"Training the next generation of scientists is one of my greatest pleasures. It is so exciting to see a student move from the initial stage of struggling to make the simplest assay work in the lab to the advanced stage of skillfully defining the direction of their project and using novel methods to achieve answers to challenging research questions. It is my sincere hope that during a student's tenure in my lab, the student and I establish a bond that will continue in the years to come."
Activation of inflammatory cells by gram-negative flagellin Activation of the innate immune response by bacteria is mediated by a group of molecules that have collectively been termed modulins. These surface-associated molecules are produced by a broad array of microbial pathogens. Monocytes, macrophages, neutrophils and epithelial cells respond to modulins by producing proinflammatory cytokines. Dr. Mizel has demonstrated that flagella from a number of gram-negative bacterial species induce proinflammatory cytokine production by monocytes and intestinal epithelial cells. He also demonstrated that the major structural protein of the flagella, flagellin, is the component required for the induction of cytokine synthesis. Flagellin signaling is mediated by a toll-like receptor (TLR) protein, TLR5, but can be modulated by another TLR,
TLR4. In view of the extraordinary potency of flagellin as an activator of cells that are involved in host defense, Dr. Mizel is focusing on the following specific aims: 1) To determine the components and pathways that are required for TLR5-dependent flagellin signal transduction and 2) To determine the mechanism by which flagellin induces a subsequent state of flagellin tolerance. Responsiveness to flagellin can be influenced by several factors including flagellin itself. Cells that are exposed to flagellin become insensitive to secondary stimulation by flagellin. This lack of responsiveness is associated with a dramatic decrease in IRAK kinase activity. This decrease in IRAK activity is not due to a decrease in the level of the IRAK protein. Other investigators have established that exposure of monocytes to LPS also results in a state of LPS non-responsiveness. LPS tolerant cells also exhibit a very low level of flagellin responsiveness. However, flagellin tolerant cells are fully responsive to LPS. Dr. Mizel is in the process of determining the mechanism for this effect of flagellin since it has important implications with regard to the host response to flagellin. These should provide insights into the factors that regulate TLR signaling and allow for complex patterns of host cell response. |
Recent Publications (selected):
Moors, MA, Liwu, L, Mizel SB. Activation of IL-1 receptor-associated kinase by gram- negative flagellin. Infect. Immun., 69:4424-4429, 2001.
McDermott, PF, Ciacci-Woolwine F, Snipes, JA, Mizel SB. High affinity interaction between gram-negative flagellin and a cell surface polypeptide results in human monocyte activation. Infect. Immun., 68:5525-5529, 2000.
Ciacci-Woolwine F, McDermott PF, Mizel SB.: Induction of cytokine synthesis by flagella from gram-negative bacteria may be dependent on the activation or differentiation state of human monocytes. Infect. Immun. 67:5176-85 (1999).
Ciacci-Woolwine F, Blomfield IC, Richardson SH, Mizel SB.: Salmonella flagellin induces tumor necrosis factor alpha in a human promonocytic cell line. Infect. Immun. 66:1127-34 (1998). |