A moonlighting serpin of Tannerella forsythia compromises the bactericidal activity of neutrophils
- 1Nationwide Children's Hospital
Abstract
Serine protease inhibitors (serpins) are extremely rare in prokaryotes, and their role in immune evasion remains unclear. We identified a bifunctional TLR2-binding serpin (miropin) produced by Tannerella forsythia that broadly suppresses neutrophil antimicrobial capacity. Miropin binding to TLR2 primed neutrophils, enhancing phagocytic capacity yet, counterintuitively, promoting bacterial persistence. Mechanistically, like other serpins, miropin acted as an irreversible suicide inhibitor of neutrophil serine proteases (NSPs), blocking their activity upon granule mobilization and NETosis. Unexpectedly, miropin, independent of its protease-inhibitory activity, bound and inhibited myeloperoxidase (MPO), thereby blocking the oxidative burst. This simultaneous suppression of oxidative and non-oxidative bactericidal mechanisms promoted bacterial survival in vivo without significantly altering the tissue inflammatory response. Thus, we identified novel moonlighting roles (TLR2 signaling and MPO inhibition) for an unorthodox prokaryotic serpin and provided context for how T. forsythia and other oral pathogens survive within the subgingival niche, an environment highly enriched in activated neutrophils.
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BibTeX
@misc{morris2026moonlighting,
title = {{A moonlighting serpin of Tannerella forsythia compromises the bactericidal activity of neutrophils}},
author = {S. C. Morris and F. Veillard and D. Mizgalska and M. Madej and M. Benedyk-Machaczka and J. Folkert and B. A. Potempa and A. Fuchs and J. Potempa and J. Bagaitkar},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.756777},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.756777v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A moonlighting serpin of Tannerella forsythia compromises the bactericidal activity of neutrophils
AU - S. C. Morris
AU - F. Veillard
AU - D. Mizgalska
AU - M. Madej
AU - M. Benedyk-Machaczka
AU - J. Folkert
AU - B. A. Potempa
AU - A. Fuchs
AU - J. Potempa
AU - J. Bagaitkar
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.756777
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.756777v1
AB - Serine protease inhibitors (serpins) are extremely rare in prokaryotes, and their role in immune evasion remains unclear. We identified a bifunctional TLR2-binding serpin (miropin) produced by Tannerella forsythia that broadly suppresses neutrophil antimicrobial capacity. Miropin binding to TLR2 primed neutrophils, enhancing phagocytic capacity yet, counterintuitively, promoting bacterial persistence. Mechanistically, like other serpins, miropin acted as an irreversible suicide inhibitor of neutrophil serine proteases (NSPs), blocking their activity upon granule mobilization and NETosis. Unexpectedly, miropin, independent of its protease-inhibitory activity, bound and inhibited myeloperoxidase (MPO), thereby blocking the oxidative burst. This simultaneous suppression of oxidative and non-oxidative bactericidal mechanisms promoted bacterial survival in vivo without significantly altering the tissue inflammatory response. Thus, we identified novel moonlighting roles (TLR2 signaling and MPO inhibition) for an unorthodox prokaryotic serpin and provided context for how T. forsythia and other oral pathogens survive within the subgingival niche, an environment highly enriched in activated neutrophils.
ER -