Nagging Questions Take Toll on Researchers (2)- TLRs essential for immune response against pathogens

For this article Karen Young Kreeger interviewed Holger Wesche, scientist at Tularik Inc. in South San Francisco, Calif. Data from the Web of Science (ISI, Philadelphia) show that this paper has been cited significantly more often than the average paper of the same type and age. C.J. Kirschning, H. Wesche, T.M. Ayres, M. Rothe, "Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide," Journal of Experimental Medicine, 188:2091-7, 1998. (Cited in 173 papers) For decades researchers have known that lipopolysaccharides, or LPS, a major component of the cell walls of Gram-negative bacteria, are an important part of the pathology of septic shock in humans. The immune system responds to LPS exposure by activating such pro-inflammatory molecules as the transcription factor NF-* B. "One way companies are trying to come up with therapies to combat sepsis is to explore the signal transduction cascades in immune cells initiated by bacterial cell wall components," says Holger Wesche, scientist at Tularik Inc. in South San Francisco, Calif. Wesche, along with lead author Carsten J. Kirschning, now at the Technical University of Munich, Germany, senior author Mike Rothe, now at Develogen, a biotech company in Goettingen, Germany, and T. Merrill Ayres at Tularik, set out to identify a receptor by which LPS or other bacterial components mediate their effects. In this paper they describe that human toll-like receptor 2 (TLR2), along with CD14, is able to transduce the LPS triggered signal across a human cell's plasma-membrane. These findings spurred the establishment of the TLRs as a family of pattern-recognizing receptors essential for the immune response against pathogens such as bacteria and fungi. Another paper--published about the same time--from a group led by Paul Godowski from Genentech Inc., also came to the same conclusion.1 The groups also found that the intracellular domain of TLR2 is homologous to the intracellular domain of the interleukin-1 receptor (IL-1RI). Before these papers were published researchers knew that the membrane protein CD14 was able to bind LPS. The problem was that CD14, in its membrane-bound form, can bind LPS, but cannot transmit its molecular signal into the cytoplasm. There had to be a co-receptor. The picture that has been emerging in the two years since the papers' publication is that specific TLRs recognize certain components of pathogens, but that there is a lot of overlap, and that recognition depends on what species of bacteria is studied. In the same year, note this paper's authors, other researchers were able to show that mice resistant to Escherichia coli LPS carry mutations in the TLR-4 gene, suggesting that, at least in mice, TLR-4 is indispensable for LPS signaling.2 "The image is still very confusing," says Wesche. Receptors in the TLR family are definitely players in recognizing bacterial cell wall components, but sorting out the individual family members' roles will take more time. The homology of the intracellular domains of TLRs and IL-1RI, says Wesche, suggests strategies for pharmaceutical intervention that would block IL-1, and hence also block LPS signal transduction. "You would have to target a lot of receptors if you want to directly intervene at the receptor level of pathogen recognition," he notes. "But, all of the toll-like receptors have one thing in common: they all have an interleukin-1-like signal transduction mechanism." The commercial upshot is that targeting the interleukin-1 signal transduction cascade would also result in targeting LPS responses. Karen Young Kreeger (kykreeger@aol.com) is a contributing editor for The Scientist. References 1. R.B Yang et al., "Toll-like receptor-2 mediates lipopolysaccharide-induced signaling," Nature, 395:284-8, 1998. (Cited in 294 papers) 2. A. Poltorak et al., "Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene," Science, 282:2085-8, 1998. (Cited in 275 papers)

Nagging Questions Take Toll on Researchers (2)- TLRs essential for immune response against pathogens

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