title: ESX-5-deficient Mycobacterium marinum is hypervirulent in adult zebrafish.
abstract: ESX-5 is a mycobacterial type VII protein secretion system responsible for transport of numerous PE and PPE proteins. It is involved in the induction of host cell death and modulation of the cytokine response in vitro. In this work, we studied the effects of ESX-5 in embryonic and adult zebrafish using Mycobacterium marinum. We found that ESX-5-deficient M. marinum was slightly attenuated in zebrafish embryos. Surprisingly, the same mutant showed highly increased virulence in adult zebrafish, characterized by increased bacterial loads and early onset of granuloma formation with rapid development of necrotic centres. This early onset of granuloma formation was accompanied by an increased expression of pro-inflammatory cytokines and tissue remodelling genes in zebrafish infected with the ESX-5 mutant. Experiments using RAG-1-deficient zebrafish showed that the increased virulence of the ESX-5 mutant was not dependent on the adaptive immune system. Mixed infection experiments with wild-type and ESX-5 mutant bacteria showed that the latter had a specific advantage in adult zebrafish and outcompeted wild-type bacteria. Together our experiments indicate that ESX-5-mediated protein secretion is used by M. marinum to establish a moderate and persistent infection.
authors.affiliation: Department of Medical Microbiology and Infection Control, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Eveline M
authors.initials: EM
authors.lastname: Weerdenburg
authors.forename: Abdallah M
authors.initials: AM
authors.lastname: Abdallah
authors.forename: Suman
authors.initials: S
authors.lastname: Mitra
authors.forename: Karin
authors.initials: K
authors.lastname: de Punder
authors.forename: Nicole N
authors.initials: NN
authors.lastname: van der Wel
authors.forename: Steve
authors.initials: S
authors.lastname: Bird
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Appelmelk
authors.forename: Wilbert
authors.initials: W
authors.lastname: Bitter
authors.forename: Astrid M
authors.initials: AM
authors.lastname: van der Sar
mesh_terms: D000818:Animals; D058491:Bacterial Load; D016207:Cytokines / Q000096:biosynthesis; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006099:Granuloma / Q000473:pathology; D054884:Host-Pathogen Interactions; D019910:Mycobacterium marinum / Q000235:genetics* / Q000472:pathogenicity*; D009336:Necrosis / Q000473:pathology; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics* / Q000378:metabolism*; D015027:Zebrafish / Q000382:microbiology*
chemical_list: D016207:Cytokines; D037521:Virulence Factors