title: The proprotein convertase subtilisin/kexin furinA regulates zebrafish host response against Mycobacterium marinum.
abstract: Tuberculosis is a chronic bacterial disease with a complex pathogenesis. An effective immunity against Mycobacterium tuberculosis requires both the innate and adaptive immune responses, including proper T helper (Th) type 1 cell function. FURIN is a proprotein convertase subtilisin/kexin (PCSK) enzyme, which is highly expressed in Th1 type cells. FURIN expression in T cells is essential for maintaining peripheral immune tolerance, but its role in the innate immunity and infections has remained elusive. Here, we utilized Mycobacterium marinum infection models in zebrafish (Danio rerio) to investigate how furin regulates host responses against mycobacteria. In steady-state furinAtd204e/+ fish reduced furinA mRNA levels associated with low granulocyte counts and elevated Th cell transcription factor expressions. Silencing furin genes reduced the survival of M. marinum-infected zebrafish embryos. A mycobacterial infection upregulated furinA in adult zebrafish, and infected furinAtd204e/+ mutants exhibited a proinflammatory phenotype characterized by elevated tumor necrosis factor a (tnfa), lymphotoxin alpha (lta) and interleukin 17a/f3 (il17a/f3) expression levels. The enhanced innate immune response in the furinAtd204e/+ mutants correlated with a significantly decreased bacterial burden in a chronic M. marinum infection model. Our data show that upregulated furinA expression can serve as a marker for mycobacterial disease, since it inhibits early host responses and consequently promotes bacterial growth in a chronic infection.
authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland.
authors.forename: Markus J T
authors.initials: MJ
authors.lastname: Ojanen
authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland.
authors.forename: Hannu
authors.initials: H
authors.lastname: Turpeinen
authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland.
authors.forename: Zuzet M
authors.initials: ZM
authors.lastname: Cordova
authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland.
authors.forename: Milka M
authors.initials: MM
authors.lastname: Hammarén
authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland.
authors.forename: Sanna-Kaisa E
authors.initials: SK
authors.lastname: Harjula
authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland.
authors.forename: Mataleena
authors.initials: M
authors.lastname: Parikka
authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland Department of Pediatrics, Tampere University Hospital, Tampere, Finland Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland Department of Pediatrics, Medical Research Center Oulu, University of Oulu, Oulu, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Rämet
authors.affiliation: BioMediTech, University of Tampere, Tampere, Finland Department of Dermatology, Tampere University Hospital, Tampere, Finland Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland marko.pesu@uta.fi.
authors.forename: Marko
authors.initials: M
authors.lastname: Pesu
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D004195:Disease Models, Animal; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D006098:Granulocytes / Q000166:cytology / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D020381:Interleukin-17 / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000378:metabolism; D060172:Morpholinos / Q000235:genetics; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology*; D019910:Mycobacterium marinum / Q000276:immunology*; D043484:Proprotein Convertases / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020860:Subtilisin / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology / Q000276:immunology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D020381:Interleukin-17; D008233:Lymphotoxin-alpha; D060172:Morpholinos; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D029961:Zebrafish Proteins; C551315:FurinA protein, zebrafish; D043484:Proprotein Convertases; D020860:Subtilisin