Gram negative anaerobic bacteria are the major etiological agents of periodontal diseases. In addition, they have been shown to be associated with other health complications such as cardiovascular diseases, diabetes, and preterm low birth weight babies. Both P. gingivalis and Prev. intermedia lack the capacity to synthesize hemin and must acquire the nutrient from the environment. Despite the importance of hemin acquisition in the periodontopathogens, major gaps in knowledge exist regarding the mechanisms of uptake and regulation of the nutrient. Several loci encoding hemin transport proteins have been identified on the genome of P. gingivalis W83;however, the contribution of these loci to hemin uptake in this organism remains unknown. Also, the role of the proteins encoded by the loci is not well defined. We have identified an operon, hmuYRSTUV, required for growth of P. gingivalis with hemoglobin-haptoglobin complexes as a hemin source. A homolog of the operon is also present on the genome of other Gram-negative anaerobic bacteria including Prev. intermedia 17. Our preliminary data indicate that the hmu operon is iron regulated. Although the ferric uptake regulator, Fur, was demonstrated to regulate the expression of hemin uptake loci in variety of bacteria, our preliminary studies show the peroxide responsive regulator, OxyR, plays a role in regulation of expression of the hmu locus. Thus, first we will characterize the OxyR-mediated mechanism of regulation. Second, we will further define the role of the hmu locus in hemin uptake in P. gingivalis. We will start our characterization from comparison of the role of the hmu locus with the other two hemin uptake loci, iht and tlr, present on the genome of P. gingivalis W83 in hemin uptake in this organism. Next, we will test the hypothesis that the hmu operon is an important hemin acquisition mechanism in both periodontopathogens and encodes proteins necessary to extract the hemin molecule from host hemoproteins and transport the hemin across both membranes (into the cytoplasm). Thus we will determine the cellular location of the hmu - encoded proteins, examine the ability of the proteins to interact with each other and with other proteins, and define the contribution of proteins encoded by the locus to hemin uptake in P. gingivalis W83. Lastly, to broaden our understanding of the role of hemin in virulence of P. gingivalis, we will examine the role of hemin and hemoproteins on gene expression in this bacterium.

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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Lunsford, Dwayne
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Virginia Commonwealth University
Schools of Dentistry
United States
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Wunsch, Christopher M; Lewis, Janina P (2015) Porphyromonas gingivalis as a Model Organism for Assessing Interaction of Anaerobic Bacteria with Host Cells. J Vis Exp :e53408
Anaya-Bergman, C; Rosato, A; Lewis, J P (2015) Iron- and hemin-dependent gene expression of Porphyromonas gingivalis. Mol Oral Microbiol 30:39-61
Sengupta, Dipanwita; Kang, Dae-Joong; Anaya-Bergman, Cecilia et al. (2014) Interaction of Prevotella intermedia strain 17 leucine-rich repeat domain protein AdpF with eukaryotic cells promotes bacterial internalization. Infect Immun 82:2637-48
Svintradze, David V; Peterson, Darrell L; Collazo-Santiago, Evys A et al. (2013) Structures of the Porphyromonas gingivalis OxyR regulatory domain explain differences in expression of the OxyR regulon in Escherichia coli and P. gingivalis. Acta Crystallogr D Biol Crystallogr 69:2091-103
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Singh, Amrita; Wyant, Tiana; Anaya-Bergman, Cecilia et al. (2011) The capsule of Porphyromonas gingivalis leads to a reduction in the host inflammatory response, evasion of phagocytosis, and increase in virulence. Infect Immun 79:4533-42
Lewis, Janina P (2010) Metal uptake in host-pathogen interactions: role of iron in Porphyromonas gingivalis interactions with host organisms. Periodontol 2000 52:94-116
Iyer, Divya; Anaya-Bergman, Cecilia; Jones, Kevin et al. (2010) AdpC is a Prevotella intermedia 17 leucine-rich repeat internalin-like protein. Infect Immun 78:2385-96
Anaya-Bergman, Cecilia; He, Jia; Jones, Kevin et al. (2010) Porphyromonas gingivalis ferrous iron transporter FeoB1 influences sensitivity to oxidative stress. Infect Immun 78:688-96

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