title: Mycobacterium tuberculosis cell wall released fragments by the action of the human lung mucosa modulate macrophages to control infection in an IL-10-dependent manner.
abstract: Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis, is a major public health challenge facing the world. During infection, M.tb is deposited in the lung alveolar space where it comes in contact with the lung mucosa, known as alveolar lining fluid (ALF), an environment that M.tb encounters at different stages of the infection and disease. ALF is abundant in homeostatic and antimicrobial hydrolytic enzymes, also known as hydrolases. Here we demonstrate that ALF hydrolases, at their physiological concentrations and upon contact with M.tb, release M.tb cell envelope fragments into the milieu. These released fragments are bioactive, but non-cytotoxic, regulate the function of macrophages, and thus are capable of modulating the immune response contributing to the control of M.tb infection by human macrophages. Specifically, macrophages exposed to fragments derived from the exposure of M.tb to ALF were able to control the infection primarily by increasing phagosome-lysosome fusion and acidification events. This enhanced control was found to be dependent on fragment-induced interleukin-10 (IL-10) production but also involves the STAT3 signaling pathway in an IL-10-independent manner. Collectively our data indicate that M.tb fragments released upon contact with lung mucosa hydrolases participate in the host immune response to M.tb infection through innate immune modulation.
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: J
authors.initials: J
authors.lastname: Arcos
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Sasindran
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: J I
authors.initials: JI
authors.lastname: Moliva
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Scordo
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sidiki
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: H
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: P
authors.initials: P
authors.lastname: Venigalla
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: H V
authors.initials: HV
authors.lastname: Kelley
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lin
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: L
authors.initials: L
authors.lastname: Diangelo
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Silwani
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.|Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.|Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: J
authors.initials: J
authors.lastname: Turner
authors.affiliation: Department of Microbial Infection and Immunity, Columbus, Ohio, USA.|Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Torrelles
mesh_terms: D002473:Cell Wall / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D008561:Membrane Fusion; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000276:immunology*
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; D006867:Hydrolases