The innate and adaptive immune systems are irrevocably linked and both play primary roles in the induction and/or prevention of infections, including periodontal disease. Critical to the initiation of innate and adaptive immune responses to microbial antigens is the participation of Toll-like receptors (TLRs), a family of pattern- recognition receptors (PRRs) that detect conserved molecular products of microorganisms. We propose that the immune regulation exerted by the innate immune system upon its interaction with virulence antigens is the basis for the development of therapies geared to manipulate the effector immune response to the advantage and protection of the host. The fundamental hypothesis of our studies is that each microbial antigen is unique in its initial interaction with the host, thus resulting in differences in receptor recognition, activation of signaling pathways and cellular responses. In this regard, we have shown differences in the adaptive immune responses to the hemagglutinin/adhesin virulence antigens Kgp-HArep and HagB derived from Porphyromonas ginigivalis, which suggest that their interactions with the innate immune system differ. We plan to focus our investigations on the TLRs and on dendritic cells since these antigen-presenting cells have the exquisite property of activating na?ve T cells and thus are critically involved in innate and adaptive responses. In addition, our investigations will pursue an understanding of the ensuing adaptive immune response. Therefore, the aims of this proposal are (1) to determine the role of TLRs in the innate and adaptive response to Kgp-HArep and HagB stimulation;(2) to determine if innate and effector cell responses to Kgp- HArep and HagB require lipid rafts and how the induction of a specific effector response or the use of a certain TLR affects the particular recruitment and concentration of signaling molecules into lipid rafts;and (3) to determine the role of CD25+CD4+ Treg cells in immune responses to Kgp-HArep and HagB and in P. gingivalis infection. It is anticipated that these studies will lead to an understanding of the cellular events that occur when host cells encounter the virulence antigens HArep and HagB, and will provide 1) insight into their role in pathogenesis/immunity and 2) relavant information for the development of vaccines or therapies that will specifically protect or ameliorate infections by the pathogen Porphyromonas gingivalis. Porphyromonas gingivalis is a major etiologic agent of periodontal disease. This inflammatory disease is widespread and associations have been made between this disease and serious systemic conditions such as cardiovascular diseases. Since the immunoregulatory properties of P. gingivalis antigens in host responses are poorly understood, it becomes critical to understand the host cellular responses, including the signaling pathways activated, to major antigens of P. gingivalis, in order to develop novel therapies and vaccines by which periodontal disease can be ameliorated or controlled.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Lumelsky, Nadya L
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University of Alabama Birmingham
Schools of Dentistry
United States
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Gaddis, Dalia E; Maynard, Craig L; Weaver, Casey T et al. (2013) Role of TLR2-dependent IL-10 production in the inhibition of the initial IFN-? T cell response to Porphyromonas gingivalis. J Leukoc Biol 93:21-31
Zhang, Ping; Liu, Jianzhong; Xu, Qingan et al. (2011) TLR2-dependent modulation of osteoclastogenesis by Porphyromonas gingivalis through differential induction of NFATc1 and NF-kappaB. J Biol Chem 286:24159-69
Gaddis, Dalia E; Michalek, Suzanne M; Katz, Jannet (2011) TLR4 signaling via MyD88 and TRIF differentially shape the CD4+ T cell response to Porphyromonas gingivalis hemagglutinin B. J Immunol 186:5772-83
Salam, Mohammad Abdus; Katz, Jannet; Michalek, Suzanne M (2010) Role of Toll-like receptors in host responses to a virulence antigen of Streptococcus mutans expressed by a recombinant, attenuated Salmonella vector vaccine. Vaccine 28:4928-36
Gaddis, Dalia E; Michalek, Suzanne M; Katz, Jenny (2009) Requirement of TLR4 and CD14 in dendritic cell activation by Hemagglutinin B from Porphyromonas gingivalis. Mol Immunol 46:2493-504
Zhang, Ping; Lewis, Janina P; Michalek, Suzanne M et al. (2007) Role of CD80 and CD86 in host immune responses to the recombinant hemagglutinin domain of Porphyromonas gingivalis gingipain and in the adjuvanticity of cholera toxin B and monophosphoryl lipid A. Vaccine 25:6201-10
Katz, Jannet; Zhang, Ping; Martin, Michael et al. (2006) Toll-like receptor 2 is required for inflammatory responses to Francisella tularensis LVS. Infect Immun 74:2809-16
Salam, Mohammad Abdus; Katz, Jannet; Zhang, Ping et al. (2006) Immunogenicity of Salmonella vector vaccines expressing SBR of Streptococcus mutans under the control of a T7-nirB (dual) promoter system. Vaccine 24:5003-15
Zhang, Ping; Yang, Qiu-Bo; Balkovetz, Daniel F et al. (2005) Effectiveness of the B subunit of cholera toxin in potentiating immune responses to the recombinant hemagglutinin/adhesin domain of the gingipain Kgp from Porphyromonas gingivalis. Vaccine 23:4734-44
Zhang, Ping; Martin, Michael; Michalek, Suzanne M et al. (2005) Role of mitogen-activated protein kinases and NF-kappaB in the regulation of proinflammatory and anti-inflammatory cytokines by Porphyromonas gingivalis hemagglutinin B. Infect Immun 73:3990-8

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