title: Identification of Mycobacterium tuberculosis clinical isolates with altered phagocytosis by human macrophages due to a truncated lipoarabinomannan.
abstract: Phenotypically distinct clinical isolates of Mycobacterium tuberculosis are capable of altering the balance that exists between the pathogen and human host and ultimately the outcome of infection. This study has identified two M. tuberculosis strains (i.e. HN885 and HN1554) among a bank of clinical isolates with a striking defect in phagocytosis by primary human macrophages when compared with strain Erdman, a commonly used laboratory strain for studies of pathogenesis. Mass spectrometry in conjunction with NMR studies unequivocally confirmed that both HN885 and HN1554 contain truncated and more branched forms of mannose-capped lipoarabinomannan (ManLAM) with a marked reduction of their linear arabinan (corresponding mainly to the inner Araf-alpha(1-->5)-Araf unit) and mannan (with fewer 6-Manp residues and more substitutions in the linear Manp-alpha(1-->6)-Manp unit) domains. The truncation in the ManLAM molecules produced by strains HN885 and HN1554 led to a significant reduction in their surface availability. In addition, there was a marked reduction of higher order phosphatidyl-myo-inositol mannosides and the presence of dimycocerosates, triglycerides, and phenolic glycolipid in their cell envelope. Less exposed ManLAM and reduced higher order phosphatidyl-myo-inositol mannosides in strains HN885 and HN1554 resulted in their low association with the macrophage mannose receptor. Despite reduced phagocytosis, ingested bacilli replicated at a fast rate following serum opsonization. Our results provide evidence that the clinical spectrum of tuberculosis may be dictated not only by the host but also by the amounts and ratios of surface exposed mycobacterial adherence factors defined by strain genotype.
authors.affiliation: Center for Microbial Interface Biology, Division of Infectious Diseases, Department of Internal Medicine, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Jordi B
authors.initials: JB
authors.lastname: Torrelles
authors.forename: Rose
authors.initials: R
authors.lastname: Knaup
authors.forename: Avina
authors.initials: A
authors.lastname: Kolareth
authors.forename: Tatiana
authors.initials: T
authors.lastname: Slepushkina
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kaufman
authors.forename: Peter
authors.initials: P
authors.lastname: Kang
authors.forename: Preston J
authors.initials: PJ
authors.lastname: Hill
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Brennan
authors.forename: Delphi
authors.initials: D
authors.lastname: Chatterjee
authors.forename: John T
authors.initials: JT
authors.lastname: Belisle
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
mesh_terms: D002478:Cells, Cultured; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D008970:Molecular Weight; D009169:Mycobacterium tuberculosis / Q000302:isolation & purification*; D010587:Phagocytosis
chemical_list: D008070:Lipopolysaccharides; C050016:lipoarabinomannan
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