title: Naturally Occurring Subclinical Endotoxemia in Humans Alters Adaptive and Innate Immune Functions through Reduced MAPK and Increased STAT1 Phosphorylation.
abstract: Multiple studies have shown correlates of immune activation with microbial translocation and plasma LPS during HIV infection. It is unclear whether this activation is due to LPS, residual viral replication, or both. Few studies have addressed the effects of persistent in vivo levels of LPS on specific immune functions in humans in the absence of chronic viral infection or pathological settings such as sepsis. We previously reported on a cohort of HIV-negative men with subclinical endotoxemia linked to alterations in CD4/CD8 T cell ratio and plasma cytokine levels. This HIV-negative cohort allowed us to assess cellular immune functions in the context of different subclinical plasma LPS levels ex vivo without confounding viral effects. By comparing two samples of differing plasma LPS levels from each individual, we now show that subclinical levels of plasma LPS in vivo significantly alter T cell proliferative capacity, monocyte cytokine release, and HLA-DR expression, and induce TLR cross-tolerance by decreased phosphorylation of MAPK pathway components. Using this human in vivo model of subclinical endotoxemia, we furthermore show that plasma LPS leads to constitutive activation of STAT1 through autocrine cytokine signaling, suggesting that subclinical endotoxemia in healthy individuals might lead to significant changes in immune function that have thus far not been appreciated.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; and.
authors.forename: Christine D
authors.initials: CD
authors.lastname: Palmer
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; and.
authors.forename: Marisol
authors.initials: M
authors.lastname: Romero-Tejeda
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Sirignano
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; and.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; and.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; and Department of Viral Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, 20251 Hamburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; and sjost@partners.org.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jost
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000328:Adult; D049109:Cell Proliferation; D019446:Endotoxemia / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008070:Lipopolysaccharides / Q000097:blood* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases