title: ESX1-dependent fractalkine mediates chemotaxis and Mycobacterium tuberculosis infection in humans.
abstract: Mycobacterium tuberculosis-induced cellular aggregation is essential for granuloma formation and may assist establishment and early spread of M. tuberculosis infection. The M. tuberculosis ESX1 mutant, which has a non-functional type VII secretion system, induced significantly less production of the host macrophage-derived chemokine fractalkine (CX3CL1). Upon infection of human macrophages ESX1-dependent fractalkine production mediated selective recruitment of CD11b+ monocytic cells and increased infection of neighbouring cells consistent with early local spread of infection. Fractalkine levels were raised in vivo at tuberculous disease sites in humans and were significantly associated with increased CD11b+ monocytic cellular recruitment and extent of granulomatous disease. These findings suggest a novel fractalkine-dependent ESX1-mediated mechanism in early tuberculous disease pathogenesis in humans. Modulation of M. tuberculosis-mediated fractalkine induction may represent a potential treatment option in the future, perhaps allowing us to switch off a key mechanism required by the pathogen to spread between cells.
authors.affiliation: Tuberculosis Research Centre, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom. Electronic address: s.hingley-wilson@surrey.ac.uk.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Hingley-Wilson
authors.affiliation: Tuberculosis Research Centre, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Connell
authors.affiliation: Tuberculosis Research Centre, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom.
authors.forename: Katrina
authors.initials: K
authors.lastname: Pollock
authors.affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Tsungda
authors.initials: T
authors.lastname: Hsu
authors.affiliation: University of Oxford, Nuffield Department of Medicine, The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom.
authors.forename: Elma
authors.initials: E
authors.lastname: Tchilian
authors.affiliation: Tuberculosis Service, St Mary's Hospital, Imperial College Healthcare, National Health Service Trust, London W2 1PG, United Kingdom.
authors.forename: Anny
authors.initials: A
authors.lastname: Sykes
authors.affiliation: Tuberculosis Research Centre, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Grass
authors.affiliation: Tuberculosis Research Centre, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom.
authors.forename: Lee
authors.initials: L
authors.lastname: Potiphar
authors.affiliation: Tuberculosis Research Centre, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom.
authors.forename: Samuel
authors.initials: S
authors.lastname: Bremang
authors.affiliation: Tuberculosis Service, St Mary's Hospital, Imperial College Healthcare, National Health Service Trust, London W2 1PG, United Kingdom.
authors.forename: Onn Min
authors.initials: OM
authors.lastname: Kon
authors.affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.affiliation: Tuberculosis Research Centre, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom.
authors.forename: Ajit
authors.initials: A
authors.lastname: Lalvani
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology*; D018845:CD11 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000378:metabolism / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000382:microbiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity*; D014376:Tuberculosis / Q000382:microbiology*
chemical_list: D001426:Bacterial Proteins; D018845:CD11 Antigens; D054428:Chemokine CX3CL1; D020782:Matrix Metalloproteinases
keywords: ESX-1; Fractalkine; Infection; Mycobacterium; Tuberculosis