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 infection is dependent upon the organized actions of the molecules and cells which constitute the innate immune system. This system enables the host to mount an immediate response to infection that ultimately kills the infectious agent, clears infected tissues and initiates repair processes. 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 10 TLR family members subsets of which are expressed in epithelial cells, endothelial cells as well as leukocyte subtypes found in tissue and blood. TLRs sense conserved structural components of microbes which include cell wall or membrane components of bacteria and fungi as well as modified nucleic acids of certain bacteria and viruses (see figure). Upon direct binding of a cognate microbial agonist, TLR signaling activates the expression and cellular release of cytokines, chemokines and other mediators that facilitate local inflammation and recruit immune cells to the site of infection. In addition to providing immediate protection for the host, this TLR-induced response drives the activation of T and B lymphocytes which ultimately provide long term adaptive immunity. In addition to microbial components, TLRs also sense products of tissue damage and this activity 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. Specific projects in the lab aim to

1)Define TLR agonist specificity and mechanisms of microbial recognition. 2) Define the signaling and physiologic function of TLRs within the host. 3) Assess the effects of naturally occurring genetic polymorphisms on TLR function.

Within this framework, our lab utilizes a combination of biochemical, molecular, cellular and immunologic approaches using purified receptor components, experimentally manipulated cell lines, human blood cells, and transgenic 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.

Our lab has recently found that TLR10, which is the only remaining orphan TLR in humans, is also a heterodimeric coreceptor for TLR2. This receptor is highly expressed in B cells and preliminary data indicate a function which is unique from that of other TLRs. A transgenic TLR10 mouse model has been developed and is currently under investigation.

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., Omueti-Ayoade, K., Mutha, S.K., Hergenrother, P.J. and Tapping, R.I. (2010) Identification of novel synthetic Toll-like receptor 2 agonists by high throughput screening. J. Biol. Chem. Epub May 26, 2010.

Guan, Y., Ranoa, D.R.E., Jiang, S., Mutha, S.K., Li, X., Baudry, J. and Tapping, R.I. Human Toll-like receptors 10  and 1 share common mechanisms of innate immune sensing but not signaling. (2010) J. Immunol. 184 (9): 5094-5103.

Li, X., Jiang, S., Tapping, R.I. Toll-like receptor signaling in cell proliferation and survival. (2010) Cytokine Jan; 49(1): 1-9.

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

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]

Complete Publications List