title: Microbiota, Immune Subversion, and Chronic Inflammation.
abstract: Several host-adapted pathogens and commensals have evolved mechanisms to evade the host innate immune system inducing a state of low-grade inflammation. Epidemiological studies have also documented the association of a subset of these microorganisms with chronic inflammatory disorders. In this review, we summarize recent studies demonstrating the role of the microbiota in chronic inflammatory diseases and discuss how specific microorganisms subvert or inhibit protective signaling normally induced by toll-like receptors (TLRs). We highlight our work on the oral pathogenPorphyromonas gingivalisand discuss the role of microbial modulation of lipid A structures in evasion of TLR4 signaling and resulting systemic immunopathology associated with atherosclerosis.P. gingivalisintrinsically expresses underacylated lipid A moieties and can modify the phosphorylation of lipid A, leading to altered TLR4 signaling. UsingP. gingivalismutant strains expressing distinct lipid A moieties, we demonstrated that expression of antagonist lipid A was associated withP. gingivalis-mediated systemic inflammation and immunopathology, whereas strains expressing agonist lipid A exhibited modest systemic inflammation. Likewise, mice deficient in TLR4 were more susceptible to vascular inflammation after oral infection withP. gingivaliswild-type strain compared to mice possessing functional TLR4. Collectively, our studies support a role forP. gingivalis-mediated dysregulation of innate and adaptive responses resulting in immunopathology and systemic inflammation. We propose that anti-TLR4 interventions must be designed with caution, given the balance between the protective and destructive roles of TLR signaling in response to microbiota and associated immunopathologies.
authors.affiliation: Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine , Boston, MA , USA.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Kramer
authors.affiliation: Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine , Boston, MA , USA.
authors.forename: Caroline Attardo
authors.initials: CA
authors.lastname: Genco
keywords: atherosclerosis; immune dysregulation; immune subversion; inflammation; innate immunity; microbiota; toll-like receptors