Porphyromonas gingivalis is a member of the dysbiotic oral microbiome associated with oral inflam... more Porphyromonas gingivalis is a member of the dysbiotic oral microbiome associated with oral inflammation and periodontal disease. Intriguingly, epidemiological studies link P. gingivalis to an increased risk of pancreatic cancer. Given that oral bacteria are detected in human pancreatic cancer, and both mouse and human pancreata harbor microbiota, we explored the involvement of P. gingivalis in pancreatic tumorigenesis using cell lines and a xenograft model. Live P. gingivalis induced proliferation of pancreatic cancer cells; however, surprisingly, this effect was independent of Toll-like receptor 2, the innate immune receptor that is engaged in response to P. gingivalis on other cancer and immune cells, and is required for P. gingivalis to induce alveolar bone resorption. Instead, we found that P. gingivalis survives inside pancreatic cancer cells, a trait that can be enhanced in vitro and is increased by hypoxia, a central characteristic of pancreatic cancer. Increased tumor cell p...
Enteropathogenic Escherichia coli (EPEC), a common cause of infant diarrhea, is associated with h... more Enteropathogenic Escherichia coli (EPEC), a common cause of infant diarrhea, is associated with high risk of mortality in developing countries. The primary niche of infecting EPEC is the apical surface of intestinal epithelial cells. EPEC employs a type three secretion system (TTSS) to inject the host cells with dozens of effector proteins, which facilitate attachment to these cells and successful colonization. Here we show that EPEC elicit strong NF-ÎşB activation in infected host cells. Furthermore, the data indicate that active, pore-forming TTSS per se is necessary and sufficient for this NF-ÎşB activation, regardless of any specific effector or protein translocation. Importantly, upon infection with wild type EPEC this NF-ÎşB activation is antagonized by anti-NF-ÎşB effectors, including NleB, NleC and NleE. Accordingly, this NF-ÎşB activation is evident only in cells infected with EPEC mutants deleted of nleB, nleC, and nleE. The TTSS-dependent NF-ÎşB activation involves a unique pat...
Syndecan-1 (Sdc1) is an important member of the cell surface heparan sulfate proteoglycan family,... more Syndecan-1 (Sdc1) is an important member of the cell surface heparan sulfate proteoglycan family, highly expressed by epithelial cells in adult organisms. Sdc1 is involved in the regulation of cell migration, cell-cell and cell-matrix interactions, growth-factor, chemokine and integrin activity, and implicated in inflammatory responses and tumorigenesis. Gastrointestinal tract represents an important anatomic site where loss of Sdc1 expression was reported both in inflammation and malignancy. However, the biological significance of Sdc1 in chronic colitis-associated tumorigenesis has not been elucidated. To the best of our knowledge, this study is the first to test the effects of Sdc1 loss on colorectal tumor development in inflammation-driven colon tumorigenesis. Utilizing a mouse model of colitis-related colon carcinoma induced by the carcinogen azoxymethane (AOM), followed by the inflammatory agent dextran sodium sulfate (DSS), we found that Sdc1 deficiency results in increased s...
Peri-implantitis is a major health concern, with unclear pathogenesis, and with no accessible ani... more Peri-implantitis is a major health concern, with unclear pathogenesis, and with no accessible animal models. Our aim was to establish a mouse model for peri-implantitis, and to investigate mediators of inflammation. Mice were divided into implanted versus non-implanted groups. Implants were inserted immediately following the extraction of the upper first molar. Four weeks following implantation, implanted and non-implanted mice were challenged with either Porphyromonas gingivalis or vehicle (eight mice in each sub-group, thirty-two mice in total). Alveolar bone loss and expression of inflammatory mediators in the soft tissue were assessed 42 days following infection. P. gingivalis infection induced greater bone loss around implants than around teeth. In non-infected animals, the presence of the implant correlated with elevated expression of Il-10, Foxp3 and Rankl/Opg ratio, while Tnf-α levels were decreased relative to tissue around teeth. Six weeks following infection, Tnf-α increased significantly while the expression of Foxp3 decreased in the tissue around the implants. No significant differences in anti- or pro-inflammatory mediators were found around teeth of infected, relative to non-infected, mice. Oral infection with P. gingivalis of mice with implants induced bone loss and a shift in gingival cytokine expression. This mouse model enables exploration of the pathogenesis of peri-implantitis and testing of novel treatments. This article is protected by copyright. All rights reserved.
Proceedings of the National Academy of Sciences, 2017
The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critica... more The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3–AXL–MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium. In contrast to protein S, the other TAM ligand, which was constitutively expressed postnatally, expression of GAS6 initiated only 3–4 wk after birth. Further analysis revealed that GAS6 expression was induced by the oral microbiota in a myeloid differentiation primary response gene 88 (MyD88)-dependent fashion. Mice lacking GAS6 presented higher levels of inflammatory cytokines, elevated frequencies of neutrophils, and up-regulated activity of enzymes, generating reactive n...
We often conceive of the immune system in binary terms - on/off, or good/bad. Such thinking birth... more We often conceive of the immune system in binary terms - on/off, or good/bad. Such thinking birthed the image of immunity as a double-edged sword - too much, and we suffer the consequences of inflammatory tissue damage and autoimmunity, whereas too little puts us at risk of infection. Human pathology, however, defies simple categorization, and conditions such as common variable immune deficiency (CVID) manifest both edges of the sword - lymphoproliferation and autoimmunity coexist with antibody deficiency and increased susceptibility to infection. The emerging paradigm of immunity is one of multiple regulatory signals, and checks on those signals, that modulate the response state of the system. Recent descriptions of individuals carrying mutations in some of these pathways has revealed their role in autoimmunity. This article is protected by copyright. All rights reserved.
Porphyromonas gingivalis is a member of the dysbiotic oral microbiome associated with oral inflam... more Porphyromonas gingivalis is a member of the dysbiotic oral microbiome associated with oral inflammation and periodontal disease. Intriguingly, epidemiological studies link P. gingivalis to an increased risk of pancreatic cancer. Given that oral bacteria are detected in human pancreatic cancer, and both mouse and human pancreata harbor microbiota, we explored the involvement of P. gingivalis in pancreatic tumorigenesis using cell lines and a xenograft model. Live P. gingivalis induced proliferation of pancreatic cancer cells; however, surprisingly, this effect was independent of Toll-like receptor 2, the innate immune receptor that is engaged in response to P. gingivalis on other cancer and immune cells, and is required for P. gingivalis to induce alveolar bone resorption. Instead, we found that P. gingivalis survives inside pancreatic cancer cells, a trait that can be enhanced in vitro and is increased by hypoxia, a central characteristic of pancreatic cancer. Increased tumor cell p...
Enteropathogenic Escherichia coli (EPEC), a common cause of infant diarrhea, is associated with h... more Enteropathogenic Escherichia coli (EPEC), a common cause of infant diarrhea, is associated with high risk of mortality in developing countries. The primary niche of infecting EPEC is the apical surface of intestinal epithelial cells. EPEC employs a type three secretion system (TTSS) to inject the host cells with dozens of effector proteins, which facilitate attachment to these cells and successful colonization. Here we show that EPEC elicit strong NF-ÎşB activation in infected host cells. Furthermore, the data indicate that active, pore-forming TTSS per se is necessary and sufficient for this NF-ÎşB activation, regardless of any specific effector or protein translocation. Importantly, upon infection with wild type EPEC this NF-ÎşB activation is antagonized by anti-NF-ÎşB effectors, including NleB, NleC and NleE. Accordingly, this NF-ÎşB activation is evident only in cells infected with EPEC mutants deleted of nleB, nleC, and nleE. The TTSS-dependent NF-ÎşB activation involves a unique pat...
Syndecan-1 (Sdc1) is an important member of the cell surface heparan sulfate proteoglycan family,... more Syndecan-1 (Sdc1) is an important member of the cell surface heparan sulfate proteoglycan family, highly expressed by epithelial cells in adult organisms. Sdc1 is involved in the regulation of cell migration, cell-cell and cell-matrix interactions, growth-factor, chemokine and integrin activity, and implicated in inflammatory responses and tumorigenesis. Gastrointestinal tract represents an important anatomic site where loss of Sdc1 expression was reported both in inflammation and malignancy. However, the biological significance of Sdc1 in chronic colitis-associated tumorigenesis has not been elucidated. To the best of our knowledge, this study is the first to test the effects of Sdc1 loss on colorectal tumor development in inflammation-driven colon tumorigenesis. Utilizing a mouse model of colitis-related colon carcinoma induced by the carcinogen azoxymethane (AOM), followed by the inflammatory agent dextran sodium sulfate (DSS), we found that Sdc1 deficiency results in increased s...
Peri-implantitis is a major health concern, with unclear pathogenesis, and with no accessible ani... more Peri-implantitis is a major health concern, with unclear pathogenesis, and with no accessible animal models. Our aim was to establish a mouse model for peri-implantitis, and to investigate mediators of inflammation. Mice were divided into implanted versus non-implanted groups. Implants were inserted immediately following the extraction of the upper first molar. Four weeks following implantation, implanted and non-implanted mice were challenged with either Porphyromonas gingivalis or vehicle (eight mice in each sub-group, thirty-two mice in total). Alveolar bone loss and expression of inflammatory mediators in the soft tissue were assessed 42 days following infection. P. gingivalis infection induced greater bone loss around implants than around teeth. In non-infected animals, the presence of the implant correlated with elevated expression of Il-10, Foxp3 and Rankl/Opg ratio, while Tnf-α levels were decreased relative to tissue around teeth. Six weeks following infection, Tnf-α increased significantly while the expression of Foxp3 decreased in the tissue around the implants. No significant differences in anti- or pro-inflammatory mediators were found around teeth of infected, relative to non-infected, mice. Oral infection with P. gingivalis of mice with implants induced bone loss and a shift in gingival cytokine expression. This mouse model enables exploration of the pathogenesis of peri-implantitis and testing of novel treatments. This article is protected by copyright. All rights reserved.
Proceedings of the National Academy of Sciences, 2017
The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critica... more The oral epithelium contributes to innate immunity and oral mucosal homeostasis, which is critical for preventing local inflammation and the associated adverse systemic conditions. Nevertheless, the mechanisms by which the oral epithelium maintains homeostasis are poorly understood. Here, we studied the role of growth arrest specific 6 (GAS6), a ligand of the TYRO3–AXL–MERTK (TAM) receptor family, in regulating oral mucosal homeostasis. Expression of GAS6 was restricted to the outer layers of the oral epithelium. In contrast to protein S, the other TAM ligand, which was constitutively expressed postnatally, expression of GAS6 initiated only 3–4 wk after birth. Further analysis revealed that GAS6 expression was induced by the oral microbiota in a myeloid differentiation primary response gene 88 (MyD88)-dependent fashion. Mice lacking GAS6 presented higher levels of inflammatory cytokines, elevated frequencies of neutrophils, and up-regulated activity of enzymes, generating reactive n...
We often conceive of the immune system in binary terms - on/off, or good/bad. Such thinking birth... more We often conceive of the immune system in binary terms - on/off, or good/bad. Such thinking birthed the image of immunity as a double-edged sword - too much, and we suffer the consequences of inflammatory tissue damage and autoimmunity, whereas too little puts us at risk of infection. Human pathology, however, defies simple categorization, and conditions such as common variable immune deficiency (CVID) manifest both edges of the sword - lymphoproliferation and autoimmunity coexist with antibody deficiency and increased susceptibility to infection. The emerging paradigm of immunity is one of multiple regulatory signals, and checks on those signals, that modulate the response state of the system. Recent descriptions of individuals carrying mutations in some of these pathways has revealed their role in autoimmunity. This article is protected by copyright. All rights reserved.
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Papers by Gabriel Nussbaum