title: Relief from Zmp1-mediated arrest of phagosome maturation is associated with facilitated presentation and enhanced immunogenicity of mycobacterial antigens.
abstract: Pathogenic mycobacteria escape host innate immune responses by blocking phagosome-lysosome fusion. Avoiding lysosomal delivery may also be involved in the capacity of mycobacteria to evade major histocompatibility complex (MHC) class I- or II-dependent T-cell responses. In this study, we used a genetic mutant of Mycobacterium bovis BCG that is unable to escape lysosomal transfer and show that presentation of mycobacterial antigens is affected by the site of intracellular residence. Compared to infection with wild-type BCG, infection of murine bone marrow-derived dendritic cells with a mycobacterial mutant deficient in zinc metalloprotease 1 (Zmp1) resulted in increased presentation of MHC class II-restricted antigens, as assessed by activation of mycobacterial Ag85A-specific T-cell hybridomas. The zmp1 deletion mutant was more immunogenic in vivo, as measured by delayed-type hypersensitivity (DTH), antigen-specific lymphocyte proliferation, and the frequency of antigen-specific gamma interferon (IFN-γ)-producing lymphocytes of both CD4 and CD8 subsets. In conclusion, our results suggest that phagosome maturation and lysosomal delivery of BCG facilitate mycobacterial antigen presentation and enhance immunogenicity.
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Pål
authors.initials: P
authors.lastname: Johansen
authors.forename: Antonia
authors.initials: A
authors.lastname: Fettelschoss
authors.forename: Beat
authors.initials: B
authors.lastname: Amstutz
authors.forename: Petra
authors.initials: P
authors.lastname: Selchow
authors.forename: Ying
authors.initials: Y
authors.lastname: Waeckerle-Men
authors.forename: Peter
authors.initials: P
authors.lastname: Keller
authors.forename: Vojo
authors.initials: V
authors.lastname: Deretic
authors.forename: Leonhard
authors.initials: L
authors.lastname: Held
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kündig
authors.forename: Erik C
authors.initials: EC
authors.lastname: Böttger
authors.forename: Peter
authors.initials: P
authors.lastname: Sander
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000942:Antigens, Bacterial / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008247:Lysosomes / Q000382:microbiology*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000235:genetics / Q000276:immunology*; D010588:Phagosomes / Q000382:microbiology*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D037521:Virulence Factors; D007371:Interferon-gamma; D008666:Metalloendopeptidases