Abstract
The anaerobic bacterium Finegoldia magna is part of the human commensal microbiota, but is also an important opportunistic pathogen. This bacterium expresses a subtilisin-like serine proteinase, SufA, which partially degrade the antibacterial chemokine MIG/CXCL9. Here, we show that MIG/CXCL9 is produced by human keratinocytes in response to inflammatory stimuli. In contrast to the virulent human pathogen Streptococcus pyogenes, the presence of F. magna had no enhancing effect on the MIG/CXCL9 expression by keratinocytes, suggesting poor detection of the latter by pathogen-recognition receptors. When MIG/CXCL9 was exposed to SufA-expressing F. magna, the molecule was processed into several smaller fragments. Analysis by mass spectrometry showed that SufA cleaves MIG/CXCL9 at several sites in the COOH-terminal region of the molecule. At equimolar concentrations, SufA-generated MIG/CXCL9 fragments were not bactericidal against F. magna, but retained their ability to kill S. pyogenes. Moreover, the SufA-generated MIG/CXCL9 fragments were capable of activating the angiostasis-mediating CXCR3 receptor, which is expressed on endothelial cells, in an order of magnitude similar to that of intact MIG/CXCL9. F. magna expresses a surface protein called FAF that is released from the bacterial surface by SufA. Soluble FAF was found to bind and inactivate the antibacterial activity of MIG/CXCL9, thereby further potentially promoting the survival of F. magna. The findings suggest that SufA modulation of the inflammatory response could be a mechanism playing an important role in creating an ecologic niche for F. magna, decreasing antibacterial activity and suppressing angiogenesis, thus providing advantage in survival for this anaerobic opportunist compared with competing pathogens during inflammation.
Highlights
The mucosal surfaces and skin of the human body are colonized by a large number of bacterial species constituting the normal microbiota
SufA Cleaves MIG/CXCL9 Produced by Keratinocytes—To analyze the production of MIG/CXCL9 by inflamed human keratinocytes, a human keratinocyte cell line (HaCaT) was stimulated with IFN-␥, the latter a key cytokine in the inflammatory response during bacterial infection
This study shows that SufA, released by F. magna, can cleave the antibacterial chemokine MIG/CXCL9, rendering the molecule less active as an antibacterial agent but retaining its receptor-activating activity against the CXCR3 receptor that is involved in suppression of angiogenesis
Summary
The mucosal surfaces and skin of the human body are colonized by a large number of bacterial species constituting the normal microbiota. SufA-generated MIG/CXCL9 fragments were not bactericidal against F. magna, but retained their ability to kill S. pyogenes. Bacteria were incubated with MIG/CXCL9 (0.28 M) together with various concentrations of FAF, and the bactericidal activity was determined as above.
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