The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

The ability of host cells to sense and respond to non-self is dependent upon a number of secreted and cell-associated molecules of the innate immune system. Over the past decade, a family of transmembrane receptors known as Toll-like receptors (TLRs) have emerged as critical essential elements of innate immune defense in higher vertebrates. Humans possess ten TLR family members subsets of which are expressed in epithelial cells, endothelial cells as well as leukocyte subtypes found in tissue and blood. These transmembrane receptors discriminate self from nonself through recognition of conserved structural components of viruses, bacteria, fungi, and protozoans. These include cell wall or membrane components of bacteria and fungi as well as modified nucleic acids of certain bacteria and viruses (see figure). Upon engaging a cognate microbial agonist, TLRs activate intracellular signals which induce the expression and cellular release of cytokines, chemokines and other mediators that facilitate local inflammation. In addition to providing immediate protection for the host, the engagement of TLRs drives antigen presentation and T and B cell responses associated with adaptive immunity. In this context, it is not surprising that inappropriate TLR activation is directly associated with a variety of inflammatory disorders ranging from sepsis, atherosclerosis, asthma, and certain autoimmune diseases.

Research in our lab is currently focused on understanding the evolution and biologic function of the TLR2 subfamily. TLR2 is unique among mammalian TLRs in that it requires heterodimeric association with other related TLR family members, namely TLR1 or TLR6, in order to function. The TLR2 subfamily mediates responses to a wide variety of microbial and fungal components as well as self products of tissue damage and inflammation. A central question is how this receptor system mediates responses to such a structurally diverse range of agonists. Our lab has recently found that TLR10, which is the only remaining orphan TLR in humans, is also a coreceptor for TLR2. This receptor is highly expressed in B cells and preliminary data indicate a unique signaling function. A transgenic TLR10 mouse model has been developed and is currently under investigation.

With respect to the TLR2 subfamily, specific projects in the lab aim to:

• Identify novel agonists and define mechanisms of microbial recognition.
• Determine the subcellular trafficking patterns and signaling locations.
• Uncover the mechanisms by which gene expression is regulated.
• Define the agonist specificity and signaling function of TLR10.
• Identify and characterize genetic variants of TLR2 subfamily members.

Within this framework, our lab utilizes a combination of biochemistry, molecular biology, cellular biology, and human population genetics techniques involving purified components, experimentally manipulated cell lines, blood cells, and TLR deficient mouse models. Research in our laboratory attempts to address the core question of how the innate immune system ultimately senses the presence of infection, identifies the type of invading pathogen, and mediates the appropriate response. This question is central to understanding basic immune defense as well as the pathogenesis of a wide variety of deleterious immune conditions.

The genetic basis of host resistance to Yersinia pestis.
A second unrelated project in the lab investigates host resistance to Yersinia pestis, the causative agent of plague. We have identified several inbred laboratory mouse strains that are resistant to Y. pestis in a septicemic model of plague. Through classical forward genetics methods the genetic loci responsible for conferring host resistance in each strain is being mapped. The identification of the genes responsible will be utilized to examine the molecular and cellular basis for host resistance which we anticipate will provide novel insights into plague pathogenesis.

Representative Publications

Guan, Y., Ranoa, D.R.E., Jiang, S., Mutha, S.K., Li, X., Baudry, J. and Tapping, R.I. (2009) Human Toll-like receptors 10  and 1 share common mechanisms of innate immune sensing but not signaling. Under revision in J. Immunol.

Tapping, R.I. Innate immune sensing and activation of cell surface Toll-like receptors. (2009) Sem. Immunol. Aug; 21 (4): 175-184.

Liang, S., Hosur, K.B., Lu, S., Nawar, H.F., Weber, B.R., Tapping, R.I., Connell, T.D., and Hajishengallis, G.  Mapping of a microbial protein domain involved in binding and activation of the TLR2/TLR1 heterodimer. (2009) J. Immunol. Mar 1; 182(5):2978-85.

Turner J.K, Xu, J.L., and Tapping R.I. Substrains of 129 mice are resistant to Yersinia pestis KIM5: Implications for IL-10 deficient mice. (2009)  Infect Immun Jan; 77(1): 367-73.  Featured in Faculty of 1000.

Turner J.K., McAllister M., Xu, J.L., and Tapping, R.I.  Resistance of BALB/cJ mice to Yersinia pestis maps to the major histocompatibility complex of chromosome 17. (2008) Infect Immun Sep;76(9):4092-9.

Tapping, R.I., Omueti, K.O., and Johnson, C.M. 2007. Genetic polymorphisms within the human Toll-like receptor 2-subfamily. Biochem. Soc. Trans., 35(6):1445-8.

Johnson, C.M. and Tapping, R.I. 2007. TLR2 expression is induced through chromatin remodeling around a proximal NF-kB element. J Biol Chem., 282(43):31197-205.

Schumann, R.R. and Tapping. R.I. 2007. Genomic variants of TLR1-It takes two to tango. Eur. J. Immunol., 37(8):2059-62. [Abstract]

Johnson, C.M., Lyle, E.A., Omueti, K.O., Stepensky V.A., and Tapping, R.I. 2007. Cutting Edge: A common single nucleotide polymorphism impairs surface trafficking and functional responses of Toll-like receptor 1 but protects against leprosy. J. Immunol., 178(12):7520-4. [Abstract]

Omueti, K.O., Muzar, D.J., Thompson, K.S., Lyle, E.A., and Tapping, R.I. 2007. The polymorphism P315L of Toll-like receptor 1 impairs innate immune sensing of microbial cell wall components. J. Immunol., 178 (10):6387-94. [Abstract]

Omueti K.O., Beyer J.M., Johnson C.M., Lyle E.A., and Tapping R.I. 2005. Domain exchange between human toll-like receptors 1 and 6 reveals a region required for lipopeptide discrimination. J Biol Chem 280:36616–25. Epub 2005 Aug 29. [Abstract]