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Infect Immun. 2015 Apr;83(4):1431-42. doi: 10.1128/IAI.03135-14. Epub 2015 Jan 26.

The proprotein convertase subtilisin/kexin furinA regulates zebrafish host response against Mycobacterium marinum.

Author information

  • 1BioMediTech, University of Tampere, Tampere, Finland.
  • 2BioMediTech, 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.
  • 3BioMediTech, University of Tampere, Tampere, Finland Department of Dermatology, Tampere University Hospital, Tampere, Finland Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland marko.pesu@uta.fi.

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.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

PMID:
25624351
[PubMed - indexed for MEDLINE]
PMCID:
PMC4363408
Free PMC Article
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