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Infect Immun. 2017 Nov 17;85(12). pii: e00544-17. doi: 10.1128/IAI.00544-17. Print 2017 Dec.

Stenotrophomonas maltophilia Serine Protease StmPr1 Induces Matrilysis, Anoikis, and Protease-Activated Receptor 2 Activation in Human Lung Epithelial Cells.

Author information

1
Department of Microbiology and Immunology, Northwestern University Medical School, Chicago, Illinois, USA.
2
Department of Microbiology and Immunology, Northwestern University Medical School, Chicago, Illinois, USA n-cianciotto@northwestern.edu.

Abstract

Stenotrophomonas maltophilia is an emerging, opportunistic nosocomial pathogen that can cause severe disease in immunocompromised individuals. We recently identified the StmPr1 and StmPr2 serine proteases to be the substrates of the Xps type II secretion system in S. maltophilia strain K279a. Here, we report that a third serine protease, StmPr3, is also secreted in an Xps-dependent manner. By constructing a panel of protease mutants in strain K279a, we were able to determine that StmPr3 contributes to the previously described Xps-mediated rounding and detachment of cells of the A549 human lung epithelial cell line as well as the Xps-mediated degradation of fibronectin, fibrinogen, and the cytokine interleukin-8 (IL-8). We also determined that StmPr1, StmPr2, and StmPr3 account for all Xps-mediated effects toward A549 cells and that StmPr1 contributes the most to Xps-mediated activities. Thus, we purified StmPr1 from the S. maltophilia strain K279a culture supernatant and evaluated the protease's activity toward A549 cells. Our analyses revealed that purified StmPr1 behaves more similarly to subtilisin than to trypsin. We also determined that purified StmPr1 likely induces cell rounding and detachment of A549 cells by targeting cell integrin-extracellular matrix connections (matrilysis) as well as adherence and tight junction proteins for degradation. In this study, we also identified anoikis as the mechanism by which StmPr1 induces the death of A549 cells and found that StmPr1 induces A549 IL-8 secretion via activation of protease-activated receptor 2. Altogether, these results suggest that the degradative and cytotoxic activities exhibited by StmPr1 may contribute to S. maltophilia pathogenesis in the lung by inducing tissue damage and inflammation.

KEYWORDS:

A549 cells; PAR2; Stenotrophomonas maltophilia; StmPr1; StmPr3; Xps; anoikis; matrilysis; serine protease; type II secretion

PMID:
28893914
PMCID:
PMC5695115
DOI:
10.1128/IAI.00544-17
[Indexed for MEDLINE]
Free PMC Article

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