|  Soman N. Abraham, Ph.D.
Soman N. Abraham, Ph.D.
Professor,
Director of Graduate Studies in Pathology
Departments of Pathology, Molecular Genetics and Microbiology, and Immunology
Duke University Medical Center
Box 3712
Durham, NC 27710
Phone: 919-684-3630
Fax: 919-684-2021
e-mail: soman.abraham@duke.edu Molecular Mechanisms of Host - Pathogen Cross-Talk
The last century is notable for the remarkable successes made in the area of antibiotic and vaccine development against infectious agents. However, as we begin this century, the singular most common cause of morbidity and mortality in man and animals is once again infectious diseases. With the anticipated growth in the aged and immunocompromised populations in our midst and the rapid emergence of multiresistant bacteria, there is an acute need for the development of alternate approaches to curb microbial infections and their harmful sequellae.
This laboratory is interested in developing innovative approaches for curbing microbial infections through the study of the molecular interactions occurring between pathogenic bacteria and prominent immune and epithelial cells. We believe that there is a significant amount of crosstalk occurring between bacteria and host cells during infection and that the outcome of this interaction dictates both how quickly the infection is cleared and the severity of the pathology associated with the infection. We also believe that through deciphering this crosstalk we should be able to selectively promote certain beneficial interactions while abrogating the harmful ones. In so doing, we hope to minimize the severity of the infection and achieve more rapid clearance of the pathogen.
There are two major research areas being pursued in this laboratory. The first is centered around elucidating how mast cells, frequently overlooked players in initiating and maintaining host immune responses, mobilize key components of the immune system during bacterial infections. Ultimately, the goal of these studies is to harness some of these activities attributed to mast cells for therapeutic or vaccine development purposes. The second area of research within our laboratory focuses on understanding how uropathogenic Escherichia coli, the overwhelmingly predominate causative agent of urinary tract infections, successfully gains entry into epithelial cells of the bladder to cause infection. This subject is especially intriguing because of the role the bladder plays as a reservoir for urine. Predictably the "water-tight" epithelial barrier of the bladder is especially difficult for bacteria to breech. Yet, E.coli, which compared to other pathogens have no specialized organelles for cell entry, appears to achieve this feat. We believe that by investigating the molecular events associated with the entry of E.coli into bladder epithelial cells and the resulting break down of the bladder barrier, we will be able to develop novel strategies to prevent these infections.
Other studies currently undertaken by one or more members of the laboratory include (i) examination of how particulate allergens interact with pulmonary mast cells to trigger air way hyperesponses and pulmonary inflammation. (ii) investigation of how, during infection, highly virulent pathogens such as Yersinia pestis, Salmonella typhimurium, etc., actively remodel the draining lymph nodes, the epicenter of the adaptive immune response (iii) investigation of how Pseudomonas aeruginosa co-opts cellular entities generally known as lipid rafts to colonize the airways.
Our studies are located at the intersection of cell biology, molecular biology, immunology and bacterial pathogenesis. Cumulatively, our studies should facilitate the design of innovative strategies to combat pathogens that selectively potentiate the hosts immune response without evoking some of its harmful side effects.
Movies 1 and 2 reveal morphological aspects of the interactions of mast cells with bacteria.
Christian Kunders Gallery of Microscopic Images
Selected Publications
Malaviya R, Ikeda T, Ross E, Abraham SN. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-a. Nature 1996. 381:77-80. [Abstract]
Baorto DM, Gao Z, Malaviya R, Dustin M, Van der Merwe A, Lublin D, Abraham SN: Survival of FimH-expressing Escherichia coli in macrophages by co-opting glycolipid trafficking. Nature 1997; 389:636-639. [Abstract]
Belaaouaj A, McCarthy R, Baumann M, Gao Z, Ley, TJ, Abraham S N, Shapiro SD. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nature Medicine. 1998, 4:615-618. [Abstract]
Malaviya R, Gao A, Thankavel K, van der Merwe A, and Abraham, SN. The mast cell TNF-_ response to FimHexpressing E. coli is mediated by the glycolphosphatidylinositol-anchored molecule, CD48. Proc Natl Acad Sci USA 1999;96:8110-8115. [Abstract]
Shin J. S, Gao Z, Abraham SN. Involvement of cellular caveolae in bacterial entry into mast cells. Science 2000;289(5480):785-8. [Abstract]
McLachlan JB, Hart JP, Pizzo SV, Staats, HF, Gunn MD and Abraham SN. TNF-_ From peripheral mast cells mediates hypertrophy of draining nodes during infection. Nature Immunology 2003, 4: 1199-1205. [Abstract]
Duncan M, Shin J-S, Carson J, Abraham SN. Bacterial penetration of bladder epithelium through lipid rafts. J Biol Chem. 2004 2004 279(18):18944-51. [Abstract]
Zaas, D, Duncan, MJ, Wright,JR, Abraham,SN. The role of lipid rafts in the pathogenesis of bacterial infections. 2005 Biochimica et Biophysica Acta 1746(3):305-13. [Abstract]
Shin J-S, Shelburne CP, Jin C, LeFurgey EA and Abraham SN. Harboring of Particulate Allergens within Secretory Compartments by Mast Cells Following IgE/FceRI-Lipid Raft Mediated Phagocytosis J. Immunol. 2006 179:5791-800. [Abstract]
Song J, Duncan M, Li G, Chen C, Grady R, Stapleton A, and Abraham SN. A Novel TLR4 Mediated Signaling Pathway Leading to IL-6 Responses in Human Bladder Epithelial Cells. PLoS Pathog 2007. [Abstract]
Bishop BL, Duncan MJ, Song J, Li G, Zaas DW, Abraham SN. Cyclic AMP regulated exocytosis of E.coli from infected Bladder Cells. Nature Medicine 2007 13 (5):625-30 [Abstract]
Song J, Bishop BL, Li G, Duncan MJ and Abraham SN. 2007. TLR4 initiated and cAMP mediated abrogation of bacterial invasion of the bladder. Cell Host & Microbe 2007 1: 287-298 [Abstract]
McLachlan JB, Shelburne CP, Hart JP, Pizzo SV, Goyal R, Brooking R, Staats HF and Abraham SN Mast cell activators: a new class of highly effective vaccine adjuvants. Nature Medicine. 2008 5:536-41. [Abstract]
Song J, and Abraham SN.TLR mediated immune responses in the urinary tract. Curr. Opin. Microbiol. 2008 11(1):66-73. [Abstract]
Zaas DW, Swan ZD, Brown BJ, Li G, Randell SH, Degan S, Sunday ME, Wright JR, Abraham SN.Counteracting signaling activities in lipid rafts associated with the invasion of lung epithelial cells by Pseudomonas aeruginosa.J Biol Chem. 2009 Feb 11. [Epub ahead of print] [Abstract] |