Fusobacterium nucleatum-associated β-Defensin Inducer (FAD-I)

Gupta, Sanhita; Ghosh, Santosh K.; Scott, Mary E.; Bainbridge, Brian W.; Jiang, Bin; Lamont, Richard J.; McCormick, Thomas S.; Weinberg, Aaron

doi:10.1074/jbc.m110.133140

Cited by 28 publications

(32 citation statements)

References 75 publications

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“…In the present study, we focused on the induction of both hBD-2 and hBD-3 by A. baumannii on primary oral and skin epithelial cells. We previously showed that the Fusobacterium nucleatum cell wall (FnCW) induces hBD expression on primary oral epithelial cells (27). In contrast to the findings obtained with FnCW, we found that A. baumannii induces hBD-3 better than it induces hBD-2, suggesting that A. baumannii induces hBD expression via a mechanism different from that of FnCW.…”

Section: Discussioncontrasting

confidence: 75%

“…2A and B, respectively). We previously showed that the cell wall of the oral commensal bacterium Fusobacterium nucleatum (FnCW) induces hBD-2 (22,27), with very little hBD-3 expression being observed in primary oral epithelial cells. We discovered that A. baumannii, in contrast to FnCW, preferentially induced hBD-3 transcripts over hBD-2 transcripts.…”

Section: Resultsmentioning

confidence: 99%

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Epithelial Innate Immune Response to Acinetobacter baumannii Challenge

et al. 2014

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dCurrently, Acinetobacter baumannii is recognized as one of the major pathogens seriously threatening our health care delivery system. Aspects of the innate immune response to A. baumannii infection are not yet well understood. Human ␤-defensins (hBDs) are epithelial cell-derived cationic antimicrobial peptides (AMPs) that also function to bridge the innate and adaptive immune system. We tested the induction of hBD-2 and -3 by A. baumannii on primary oral and skin epithelial cells and found that A. baumannii induces hBD-3 transcripts to a greater extent than it induces hBD-2 transcripts on both types of cells. In addition, we found that A. baumannii is susceptible to hBD-2 and -3 killing at submicromolar concentrations. Moreover, hBD-3 induction by A. baumannii was found to be dependent on epidermal growth factor receptor (EGFR) signaling. Inhibition of mitogen-activated protein kinase resulted in reduced expression of both hBD-2 and -3. Lastly, a disintegrin and metalloprotease 17 (ADAM17; also known as TACE) was found to be critical for hBD-3 induction, while ADAM10 and dual oxidase 1 (Duox1) were not required for hBD-3 induction. Induction of AMPs is an important component of innate sensing of pathogens and may play an important role in triggering systemic immune responses to A. baumannii infection. Further studies on the interactions between epithelial cells and A. baumannii will help us understand early stages of infection and may shed light on why some individuals are more vulnerable to A. baumannii infection.

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Section: Discussioncontrasting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Epithelial Innate Immune Response to Acinetobacter baumannii Challenge

et al. 2014

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“…While colonizing, certain bacteria promote activation of human beta defensin (hBD) expression in the oral mucosa (1)(2)(3). By virtue of their antimicrobial and immunoregulatory properties, these epithelial-cell-derived innate response peptides contribute to the homeostasis between the bacterium and the host (4).…”

mentioning

confidence: 99%

“…By virtue of their antimicrobial and immunoregulatory properties, these epithelial-cell-derived innate response peptides contribute to the homeostasis between the bacterium and the host (4). Human beta defensin 2 (hBD-2) and hBD-3 are the two inducible members of the hBD peptide family that we and others have described in the oral cavity (1,(5)(6)(7)(8)(9)(10). Interestingly, while hBD-3 is associated with the highly proliferating, nondifferentiated stratum basale of the oral mucosa, hBD-2 is compartmentalized in the more superficial stratum spinosum and stratum granulosum; i.e., nonproliferating yet differentiating regions of the oral mucosa (11,12).…”

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confidence: 99%

“…In addition to its role in oral community architecture, we and others have shown that the cell wall of F. nucleatum induces hBD-2 expression in normal primary human oral epithelial cells (HOECs) (1,5,10,23). The presence of F. nucleatum in oral biofilms colonizing oral surfaces may be a reason why the generally inducible hBD-2 is constitutively expressed in the upper strata of the oral mucosa, a trait apparently unique to this site compared to other mucosal body sites (5,11,17).…”

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FAD-I, a Fusobacterium nucleatum Cell Wall-Associated Diacylated Lipoprotein That Mediates Human Beta Defensin 2 Induction through Toll-Like Receptor-1/2 (TLR-1/2) and TLR-2/6

Bhattacharyya¹,

Ghosh²,

Shokeen

et al. 2016

Infect Immun

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We previously identified a cell wall-associated protein from Fusobacterium nucleatum, a Gram-negative bacterium of the oral cavity, that induces human beta defensin 2 (hBD-2) in primary human oral epithelial cells (HOECs) and designated it FAD-I (Fusobacterium-associated defensin inducer). Here, we report differential induction of hBD-2 by different strains of F. nucleatum; ATCC 25586 and ATCC 23726 induce significantly more hBD-2 mRNA than ATCC 10953. Heterologous expression of plasmid-borne fadI from the highly hBD-2-inducing strains in a ⌬fadI mutant of ATCC 10953 resulted in hBD-2 induction to levels comparable to those of the highly inducing strains, indicating that FAD-I is the principal F. nucleatum agent for hBD-2 induction in HOECs. Moreover, anti-FAD-I antibodies blocked F. nucleatum induction of hBD-2 by more than 80%. Recombinant FAD-I (rFAD-I) expressed in Escherichia coli triggered levels of hBD-2 transcription and peptide release in HOECs similar to those of native FAD-I (nFAD-I) isolated from F. nucleatum ATCC 25586. Tandem mass spectrometry revealed a diacylglycerol modification at the cysteine residue in position 16 for both nFAD-I and rFAD-I. Cysteine-to-alanine substitution abrogated FAD-I's ability to induce hBD-2. Finally, FAD-I activation of hBD-2 expression was mediated via both Toll-like receptor-1/2 (TLR-1/2) and TLR-2/6 heterodimerization. Microbial molecules like FAD-I may be utilized in novel therapeutic ways to bolster the host innate immune response at mucosal surfaces.T he epithelial surfaces of the oral cavity are sites of active bacterial colonization. While colonizing, certain bacteria promote activation of human beta defensin (hBD) expression in the oral mucosa (1-3). By virtue of their antimicrobial and immunoregulatory properties, these epithelial-cell-derived innate response peptides contribute to the homeostasis between the bacterium and the host (4). Human beta defensin 2 (hBD-2) and hBD-3 are the two inducible members of the hBD peptide family that we and others have described in the oral cavity (1, 5-10). Interestingly, while hBD-3 is associated with the highly proliferating, nondifferentiated stratum basale of the oral mucosa, hBD-2 is compartmentalized in the more superficial stratum spinosum and stratum granulosum; i.e., nonproliferating yet differentiating regions of the oral mucosa (11,12). This, along with other results showing that hBD-2 is induced as a result of inflammation via MAPK or NF〉 (5) while hBD-3 is activated through epidermal growth factor receptor (13, 14), strongly suggests that the latter is more involved in wound healing while the former plays a more active role in inhibiting microbial invasion during mucosal-barrier disruption (15-17). Moreover, in addition to their antimicrobial properties (18, 19), both peptides have been shown to act as chemokines in recruiting lymphoid and myeloid cells from the bloodstream (20).Fusobacterium nucleatum, a ubiquitous Gram-negative bacterium of the human oral cavity, has been extensively studied for its propert...

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