Richard I. Tapping
Assistant Professor of
Microbiology
tapping@life.uiuc.edu
B.S. (Biochemistry), University of
Waterloo, Canada, 1987
Ph.D. (Biochemistry), McMaster University, Canada, 1995
Postdoctoral (Immunology), Scripps Research Institute,
1995-1999
Senior Research Associate (Immunology), Scripps Research
Institute, 1999-2002
The Role of Toll-like Receptors in Host Innate Immune Defense
The innate immune system is the first line of host defense to a variety of pathogens. To be effective, all pathogens must overcome the physical and chemical barriers of the innate immune system as well as cellular responses that occur immediately following infection. In addition to providing immediate protection for the host, a rapid innate immune response serves to initiate antigen presentation leading to adaptive responses and immunologic memory. The ability of host cells to sense and respond to infection is dependent upon a number of secreted and cell associated molecules of the innate immune system. Research in my laboratory is focused on a family of cell surface molecules called Toll-like receptors (TLRs) that are central elements of this innate immune recognition system.
The essential role of TLRs in immune defense was first appreciated in Drosophila. This function appears to have been maintained throughout evolution and even exists as a component of host defense against pathogens in plants. This illustrates the ancient origins of innate immunity. In humans at least ten functional TLR family members exist and these are sequentially numbered from 1 to 10. All TLRs are transmembrane receptors whose extracellular domain mediates recognition of conserved structural components of viruses, microbes, or fungi. For example, the agonists for mammalian TLRs 3, 4 and 5 include molecules such as double stranded RNA intermediates of viral replication, lipopolysaccharide of Gram-negative enteric bacteria, and bacterial flagellin, respectively (see figure). The intracellular domain of each TLR initiates signaling events in response to these stimuli which culminate in proinflammatory gene expression.
Subsets of TLRs are expressed in a variety of cell types and have been shown to be central for enabling epithelial cells, endothelial cells and a number of leukocytes to respond to infection. TLRs figure prominently in enabling neutrophils and macrophages to kill their intracellular cargo following phagocytosis and initiating the cellular release of mediators that facilitate local inflammation. Most notably, the engagement of TLRs on dendritic cells is central to driving their maturation and their eventual presentation of antigen in secondary lymphoid tissues. B cell responses are also dependent upon engagement of TLRs. Given their central role in initiating these events, it is not surprising that TLR function is directly associated with a variety of inflammatory disorders ranging from sepsis, atherosclerosis, asthma, and certain autoimmune disorders such as lupus.
Despite many rapid advances in this field, the ligands for many TLRs and the mechanism by which TLRs recognize microbial products and initiate intracellular signaling remain ill defined. Research in our lab is currently focused on a subfamily of TLRs including TLR2 and other phylogenetically related TLR members, namely TLRs 1, 6 and 10. TLR2 is unique among mammalian TLRs in possessing the ability to mediate responses to wide variety of microbial and fungal components. Additionally TLR2 is unique in its need to associate with other related TLRs in order to function.
Our investigation of this TLR2 subfamily aims to:
- Better define the microbial ligands and extracellular domains of the receptors involved in recognition.
- Determine the molecular mechanisms by which cellular responses are initiated.
- Characterize the regulation of TLR expression and their intracellular trafficking.
- Assess the biological role of these receptors using TLR deficient mice.
- Identify and characterize single nucleotide polymorphisms within the human population that are important for TLR function.
Our research utilizes a combination of molecular biology, cellular biology, cellular imaging and immunologic techniques within the context of experimentally manipulated cell lines, murine models, as well as immune cells derived from human peripheral blood. As TLRs are central to initiating both an immediate inflammatory response as well as cellular processes leading to adaptive immunity, this research has many practical clinical implications. The most direct is the rational design of methods to control a variety of acute and chronic inflammatory conditions as well as the rational design of more effective vaccine adjuvants. Research in my laboratory attempts to address the core question of how the innate immune system ultimately senses the presence of infection and defines the type of invading pathogen. This question is central to understanding the pathogenesis of a wide variety of deleterious immune conditions.
Omueti KO, Beyer JM, Johnson CM, Lyle EA, Tapping RI. Domain exchange between human toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination (2005). J Biol Chem. 280, 36616-25. Epub 2005 Aug 29. [Abstract]
Hajishengallis, G., Tapping, R.I., Martin, M.H., Nawar, H., Lyle, E.A., Russell, M.W., and Connell, T.D. Toll-like receptor 2 mediates cellular activation by the B subunits of type II heat-labile enterotoxins (2005). Infect. & Immun.73, 1343-9. [Abstract]
Vinogradov, E., Paul, C.J., Li, J., Zhou, Y., Lyle, E.A., Tapping, R.I., Kropinski, A.M., and Perry, M.B. The structure and biological character of the Spirochaeta aurantia outer membrane glycolipid LGL B (2004). Eur. J. Biochem. 271, 4685-4695. [Abstract]
Hajishengallis G., Newar, H., Tapping, RI., Russell, M.W. and Connell, T.D. Cytokine induction and regulation by the Type II heat-labile enterotoxins in human monocytic cells (2004). Infect. & Immun. 72, 6351-6358. [Abstract]
Lee, J.Y., Zhao, L., Youn, H.S., Weatherill, A.R., Tapping, R., Feng, L., Lee, W.H., Fitzgerald, K.A., and Hwang, D.H. (2004) "Saturated Fatty Acid Activates but Polyunsaturated Fatty Acid Inhibits Toll-like Receptor 2 Dimerized with Toll-like Receptor 6 or 1," J. Biol. Chem. 279: 16971-16979. [Abstract]
Tapping, R.I. and Tobias, P.S. (2002) "Mycobacterial lipoarabinomannan mediates physical interactions between TLR1 and TLR2 to induce signaling," J. Endotoxin Res. 9: 264-268. [Abstract]
Werts, C., Tapping, R.I., Mathison, J.C., Chuang, T.H., Kravchenko, V., Saint Girons, I., Haake, D.A., Godowski, P.J., Hayashi, F., Ozinsky, A., Underhill, D.M., Kirschning, C.J., Wagner, H., Aderem, A., Tobias, P.S., and Ulevitch, R.J. (2001) "Leptospiral lipopolysaccharide activates cells through a TLR2-dependent mechanism," Nature Immunol. 2(4): 346-352. [Abstract]
Tapping, R.I., Akashi, S., Miyake, K., Godowski, P.J., and Tobias, P.S. (2000) "Toll-like Receptor 4, but not Toll-like Receptor 2, is a Signaling Receptor for Salmonella and Escherichia Lipopolysaccharides," J. Immunol. 165: 5780-5787. [Abstract]
Tapping, R.I. and Tobias, P.S. (2000) "Soluble CD14 Mediated Cellular Responses to Lipopolysacchride," Chem. Immunol. 74: 108-121. [Abstract]
Tobias, P.S., Lee, H., Orr, S., Soldau, K., and Tapping, R.I. (2000) "Innate Immune System Recognition of Microbial Pathogens," Immunol. Res. 21(2-3): 341-343. [Abstract]
View Richard I. Tapping's publications at the National Library of Medicine (PubMed)