A bipartite bacterial virulence factor targets the complement system and neutrophil activation.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8208664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1460-2075 (Electronic) Linking ISSN: 02614189 NLM ISO Abbreviation: EMBO J Subsets: MEDLINE

Publication: 2024- : [London] : Nature Publishing Group
Original Publication: Eynsham, Oxford, England : Published for the European Molecular Biology Organization by IRL Press, [c1982-

Virulence Factors*/metabolism ; Virulence Factors*/genetics ; Virulence Factors*/immunology ; Treponema denticola*/pathogenicity ; Treponema denticola*/immunology ; Treponema denticola*/metabolism ; Treponema denticola*/genetics ; Neutrophils*/immunology ; Neutrophil Activation* ; Bacterial Proteins*/metabolism ; Bacterial Proteins*/genetics ; Bacterial Proteins*/immunology ; Complement System Proteins*/metabolism ; Complement System Proteins*/immunology; Animals ; Mice ; Humans ; Immune Evasion ; Immunity, Innate

Competing Interests: Disclosure and competing interests statement. The authors declare no competing interests.
The complement system and neutrophils constitute the two main pillars of the host innate immune defense against infection by bacterial pathogens. Here, we identify T-Mac, a novel virulence factor of the periodontal pathogen Treponema denticola that allows bacteria to evade both defense systems. We show that T-Mac is expressed as a pre-protein that is cleaved into two functional units. The N-terminal fragment has two immunoglobulin-like domains and binds with high affinity to the major neutrophil chemokine receptors FPR1 and CXCR1, blocking N-formyl-Met-Leu-Phe- and IL-8-induced neutrophil chemotaxis and activation. The C-terminal fragment functions as a cysteine protease with a unique proteolytic activity and structure, which degrades several components of the complement system, such as C3 and C3b. Murine infection studies further reveal a critical T-Mac role in tissue damage and inflammation caused by bacterial infection. Collectively, these results disclose a novel innate immunity-evasion strategy, and open avenues for investigating the role of cysteine proteases and immunoglobulin-like domains of gram-positive and -negative bacterial pathogens.
(© 2025. The Author(s).)

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P30 GM133893 United States GM NIGMS NIH HHS; DE-SC0012704 U.S. Department of Energy (DOE); ACB-12002 HHS | NIH | National Cancer Institute (NCI); S10 OD012331 United States OD NIH HHS; R01 DE030667 United States DE NIDCR NIH HHS; 1S10 OD017992 HHS | NIH | National Institute of General Medical Sciences (NIGMS); S10 OD012289 United States OD NIH HHS; S10 OD012289 United States CD ODCDC CDC HHS; R25 GM095459 United States GM NIGMS NIH HHS; DE023080 HHS | NIH | National Institute of Dental and Craniofacial Research (NIDR); R01 DE027073 United States DE NIDCR NIH HHS; DE027073 HHS | NIH | National Institute of Dental and Craniofacial Research (NIDR); S10 OD017992 United States OD NIH HHS; GM095459 HHS | NIH | National Institute of General Medical Sciences (NIGMS); P30 GM138396 United States GM NIGMS NIH HHS; AGM-12006 HHS | NIH | National Institute of General Medical Sciences (NIGMS); DE030667 HHS | NIH | National Institute of Dental and Craniofacial Research (NIDR); R01 DE023080 United States DE NIDCR NIH HHS; DE034063 HHS | NIH | National Institute of Dental and Craniofacial Research (NIDR); P30 CA016059 United States CA NCI NIH HHS; R01 DE034063 United States DE NIDCR NIH HHS

Keywords: Complement System; Cysteine Protease; Immune Evasion; Immunoglobulin-like Domain; Neutrophils

0 (Virulence Factors)
0 (Bacterial Proteins)
9007-36-7 (Complement System Proteins)

Date Created: 20250103 Date Completed: 20250430 Latest Revision: 20250430

20250430

PMC11833123

10.1038/s44318-024-00342-8

39753953