PUBLICATION
The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum
- Authors
- Ojanen, M.J., Turpeinen, H., Cordova, Z.M., Hammarén, M.M., Harjula, S.K., Parikka, M., Rämet, M., Pesu, M.
- ID
- ZDB-PUB-150128-9
- Date
- 2015
- Source
- Infection and Immunity 83(4): 1431-42 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- CD3 Complex/biosynthesis
- Cell Differentiation/immunology
- Disease Models, Animal
- Gene Silencing
- Genetic Predisposition to Disease
- Granulocytes/cytology
- Granulocytes/immunology
- Immunity, Innate/genetics
- Interleukin-17/metabolism
- Lymphotoxin-alpha/metabolism
- Morpholinos/genetics
- Mycobacterium Infections, Nontuberculous/immunology*
- Mycobacterium marinum/immunology*
- Proprotein Convertases/genetics
- Proprotein Convertases/immunology*
- RNA, Messenger/biosynthesis
- Subtilisin/immunology*
- Th1 Cells/immunology
- Tuberculosis/immunology
- Tumor Necrosis Factor-alpha/metabolism
- Zebrafish/embryology
- Zebrafish/immunology*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/immunology*
- PubMed
- 25624351 Full text @ Infect. Immun.
Citation
Ojanen, M.J., Turpeinen, H., Cordova, Z.M., Hammarén, M.M., Harjula, S.K., Parikka, M., Rämet, M., Pesu, M. (2015) The Proprotein Convertase Subtilisin/Kexin FurinA Regulates Zebrafish Host Response against Mycobacterium marinum. Infection and Immunity. 83(4):1431-42.
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 furinA(td204e/+) fish reduced furinA mRNA levels associated with low granulocyte counts and elevated Th cell transcription factor expressions. Silencing furin genes reduced the survival of the M. marinum infected zebrafish embryos. A mycobacterial infection up-regulated furinA in adult zebrafish, and infected furinA(td204e/+) mutants exhibited a pro-inflammatory 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 furinA(td204e/+) mutants correlated with a significantly decreased bacterial burden in a chronic M. marinum infection model. Our data show that up-regulated 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping