Richard J. Lamont, PhD

Richard J. Lamont, PhD

Richard J. Lamont, PhD

Richard J. Lamont

Delta Dental Endowed Professor

Chair, Oral Immunology and Infectious Diseases

Room 221B, Baxter I

Phone: 502 852 2112

email:rich.lamont@louisville.edu

Research Interests:

The oral cavity is a complex ecosystem that is home to a diverse assemblage of bacteria with a spectrum of pathogenic potentials.  On tooth surfaces these organisms assemble into a complex multispecies biofilm community, commonly known as dental plaque.  Community formation is a dynamic process involving attachment of bacteria to oral surfaces, cohesion and communication among constituent organisms, and adaptation to the biofilm environment.  The composition and metabolic status of the resulting community determines whether the biofilm exists in commensal harmony with the host, or becomes a precursor to caries and periodontal disease, two of the most common bacterial diseases of humans.

Major Projects

1.  Molecular and cellular dialog between Porphyromonas gingivalis and gingival epithelial cells (GECs). 

In the latter decades of the 20th century the scientific community began to appreciate that epithelial cells are not simply a passive barrier to microbial intrusion, but rather constitute an interactive interface that can sense the presence of bacteria and signal their presence to underlying immune cells.  Colonizing bacteria, SerB for their part, can subvert host cell signaling systems to direct their uptake into the otherwise non-professionally phagocytic epithelial cells, and to manipulate host cell physiology.  My group was among the first to show that P. gingivalis actively invades epithelial cells, which we established in a novel model system utilizing primary cultures of GECs.  Dissection of the molecular and cellular dialog between P. gingivalis and GECs then became a major research focus. We have found that internalization of P. gingivalis is effectuated by a limited number of functionally versatile invasins, including the FimA fimbriae and the serine phosphatase SerB, which impact cytoskeletal integrity and thus allow bacteria entry.  Co-habiting bacteria and GECs remain viable and adaptation of both cell types involves major changes in the transcriptome and expressed proteome.  Phenotypic consequences for the host cell  include disruption of cytokine signaling (see 2. below) along suppression of apoptotic cell death pathways, acceleration through the cell cycle and initiation of the epithelial-mesenchymal transition.  Collectively, this work defined a new aspect of the P. gingivalis-host interaction with relevance for homeostatic imbalance, long term P. gingivalis survival in the host, and recrudescence of infection.

  1. Sztukowska MN, Ojo A, Ahmed S, Carenbauer AL, Wang Q, Shumway B, Jenkinson HF, Wang H, Darling DS, Lamont RJ. 2016.  Porphyromonas gingivalis initiates a mesenchymal-like transition through ZEB1 in gingival epithelial cells. Cell Microbiol 18:844-858. PMC5135094
  2. Wang Q, Sztukowska M, Ojo A, Scott DA, Lamont RJ, Wang H. 2015. FOXO responses to Porphyromonas gingivalis in epithelial cells. Cell Microbiol 17:1605-1617.  PMC4624012
  3. Moffatt CE, Inaba H, Hirano T, Lamont RJ.  2012.  Porphyromonas gingivalis SerB-mediated dephosphorylation of host cell cofilin modulates invasion efficiency. Cell Microbiol 14:577-588.  PMC3449298
  4. Tribble GD, Mao S, James CE, Lamont RJ. 2006. A Porphyromonas gingivalis haloacid dehalogenase family phosphatase interacts with human phosphoproteins and is important for invasion. Proc Natl Acad Sci U S A 103:11027-11032.


2.  Local chemokine paralysis induced by P. gingivalis.

P. gingivalis exhibits a ‘dual personality’ in terms of host innate immunity, inducing both pro- and anti- inflammatory responses in a context dependent manner.  One major anti-inflammatory property is the suppression of the neutrophil and T-cell chemokines in GECs even in the presence of otherwise stimulatory bacteria.  We discovered this phenomenon in collaboration with Dr. Darveau’s group and coined the phrase ‘local chemokine paralysis’.  Subsequently my group discovered the molecular mechanism for antagonism of IL-8 production by GECs.  The SerB serine phosphatase is secreted within epithelial cells by P. gingivalis and specifically dephosphorylates the P65 subunits of the transcription factor NF-κB.  This prevents nuclear translocation of NF-κB P65 homodimers and thus reduces expression of the IL8 gene.  Local chemokine paralysis induced by P. gingivalis SerB, even if transient, could have a significant impact on immune status in the gingival crevice where microbial stimulation is constant and neutrophils are necessary to constrain the microbial challenge.  Indeed, we found that oral infection of mice with a SerB mutant of P. gingivalis resulted in less bone loss and more neutrophil recruitment in the periodontal tissues compared to infection with the parental strain. 

  1. Takeuchi H, Hirano T, Whitmore SE, Morisakai I, Amano A, Lamont RJ. 2013. The serine phosphatase SerB of Porphyromonas gingivalis suppresses IL-8 production by dephosphorylation of NF-κB RelA/p65. PLoS Pathog 9:e1003326.  PMC3630210
  2. Jauregui CE, Wang Q, Wright CJ, Takeuchi H, Uriarte SM, Lamont RJ. 2013.  Suppression of T-cell chemokines by Porphyromonas gingivalis. Infect Immun 81:2288-2295.  PMC3697598
  3. Bainbridge B, Verma RK, Eastman C, Yehia B, Rivera M, Moffatt C, Bhattacharyya I, Lamont RJ, Kesavalu L. 2010.  Role of Porphyromonas gingivalis phosphoserine phosphatase enzyme SerB in inflammation, immune response, and induction of alveolar bone resorption in rats. Infect Immun 78:4560-4569.  PMC2976320
  4. Darveau R, Belton CM, Reife R, Lamont RJ. 1998.  Local chemokine paralysis: a novel mechanism of bacterial persistence.  Infect Immun 66:1660-1665.  PMC108102

 

3.  P. gingivalis assembles into communities with antecedent colonizers

Work from the Kolenbrander lab and others had shown that oral bacteria form interspecies networks of coaggregated organisms.  Landmark studies by Slots  and Gibbons demonstrated that initial colonization of plaque by P. gingivalis requires attachment to antecedent streptococcal colonizers, and close association of P. gingivalis with streptococci has been corroborated by more recent imaging studies.  In collaboration with Dr. Demuth, we have defined P. gingivalis-S. gordonii interacting adhesinsand their functional domains.  Moreover, our group was among the pioneers of the field of sociomicrobiology: the investigation of the communication and synergy that occurs among groups of physiologically compatible organisms in communities.  We have defined chemical communication (based on AI-2) and contact dependent communication (based on a cascade of protein tyrosine phosphorylation and dephosphorylation events) between P. gingivalis and S. gordonii.  The importance of this interaction in vivo was demonstrated by our finding that communities of P. gingivalis and S. gordonii cause more  alveolar bone loss in mice compared to infection with either species alone and moreover, inhibition of coadhesion prevents community-mediated bone loss.  Hence this work has identified additional targets for potential therapeutic intervention to inhibit P. gingivalis colonization and the transition of the plaque biofilm to a pathogenic entity. 

  1. Wright CJ, Xue P, Hirano T, Liu C, Whitmore SE, Hackett M, Lamont RJ. 2014. Characterization of a bacterial tyrosine kinase in Porphyromonas gingivalis involved in polymicrobial synergy. MicrobiologyOpen 3:383-394. PMC4082711
  2. Chawla A, Hirano T, Bainbridge BW, Demuth DR, Xie H, Lamont RJ. 2010.  Community signalling between Streptococcus gordonii and Porphyromonas gingivalis is controlled by the transcriptional regulator CdhR.  Mol Microbiol 78:1510-1522.  PMC3017474
  3. Maeda K, Tribble GT, Tucker CM, Anaya C, Shizukuishi S, Lewis JP, Demuth DR, Lamont RJ. 2008. A Porphyromonas gingivalis tyrosine phosphatase is a multifunctional regulator of virulence attributes.  Mol Microbiol 69:1153-1164.  PMC2537464
  4. Daep CA, Novak EA, Lamont RJ, Demuth DR. 2011. Structural dissection and in vivo effectiveness of a peptide inhibitor of Porphyromonas gingivalis adherence to Streptococcus gordonii. Infect Immun.79:67-74.


4.  Establishing the pathogenic credentials of Filifactor alocis. 

The oral microbiome project has identified a number of as yet uncultivable, and difficult to culture, organisms with as strong an association with periodontal  disease as the ‘classical’ pathogens such as P. gingivalis.  The challenge now is to determine whether such organisms are active pathogens or more passively associated with the inflammatory environment of periodontal lesions.  We have focused our attention on the Gram-positive organism F. alocis which is present in high numbers in periodontitis, and we are investigating its interactions with other periodontal bacteria, epithelial cells, and neutrophils, and its pathogenic properties in animal models. 

  1. Armstrong CL, Miralda I, Neff AC, Tian S, Vashishta A, Perez L, Le J, Lamont RJ, Uriarte SM. 2016. Filifactor alocis promotes neutrophil degranulation and chemotactic activity. Infect Immun 84:3423-3433.
  2. Wang Q, Jotwani R, Le J, Krauss JL, Potempa J, Coventry SC, Uriarte SM, Lamont RJ.  2014.  Filifactor alocis infection and inflammatory responses in the mouse subcutaneous chamber model.  Infect Immun 82:1205-1212.  PMC3957978
  3. Wang Q, Wright CJ, Dingming H, Uriarte SM,Lamont RJ. 2013.  Oral community interactions of Filifactor alocis in vitro.  PLoS One e76271.  PMC3789735
  4. Moffatt CE, Whitmore SE, Griffen AL, Leys EJ, Lamont RJ. 2011.  Filifactor alocis interactions with gingival epithelial cells.  Mol Oral Microbiol 26:365-373.  PMC3248241


5.  Formulating a new model of periodontal disease pathogenesis

In collaboration with Dr. Hajishengallis, and to draw all the above concepts together in combination with Dr. Hajishengallis’ conceptual advances, we have proposed a theory of periodontal disease pathogenesis based on polymicrobial synergy and dysbiosis (PSD).  The PSD model holds that periodontal disease ensues from the action of a polymicrobial community in which pathogenicity is defined by interactions among functionally specialized organisms including keystone pathogens and accessory pathogens.  Pathogenic communities then induce dysbiotic host responses which fail to control the microbial challenge and contribute to tissue destruction.  The original paper describing the PSD model has been cited over 145 times since 2012.  We are currently pursuing testable predictions based on this model which we believe will significantly advance the field. 

  1. Hajishengallis G, Lamont RJ. 2016. Dancing with the Stars: How Choreographed Bacterial Interactions Dictate Nososymbiocity and Give Rise to Keystone Pathogens, Accessory Pathogens, and Pathobionts. Trends Microbiol 24:477-489.   PMC4874887
  2. Lamont RJ, Hajishengallis G. 2015. Polymicrobial synergy and dysbiosis in inflammatory disease. Trends Mol Med 21: 172-183.   PMC4352384
  3. Hajishengallis G, Lamont RJ. 2014.  Breaking bad: manipulation of the host response by Porphyromonas gingivalis.  Eur J Immunol 44:328-338. PMC3925422
  4. Hajishengallis G, Lamont RJ. 2012. Beyond the red complex and into more complexity: the polymicrobial synergy and dysbiosis (PSD) model of periodontal disease etiology. Mol Oral Microbiol 27:409-419.  PMC3653317

 

Complete List of Published Work in MyBibliography

http://www.ncbi.nlm.nih.gov/sites/myncbi/richard.lamont.1/bibliography/40472917/public/?sort=date&direction=ascending