Research Article: Distinct Lipid A Moieties Contribute to Pathogen-Induced Site-Specific Vascular Inflammation

Date Published: July 10, 2014

Publisher: Public Library of Science

Author(s): 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, John S. Gunn.


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.

Partial Text

Host recognition of Gram-negative bacteria occurs via detection of LPS expressed on the bacterial membrane by the innate immune receptor, TLR4 [1]. This initial recognition is critical for instructing host immunity and promoting an inflammatory response that eradicates the pathogen from the host [1], [2]. However, a number of Gram-negative organisms have evolved mechanisms to modify their lipid A species, the component of bacterial LPS that directly activates the TLR4 complex, as a strategy to evade immune detection and establish infection [3]. Lipid A is initially synthesized as a β-1′,6-linked disaccharide of glucosamine that is phosphorylated and fatty acylated [4]. An unmodified version of this lipid A structure is typically expressed by E. coli and induces a robust inflammatory response [5]. Modifications to this basic lipid A structure are observed in alterations to acyl chains or terminal phosphate groups [6]. Helicobacter pylori[7], Legionella pneumophila[8], Yersinia pestis[9], and Francisella novicida[10] express underacylated lipid A moieties, in comparison to the canonical LPS expressed by E. coli, and are poorly recognized by TLR4. Yersinia pestis[11] and Francisella tularensis[12] expression of structurally divergent forms of lipid A is highly regulated by local environmental conditions such as temperature, allowing these pathogens to adapt to harsh environmental conditions in the host. It has been postulated that the ability of these pathogens to cause persistent infection and severe disease is partially due to evasion of host immune detection at TLR4 [13].




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