Development of bacterial vaccines; role of Gram-negative bacterial lipopolysaccharide (LPS) in innate immunity; host defense mechanisms against bacterial infections; role of sialidase (neuraminidase) in the inflammatory process; clinical trials in immunocompromised hosts.
Our earlier work showed that pro-inflammatory cytokines such as interferon-gamma and tumor necrosis factor-alpha are required for normal host defenses against Gram-negative bacterial infections. We now are investigating the regulatory mechanisms of cytokine expression that become altered when a beneficial response to LPS which induces these cytokines degenerates into a septic response. The inner core region of LPS is widely conserved among heterologous species of Gram-negative bacteria. Consequently, we have developed a vaccine from LPS against one such epitope for use in the prevention and/or treatment of sepsis in humans. Our laboratory is examining the utility of different adjuvants to enhance the anti-LPS antibody response, and is defining the mechanisms by which this vaccine protects against lethal sepsis in animal models. We previously observed that a neutrophil-associated sialidase which removes sialyl residues from its own and adjacent cell surfaces has an important role in neutrophil trafficking in vivo and in neutrophil/endothelial cell interactions in vitro. The laboratory is now defining the specific mechanisms by which the enzyme is regulated. Clinical trials at the Greenebaum Cancer Center not only involve participation in multi-center studies of novel antimicrobial agents, but also in our own protocols that examine immune reconstitution in patients undergoing therapy for malignancies, including stem cell transplantation.
Cross A, Asher L, Seguin M, Yuan L, Kelly N, Hammack C, Sadoff J and Gemski, Jr P. The importance of a lipopolysaccharide-initiated, cytokine-mediated host defense mechanism in mice against extraintestinally invasive Escherichia coli. J. Clin. Invest. 1995; 96:676-686.
Bhattacharjee A, Opal SM, Taylor R, Naso R, Semenuk M, Zollinger WD, Moran EE, Young L, Hammack C, Sadoff JC, and Cross AS. A non-covalent complex vaccine prepared with detoxified Escherichia coli J5 (Rc chemotype) lipopolysaccharide and Neisseria meningitidis group B outer membrane protein produces protective antibodies against Gram-negative bacteremia. J. Infect. Dis. 1996; 173:1157-1163.
Stamatos NM, Gomatos PJ, Cox J, Nelson S, Fowler A, Dow N, Wohlheiter JA, Cross AS. Desialylation of peripheral blood mononuclear cells promotes growth of HIV-1. Virology 1997; 228:123-131.
Held TK, Mielke MEA, Chedid M, Unger M, Trautmann M, Huhn D, Cross AS. G-CSF worsens the outcome of experimental Klebsiella pneumoniae pneumonia through direct interaction with the bacteria. Blood 1998; 91:2525-2535.
Held TK, Weihua X, Yuan L, Kalvakolanu DV, Cross AS. Interferon- augments macrophage activation by LPS by two distinct mechanisms: at the signal transduction level and via an autocrine mechanism involving TNF-? and IL-1. Infection and Immunity 1999; 67:206-212.