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.

Toll-like receptors (TLRs) also provide a critical link between the innate and adaptive immune system by sensing microbes and inducing dendritic cell maturation events needed for the activation of T and B lymphocyte responses. Additionally, TLR subsets are directly expressed in B lymphocytes where they have intrinsic activities which include the promotion of antibody production and maintenance of long term memory. Despite considerable research on TLRs the function of TLR10, which is highly expressed in B cells, remains unknown largely due to a lack of identifiable signaling responses and activating ligands. This knowledge gap is exacerbated by the fact that TLR10 is an inactive pseudogene in mice.

Our research overcomes the above barriers through the development and use of research tools which include anti-TLR10 antibodies and two TLR10 transgenic mouse models. The overarching goal of our research is to characterize TLR10 expression and function within the B cell lineage. This goal is addressed through studies which aim:

1) to fully characterize the profile and regulation of TLR10 expression within the human B cell lineage.

2) to characterize the in vitro function of TLR10 in modulating B cell activity.

3) to define the role of TLR10 in regulating antigen-specific adaptive immune responses.

4) to examine TLR10 as a potential therapeutic target in the treatment of autoimmune disease.

These studies have considerable implications for the development of vaccines that are effective in humans and for autoimmune conditions such as lupus where dysregulated TLR activity plays a clear B cell intrinsic role.

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

Hart, B.E. and Tapping, R.I. Differential trafficking of TLR1 I602S underlies host protection against pathogenic mycobacteria (2012). Under review in J. Immunol.

Hart, B.E. and Tapping, R.I. Cell surface trafficking of TLR1 is differentially regulated by the chaperones PRAT4A and PRAT4B. (2012) J. Biol. Chem. 287 (20): 16550-62. Epub Mar 23, 2012.

Hart, B. E. and Tapping, R.I. Genetic diversity of Toll-like receptors and immunity to Mycobacteria leprae infection. (2012) J. Tropical Med. 2012-415057 Epub Mar 18, 2012.

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]

Complete Publications List