Abstract
Tannerella forsythia and Porphyromonas gingivalis target distinct virulence factors bearing a structurally conserved C-terminal domain (CTD) to the type IX protein secretion system (T9SS). The T9SS comprises an outer membrane translocation complex which works in concert with a signal peptidase for CTD cleavage. Among prominent T9SS cargo linked to periodontal diseases are the TfsA and TfsB components of T. forsythia’s cell surface (S-) layer, the bacterium’s BspA surface antigen and a set of cysteine proteinases (gingipains) from P. gingivalis. To assess the overall role of the bacterial T9SS in the host response, human macrophages and human gingival fibroblasts were stimulated with T. forsythia and P. gingivalis wild-type bacteria and T9SS signal peptidase-deficient mutants defective in protein secretion, respectively. The immunostimulatory potential of these bacteria was compared by analyzing the mRNA expression levels of the pro-inflammatory mediators IL-6, IL-8, MCP-1 and TNF-α by qPCR and by measuring the production of the corresponding proteins by ELISA. Shot-gun proteomics analysis of T. forsythia and P. gingivalis outer membrane preparations confirmed that several CTD-bearing virulence factors which interact with the human immune system were depleted from the signal peptidase mutants, supportive of effective T9SS shut-down. Three and, more profoundly, 16 hours post stimulation, the T. forsythia T9SS mutant induced significantly less production of cytokines and the chemokine in human cells compared to the corresponding parent strain, while the opposite was observed for the P. gingivalis T9SS mutant. Our data indicate that T9SS shut-down translates into an altered inflammatory response in periodontal pathogens. Thus, the T9SS as a potential novel target for periodontal therapy needs further evaluation.
Highlights
Oral health is characterized by the symbiotic interaction between the oral microbiota and the human host
carboxy-terminal domain (CTD)-Proteins Are Depleted From the Outer Membrane of a T. forsythia and P. gingivalis T9SS Signal Peptidase Mutant
The outer membrane (OM) preparations from T. forsythia wild-type, DTanf_02580, P. gingivalis wild-type, and DPG0026 were subjected to shot-gun proteomics
Summary
Oral health is characterized by the symbiotic interaction between the oral microbiota and the human host. Periodontitis is an inflammatory biofilm disease of the tooth-supporting tissues characterized by a dysbiotic state and the prevalence of the “red complex” of Gram-negative, anaerobic pathogens-Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola (Holt and Ebersole, 2005; Socransky and Haffajee, 2005; Griffen et al, 2012). One of these bacteria, P. gingivalis, is considered as a keystone pathogen and can subvert the host immune response, disrupting the host-microbe homeostasis in the oral cavity and promoting a dysbiotic state, even when present at low quantities (Hajishengallis and Lamont, 2012). T9SS cargo proteins are either released to the environment (Lasica et al, 2017) or stay associated with the bacterial surface, predictably anchored into the OM by a glycoconjugate of so far unknown structure that is attached to the C-terminal residue (Veith et al, 2020)
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