Brand
Product Description

Supelco
Menadione (K3), analytical standard
Sigma-Aldrich
Menadione, meets USP testing specifications
Sigma-Aldrich
Menadione, crystalline
Sigma-Aldrich
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
Menadione, European Pharmacopoeia (EP) Reference Standard
USP
Menadione, United States Pharmacopeia (USP) Reference Standard
Supelco
Menadione, Pharmaceutical Secondary Standard; Certified Reference Material