David Relman

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David Relman, Assistant Professor Medicine, Division of Infectious Diseases; Microbiology and Immunology Veterans Administration Medical Center Palo Alto, CA, Tel: (650) 852-3308 or (650) 493-5000, ext. 3308, 3193 FAX: (650) 852-3291;
Email: relman@cmgm.stanford.edu

Research Program:
David A. Relman; Departments of Medicine, and Microbiology & Immunology

My investigative program falls within the general theme of microbial pathogenesis, and is divided into two research areas: 1) Molecular mechanisms of Bordetella pertussis adherence and host colonization; and 2) Use of molecular methods for microbial pathogen discovery.

1. B. pertussis, the causative agent of whooping cough, utilizes a pathogenic strategy that depends upon adherence to host cells and tissues, and the subsequent release of cytotoxic and immunomodulatory molecules. B. pertussis and the other bordetellae mimic and subvert host adherence mechanisms and related signaling pathways. Our work focusses on B. pertussis filamentous hemagglutinin (FHA), a surface-associated and secreted protein which is the dominant adherence factor. Leukocyte integrins recognize FHA and mediate Bordetella binding to monocytes and macrophages. In addition, we have discovered that an FHA RGD site induces monocyte b3-b2 integrin signaling through a pathway involving PI3-kinase, and by so doing, up-regulates its own binding to these cells. We believe that B. pertussis subverts host cellular immune responses by binding to leukocyte integrins and delivering potent immunomodulatory toxins. B. pertussis persistence in the host may be one outcome. In support of this theory, our data indicate that B. pertussis inhibits antigen-dependent CD4 T-cell proliferative responses in vitro, via FHA-mediated attachment and delivery of bacterial adenylate cyclase toxin. B. pertussis-host cell interactions may serve as a model for understanding integrin-ligand recognition, integrin-integrin signaling, and bacterial subversion of host cellular immune responses. Current ongoing projects include the following:

*Structure-function analysis of B. pertussis and B. bronchiseptica FHA, and leukocyte integrin binding domains.
*Delineation of monocyte integrin-associated signaling pathways involved in B. pertussis FHA-mediated bacterial attachment to these cells.
*Characterization of T-cell subsets that recognize B. pertussis in immune hosts
*Identification of differentially-regulated B. pertussis and monocyte genes involved in bacterial attachment to monocytes, subsequent cellular responses, and in colonization of the host respiratory tract.

Selected References

Relman DA. "Bordetella pertussis : Determinants of Virulence". In: Moss J, Iglewski B, Vaughan M, Tu AT (eds), Handbook of Natural Toxins, Vol. 8-Bacterial Toxins and Virulence Factors in Disease, Marcel Dekker, Inc., New York, 1995, pp. 367-405.

Ishibashi Y, Claus S, Relman DA. Bordetella pertussis filamentous hemagglutinin interacts with a leukocyte signal transduction complex and stimulates bacterial adherence to monocyte CR3 (CD11b/CD18). J Exp Med 1994; 180:1225-33.

Boschwitz JS, Batanghari JW, Kedem H, Relman DA. Bordetella pertussis inhibits human monocyte-dependent CD4 T cell proliferation to tetanus toxoid. J Infect Dis 1997; in press.

2. Traditional culture-dependent methods have failed to identify or detect a number of important microbial pathogens; these methods have provided a biased picture of microbial diversity. We have developed alternative approaches for the identification of previously-ignored organisms based on consensus PCR amplification of phylogenetically-useful microbial sequences (e.g. rDNA) directly from infected tissues and other clinical specimens. The agents of bacillary angiomatosis and Whipple's disease are examples of bacterial pathogens successfully characterized with these methods. We are now looking for previously-uncharacterized microbial pathogens that might be associated with a variety of chronic idiopathic diseases. Alternative experimental approaches include representational difference analysis. We are interested in gaining a more accurate sense of the diversity of microorganisms that are responsible for human disease. Current ongoing projects include the following:

*Further characterization of the uncultivated bacillus associated with Whipple's disease
*Identification of novel, previously-uncharacterized fungal and protozoan pathogens by means of tissue-based consensus PCR approaches.
*Identification and characterization of microbial pathogens associated with chronic inflammatory disorders.
*Analysis of genetic diversity within the human intestinal coccidian pathogen, Cyclospora, and related organisms
*Sequence-based analysis of bacterial diversity within the human subgingival crevice.

Selected References

Relman DA, Schmidt TM, Gajadhar A, Sogin M, Cross J, Yoder K, Sethabutr O, Echeverria P. Molecular phylogenetic analysis of Cyclospora, the human intestinal pathogen, suggests that it is closely related to Eimeria species. J Infect Dis 1996; 173:440-5.

Santamaria-Fries M, Fajardo LF, Sogin ML, Olson P, Relman DA. Lethal infection by a previously-unclassified metazoan parasite. Lancet 1996; 347:1797-1801.

Fredricks DN, Relman DA. Sequence-based identification of microbial pathogens: A reconsideration of Koch's postulates. Clin Microbiol Rev 1996; 9:18-33.

For more detailed information, you can visit the Relman Lab Home Page.

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