title: Role for lysosomal enzyme beta-hexosaminidase in the control of mycobacteria infection.
abstract: The pathogenic mycobacteria that cause tuberculosis (TB) and TB-like diseases in humans and animals elude sterilizing immunity by residing within an intracellular niche in host macrophages, where they are protected from microbicidal attack. Recent studies have emphasized microbial mechanisms for evasion of host defense; less is known about mycobactericidal mechanisms that remain intact during initial infection. To better understand macrophage mechanisms for restricting mycobacteria growth, we examined Mycobacterium marinum infection of Drosophila S2 cells. Among approximately 1,000 host genes examined by RNAi depletion, the lysosomal enzyme beta-hexosaminidase was identified as an important factor in the control of mycobacterial infection. The importance of beta-hexosaminidase for restricting mycobacterial growth during mammalian infections was confirmed in macrophages from beta-hexosaminidase knockout mice. Beta-hexosaminidase was characterized as a peptidoglycan hydrolase that surprisingly exerts its mycobactericidal effect at the macrophage plasma membrane during mycobacteria-induced secretion of lysosomes. Thus, secretion of lysosomal enzymes is a mycobactericidal mechanism that may have a more general role in host defense.
authors.affiliation: Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, CA 94143, USA.
authors.forename: Ingrid Chou
authors.initials: IC
authors.lastname: Koo
authors.forename: Yamini M
authors.initials: YM
authors.lastname: Ohol
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: J Hiroshi
authors.initials: JH
authors.lastname: Morisaki
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Cox
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
mesh_terms: D000818:Animals; D002460:Cell Line; D019281:Dimerization; D004330:Drosophila / Q000382:microbiology*; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008858:Microscopy, Phase-Contrast; D009164:Mycobacterium Infections / Q000201:enzymology / Q000473:pathology*; D034622:RNA Interference; D001619:beta-N-Acetylhexosaminidases / Q000737:chemistry / Q000502:physiology*
chemical_list: D001619:beta-N-Acetylhexosaminidases