Associate Microbiologist, Department of Medicine
Brigham and Women's Hospital

atzianabos@channing.harvard.edu

Bacteroides fragilis
Bacteroides fragilis is the obligate anaerobe most frequently isolated from sites of intraabdominal infection. Studies from this laboratory have shown that the capsular polysaccharides of B. fragilis are the primary virulence determinants of this organism and modulate the development of abscess formation associated with experimental intraabdominal sepsis. B. fragilis has multiple capsules that each possess a zwitterionic charge motif. This motif is critical to the modulation of abscess formation in vivo. Further studies have shown that the biologic basis for this activity is dependent on the interaction of these polysaccharides with CD4+ T cells and the subsequent release of cytokines and chemokines. Currently, our studies are directed toward understanding the: 1) molecular interaction of these polysaccharides with CD4+ T cells that leads to T cell activation and cytokine production and 2) immunologic basis for T cell regulation of abscess formation.

Staphylococcus aureus
Staphylococcus aureus is an opportunistic bacterial pathogen responsible for a diverse spectrum of human and animal diseases, including wound infections, osteomyelitis, endocarditis, and bacteremia leading to secondary abscesses in any of the major organ systems. Currently, the host response to this organism is poorly understood. In collaboration with Dr. Jean Lee's laboratory, we have shown that the staphylococcus produces a capsule with a zwitterionic charge motif that mediates its pathogenic potential in an experimental model of intraabdominal abscess formation. This activity is dependent on CD4+ T cells. In addition, the capsule of S. aureus can activate CD4+ T cells and induce the production of CXC chemokines (peptides that activate and recruit PMNs to sites of inflammation). Based on these data, we are investigating if CD4+ T cell activation by S. aureus capsules is critical in determining the outcome of staphylococcal infections through the release of CXC chemokines that control PMN trafficking to infected sites. This will accomplished via the use of clinically relevant, low-inoculum murine models of staphylococcal infection that mimic important aspects of human disease. The goal of these studies is to determine the role of T cells in the pathogenesis of S. aureus infections.

Role of T cells in Surgical Adhesion Formation
Adhesion formation associated with abdominal and gynecologic surgical procedures causes severe morbidity and can result in serious life-threatening complications such as intestinal obstruction and organ failure. In addition, these structures are also a major cause of infertility and chronic pelvic pain in women. Adhesions develop as a result of surgical trauma or bacterial infection. Currently, a limited number of therapeutic options are available to prevent the development of surgical adhesions. We have shown that CD4+ T cells are critical to the development of abdominal surgical adhesions in two different animal models of this host response. These data are the first to show a role for this cell type in adhesiogenesis. We are currently investigating the cellular basis for this host response and the role of T cell-derived cytokines and chemokines in adhesiogenesis. These studies should reveal a deeper understanding of the immunologic mechanisms underlying the development of surgical adhesions and identify new cellular and sub-cellular targets for the development of compounds that can be used for their prevention.

Selected Publications

Tzianabos AO, Pantosti A, Baumann H, Brisson JR, Jennings HJ, Kasper DL. The capsular polysaccharide of Bacteriodes fragilis comprises two ionically linked polysaccharides. J Biol Chem 1992;267:18230-18235. [abstract]

Tzianabos AO, Onderdonk AB, Rosner B, Cisneros RL, Kasper DL. Structural features of polysaccharides that induce intra-abdominal abscesses. Science 1993;262:416-419. [abstract]

Tzianabos AO, Onderdonk AB, Zaleznik DF, Smith RS, Kasper DL. Structural characteristics of polysaccharides that induce protection against intra-abdominal abscess formation. Infect Immun 1994;62:4881-4886. [abstract]

Tzianabos AO, Kasper DL, Cisneros RL, Smith RS, Onderdonk AB. Polysaccharide-mediated protection against abscess formation in experimental intra-abdominal sepsis. J Clin Invest 1995;96:2727-2731. [abstract]

Gibson FC, Onderdonk AB, Kasper DL, Tzianabos AO. Cellular mechanism of abscess formation by Bacteroides fragilis. J Immun 1998;160:5000-5006. [abstract]

Tzianabos AO, Russell P, Onderdonk AB, Gibson III FC, Cywes C, Chan M, Finberg RW, Kasper DL. IL-2 mediates protection against abscess formation in an experimental model of sepsis. J Immunol 1999; 163:893-897. [abstract]

Tzianabos AO, Finberg RW, Wang Y, Chan M, Onderdonk AB, Jennings HJ , Kasper DL. T cells activated by zwitterionic molecules prevent abscesses induced by pathogenic bacteria. J Biol Chem 2000; 275:6733-6740. [abstract]

Tzianabos AO, Chandraker A, Kalka-Moll W, Stingele F, Dong V, Finberg RW, Peach R, Sayegh MH. Intraabdominal abscess formation induced by bacterial pathogens requires T cells activated by the CD28/B7 T cell costimulatory pathway. Infect Immun 2000; 68:6650-6655. [abstract]

Tzianabos AO. Polysaccharide immunomodulators as therapeutic agents: structural aspects and biologic function. Clin Microbiol Rev. 2000; 13:523-33. [abstract]

Tzianabos AO, Wang Y, Lee JC. Structural rationale for the modulation of abscess formation by Staphylococcus aureus capsular polysaccharides. Proc Natl Acad Sci U S A 2001; 98:9365-70. [abstract]