Caroline Attardo Genco, Ph.D.

Professor of Medicine and MicrobiologyGenco
650 Albany Street
Office: X626; 617-414-5305
Lab: X-6; 617-414-5382
Caroline.Genco@bmc.org

B.S.  State University of New York at Fredonia
M.S. University of Rochester, School of Medicine and Dentistry
Ph.D. University of Rochester School of Medicine and Dentistry    

 

Innate Immune Responses to Mucosal Pathogens

We are examining the interactions of several mucosal pathogens with both phagocytic and non-phagocytic cells. Work with N. gonorrhoeae has established that distinct proinflammatory responses are observed in different compartments of the female lower genital tract (endocervical, ectocervical and vaginal cell lines). Using these cell lines we have demonstrated that infection with N. gonorrhoeae inhibits the apoptotic response of these cells. N. gonorrhoeae may thus establish infection by inhibiting the apoptotic response to infection, thereby resisting killing from both the host cell and the innate immune response. Current studies are focused on defining the role of toll-like receptors and intracellular signaling receptors in N. gonorrhoeae induced proinflammatory responses in epithelial cells. Work with P. gingivalis has demonstrated the invasive capabilities of these organisms for endothelial cells and has defined specific cell signaling pathways involved in this response. We have shown that 2 adhesins of this organism, the major and minor fimbriae proteins bind to and signal through TLR2 for an inflammatory response in human aortic endothelial cells. Furthermore both the major and minor fimbriae proteins can signal through TLR4 if the accessory proteins MD2 and CD14 are present. Our recent studies are focused on defining intracellular signaling receptors and pathways utilized by P. gingivalis to induce IL-1ß secretion in endothelial cells.

Regulatory Mechanisms in Bacterial Pathogens

This work is focused on understanding mechanisms utilized for bacterial colonization, and in particular in the ability of in vivo environmental factors to modulate bacterial gene expression. Transcriptional regulatory mechanisms have been defined on a global level in the pathogenic Neisseria species. We have established that the expression of virulence factors in these organisms is controlled by a global regulatory protein (ferric uptake regulator protein, Fur). We have established that the transcriptional regulatory protein Fur controls the expression of numerous genes that are required for the virulence of N. meningitidis and N. gonorrhoeae and have established that many of these genes are expressed in vivo during mucosal gonococcal infection in both men and women. Current studies are aimed at examining the regulation and expression of Fur-regulated genes in vitro, and in vivo directly in clinical specimens. We have also recently identified a novel mechanism for Fur-mediated regulation through small regulatory RNAs (sRNA) in both N. meningitidis and N. gonorrhoeae. We have established that in N. meningitidis the sRNA, NrrF functions independently of the cofactor RNA-binding protein, Hfq. Current studies are focused on defining how NrrF functions independently of Hfq and on identifying additional sRNAs using high-density oligonucleotide microarrays together with computational analysis.

Pathogen Induced Chronic Inflammatory Disorders

Chronic inflammation culminates in devastating events, results in significant host pathology, and is associated with a number of human diseases including autoimmune diseases, infectious diseases, neoplastic diseases, and inflammatory atherosclerosis. Our studies focus on two pathogens associated with chronic inflammation, Chlamydia pneumoniae and Porphyromonas gingivalis. C. pneumoniae is a respiratory pathogen that causes a mild, usually asymptomatic pneumonia. P. gingivalis induces a local host inflammatory response that results in inflammatory bone destruction, which is manifested as periodontal disease. Normally, the acute inflammatory response is self-limited, working to contain these infections until the adaptive immune response is activated. However, under some circumstances, a chronic inflammatory state can ensue, resulting in additional host pathology. Recently, both C. pneumoniae and P. gingivalis have been implicated in the pathogenesis of chronic inflammatory plaque formation although how these pathogens induce and maintain chronic inflammation is not well defined. Our laboratory has defined the role of specific innate immune signaling pathways in immune cells that contribute collectively to pathogen-induced chronic inflammation. We are examining in vitro model systems for platelets, endothelial cells, and macrophages. Using defined animal models of inflammation we are characterizing the roles of innate immune pathways in inflammatory processes in vivo. Enhanced understanding of the roles of specific innate immune signaling pathways, which participate in proinflammatory mediator expression and functional immune responses will provide a promising avenue for novel therapies for chronic inflammatory disorders.

Representative Publications

  1. Takahashi, Y., M. Davey, H. Yumoto, F.C. Gibson, and C.A. Genco. 2006. Fimbria-dependent activation of pro-inflammatory molecules in Porphyromonas gingivalis infected human aortic endothelial cells. Cell. Microbiol. 8:738-757.
  2. Liu, X, T. Olczak, H.C. Guo, D.W. Dixon, and C.A Genco. 2006. Identification of amino acid residues involved in heme binding and hemoprotein utilization in the Porphyromonas gingivalis heme receptor HmuR. Infect. Immun. 74:1222-1232.
  3. Bartolini, E., E. Frigimelica, Y. Shaik, G. Galli, J.A. Welsch, D.M. Granoff, C. Genco, G. Grandi, and R. Grifantini. 2006. Role of FNR and FNR-regulated, sugar fermentation genes in Neisseria meningitidis infection. Mol. Microbiol. 60:963-972.
  4. Mydel, P., Y. Takahashi, H. Yumoto, M. Sztukowska, M. Kubica, F.C. Gibson, D. Kurtz, J. Travis, C.A. Genco, and J. Potempa. 2006. Roles of the host oxidative immune response and the bacterial antioxidant, rubrerythrin during anaerobic infection. PLoS Pathog. 2:712-725.
  5. Al-Qutub, M.N, Braham, P.H., Karimi-Naser, K., Liu, X, Genco, C.A. and R.P. Darveau. 2006. Hemin-dependent modulation of the lipidA structure of Porphyromonas gingivalis lipopolysaccharide. Infect. Immun. 74: 4474-4485.
  6. Yazdani, B.S., S. Grogan, M. Davey, S. Sebastain, B. Szmigielski, and C.A. Genco. 2007. Expression of the iron-activated nspA and secY genes in Neisseria meningitidis group B by Fur-dependent and independent mechanisms. J. Bacteriol. 189:663-669.
  7. Mellin, J.R., S. Goswami, S. Grogan, B. Tjaden, and C.A. Genco. 2007. A novel Fur and iron-regulated small RNA, NerF, is required for indirect Fur-mediated regulation of the sdhA and sdhC genes in Neisseria meningitidis. J. Bacteriol. 189:3683-3694.
  8. Gibson, F.C. and C.A. Genco. 2007. Porphyromonas gingivalis mediated periodontal disease and atherosclerosis: Disparate disease with commonalities in pathogenesis through TLRs. Curr. Pharma. Des. 13:3665-3675.
  9. Liu, X., T. Ukai, H. Yumoto, M. Davey, F.C. Gibson, and C.A. Genco. 2008. Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids. Atherosclerosis. 196:146-154.
  10. Davey, M., X. Liu, T. Ukai, V. Jain, C. Gudino, F.C. Gibson III, D. Golenbock, A. Visintin, and C.A. Genco. 2008. Bacterial fimbriae stimulate proinflammatory activation in the endothelium through distinct TLRs. J. Immunol. 180: 2187-2195.
  11. Gibson III, F.C., T. Ukai, and C.A. Genco. 2008. Engagement of specific innate immune signaling pathways during Porphyromonas gingivalis induced chronic inflammation and atherosclerosis. Frontiers in Bioscience. 13: 2041-2059.
  12. Ukai, T., H. Yumoto, T. Miyamoto, F.C. Gibson III, and C.A. Genco. 2008. Macrophage-elicited osteoclastogenesis in response to bacterial stimulation requires Toll-like receptor 2 dependent tumor necrosis factor-alpha production. Infect. Immun. 76: 812-819.
  13. Isabella, V., L. F. Wright, K. Barth, J.M. Spence, S. Grogan, C.A. Genco, and V.L. Clark. 2008. cis- and trans-acting elements involved in regulation of norB (norZ), the gene encoding nitric oxide reductase in Neisseria gonorrhoeae. Microbiology 154:226-239.
  14. Agarwal, S., S. Sebastian, B. Szmigielski, P.A. Rice, and C.A. Genco. 2008. Expression of the gonococcal global regulatory Fur, and genes encompassing the Fur and iron regulon during in vitro and in vivo infection in women. J. Bacteriol. 190:3129-3139.
  15. Blair, P.S, S. Rex, O. Vitseva, L. Beaulieu, K. Tanriverdi, S. Chakrabarti, C. Hayashi, C.A. Genco, M. Iafrati, and J.E. Freedman. 2009. Stimulation of Toll-like receptor 2 in human platelets induces a thrombo-inflammatory response through activation of phosphoinositide 3-kinase. Cir. Res. 104: 346-354.
  16. Follows, S., J. Murlidharan, P. Massari, L.M. Wetzler, and C.A. Genco. 2009. Neisseria gonorrhoeae infection protects human cervical epithelial cells from apoptosis via expression of host anti-apoptotic proteins. Infect. Immun. 77:3602-3610.
  17. Hayashi, C.,Madrigal, A.G., X. Liu, T. Ukai, S. Goswami, C. Gudino, F.C. Gibson, and C.A. Genco. 2010. Pathogen mediated inflammatory atherosclerosis is mediated in part via TLR2 induced inflammatory responses. J. Innate Immunity. 2:334-343.
  18. Mellin, J.R., R. McClure, D. Lopez, O. Green, and C. Genco. 2010. Role of Hfq in iron dependent and independent gene regulation Neisseria meningitidis. Microbiol. 156:2316-2326.
  19. Hayashi, C., C. Gudino, F.C. Gibson, and C.A. Genco. 2010. Pathogen-induced chronic inflammation at sites distant from oral infection: Bacterial persistence and modulation of cell specific innate immune inflammatory pathways. Mol. Oral. Microbiol. 25: 305-316.
  20. Hayashi, C., J. Viereck, N. Hua, A.G. Madrigal, F.C. Gibson, J.A. Hamilton, and C.A. Genco. 2011. Porphyromonas gingivalis accelerates inflammatory atherosclerosis in the innominate artery of ApoE deficient mice. Atherosclerosis 215: 52-59.
  21. Lopez, C.A., G.G. Daaboul, S. Ahn, A. P. Reddington, M.R. Monroe, X. Zhang, R.J. Irani, C. Yu, C.A. Genco, M. Cretich, M. Chiari, B. B. Goldberg, J.H. Connor, and M. S. Ünlü. 2011. Biomolecular detection employing the Interferometric Reflectance Imaging Sensor (IRIS). J.Vis Exp 51:e2694.

 

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Primary teaching affiliate
of BU School of Medicine