title: Mycobacterium marinum SecA2 promotes stable granulomas and induces tumor necrosis factor alpha in vivo.
abstract: SecA2 is an ATPase present in some pathogenic Gram-positive bacteria, is required for translocation of a limited set of proteins across the cytosolic membrane, and plays an important role in virulence in several bacteria, including mycobacteria that cause diseases such as tuberculosis and leprosy. However, the mechanisms by which SecA2 affects virulence are incompletely understood. To investigate whether SecA2 modulates host immune responses in vivo, we studied Mycobacterium marinum infection in two different hosts: an established zebrafish model and a recently described mouse model. Here we show that M. marinum ΔsecA2 was attenuated for virulence in both host species and SecA2 was needed for normal granuloma numbers and for optimal tumor necrosis factor alpha response in both zebrafish and mice. M. marinum ΔsecA2 was more sensitive to SDS and had unique protrusions from its cell envelope when examined by cryo-electron tomography, suggesting that SecA2 is important for bacterial cell wall integrity. These results provide evidence that SecA2 induces granulomas and is required for bacterial modulation of the host response because it affects the mycobacterial cell envelope.
authors.affiliation: Department of Microbial Pathogenesis, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Brigitte Y
authors.initials: BY
authors.lastname: Watkins
authors.forename: Shilpa A
authors.initials: SA
authors.lastname: Joshi
authors.forename: David A
authors.initials: DA
authors.lastname: Ball
authors.forename: Hadley
authors.initials: H
authors.lastname: Leggett
authors.forename: Summer
authors.initials: S
authors.lastname: Park
authors.forename: Janice
authors.initials: J
authors.lastname: Kim
authors.forename: Cary D
authors.initials: CD
authors.lastname: Austin
authors.forename: Andres
authors.initials: A
authors.lastname: Paler-Martinez
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Downing
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006099:Granuloma / Q000382:microbiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D019910:Mycobacterium marinum / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D015027:Zebrafish
chemical_list: D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D014409:Tumor Necrosis Factor-alpha; D000251:Adenosine Triphosphatases; C442123:SecA2 protein, Mycobacterium