title: Mycobacteria exploit host hyaluronan for efficient extracellular replication.
abstract: In spite of the importance of hyaluronan in host protection against infectious organisms in the alveolar spaces, its role in mycobacterial infection is unknown. In a previous study, we found that mycobacteria interact with hyaluronan on lung epithelial cells. Here, we have analyzed the role of hyaluronan after mycobacterial infection was established and found that pathogenic mycobacteria can grow by utilizing hyaluronan as a carbon source. Both mouse and human possess 3 kinds of hyaluronan synthases (HAS), designated HAS1, HAS2, and HAS3. Utilizing individual HAS-transfected cells, we show that HAS1 and HAS3 but not HAS2 support growth of mycobacteria. We found that the major hyaluronan synthase expressed in the lung is HAS1, and that its expression was increased after infection with Mycobacterium tuberculosis. Histochemical analysis demonstrated that hyaluronan profoundly accumulated in the granulomatous legion of the lungs in M. tuberculosis-infected mice and rhesus monkeys that died from tuberculosis. We detected hyaluronidase activity in the lysate of mycobacteria and showed that it was critical for hyaluronan-dependent extracellular growth. Finally, we showed that L-Ascorbic acid 6-hexadecanoate, a hyaluronidase inhibitor, suppressed growth of mycobacteria in vivo. Taken together, our data show that pathogenic mycobacteria exploit an intrinsic host-protective molecule, hyaluronan, to grow in the respiratory tract and demonstrate the potential usefulness of hyaluronidase inhibitors against mycobacterial diseases.
authors.affiliation: Department of Bacteriology, Osaka City University Graduate School of Medicine, Osaka, Osaka, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hirayama
authors.forename: Mamiko
authors.initials: M
authors.lastname: Yoshimura
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Ozeki
authors.forename: Isamu
authors.initials: I
authors.lastname: Sugawara
authors.forename: Tadashi
authors.initials: T
authors.lastname: Udagawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Mizuno
authors.forename: Naoki
authors.initials: N
authors.lastname: Itano
authors.forename: Koji
authors.initials: K
authors.lastname: Kimata
authors.forename: Aki
authors.initials: A
authors.lastname: Tamaru
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ogura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Sohkichi
authors.initials: S
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D006025:Glycosaminoglycans / Q000494:pharmacology; D006651:Histocytochemistry; D054884:Host-Pathogen Interactions / Q000502:physiology*; D006801:Humans; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000378:metabolism* / Q000494:pharmacology; D008168:Lung / Q000737:chemistry / Q000378:metabolism / Q000382:microbiology; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009163:Mycobacterium bovis / Q000502:physiology; D009169:Mycobacterium tuberculosis / Q000378:metabolism / Q000502:physiology*; D051381:Rats
chemical_list: D006025:Glycosaminoglycans; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; C523794:HAS1 protein, human; C105458:HAS3 protein, human; D000076002:Hyaluronan Synthases