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Fimbrial Proteins of Porphyromonas gingivalis Mediate In Vivo Virulence and Exploit TLR2 and Complement Receptor 3 to Persist in Macrophages¹

Min Wang^*, Muhamad-Ali K. Shakhatreh^*, Deanna James^*, Shuang Liang^*, So-ichiro Nishiyama, Fuminobu Yoshimura, Donald R. Demuth^*, and George Hajishengallis^2,*,

^* Department of Periodontics/Oral Health and Systemic Disease, University of Louisville Health Sciences Center, Louisville, KY 40292; Department of Microbiology, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan; and Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, KY 40292

Porphyromonas gingivalis is an oral/systemic pathogen implicated in chronic conditions, although the mechanism(s) whereby it resists immune defenses and persists in the host is poorly understood. The virulence of this pathogen partially depends upon expression of fimbriae comprising polymerized fimbrillin (FimA) associated with quantitatively minor proteins (FimCDE). In this study, we show that isogenic mutants lacking FimCDE are dramatically less persistent and virulent in a mouse periodontitis model and express shorter fimbriae than the wild type. Strikingly, native fimbriae allowed P. gingivalis to exploit the TLR2/complement receptor 3 pathway for intracellular entry, inhibition of IL-12p70, and persistence in macrophages. This virulence mechanism also required FimCDE; indeed, mutant strains exhibited significantly reduced ability to inhibit IL-12p70, invade, and persist intracellularly, attributable to failure to interact with complement receptor 3, although not with TLR2. These results highlight a hitherto unknown mechanism of immune evasion by P. gingivalis that is surprisingly dependent upon minor constituents of its fimbriae, and support the concept that pathogens evolved to manipulate innate immunity for promoting adaptive fitness and thus their capacity to cause disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by U.S. Public Health Service Grants DE015254 and DE018292 (to G.H.), and DE14605 (to D.R.D.) from the National Institutes of Health; Grants-in-Aid for Scientific Research (15591957 to F.Y. and 17791318 to S.N.) from the Japan Society for the Promotion of Science; and the AGU High-Tech Research Center Project from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (to F.Y.).

² Address correspondence and reprint requests to Dr. George Hajishengallis, University of Louisville Health Sciences Center, 501 South Preston Street, Room 206, Louisville, KY 40292. E-mail address: g0haji01{at}louisville.eduU

³ Abbreviations used in this paper: DAP, devoid of all accessory proteins; ABC, alveolar bone crest; CEJ, cementoenamel junction; CR3, complement receptor 3; MFI, mean fluorescence intensity; MOI, multiplicity of infection.