Summary
It is now well accepted that a significant genetic component governs host susceptibility to different infectious diseases. As the Toll-like receptors (TLRs), together with their co-receptors and their downstream signalling partners, play such a crucial role in pathogen recognition and subsequent activation of the host immune response, any genetic mutation (polymorphism) that alters the protein structure and in so doing affects the ability of the TLRs or their co-receptors to bind to their associated pathogen-associated molecular patterns (PAMPs) will likely affect host susceptibility towards infection. Examination of the TLR signalling cascade suggests the existence of several bottlenecks or rate-limiting steps, obvious ones being at the level of the receptors, the adaptor proteins, TNF receptor-associated factor 6 (TRAF6), as well as at the IκB/NF-κB interaction point. Mutations to these downstream members might confer either resistance or increased susceptibility, depending on their nature. Indeed, it has been demonstrated time and again that natural variation in some of the molecules mentioned above does affect differential susceptibility to infectious diseases (e.g. invasive bacterial infections, tuberculosis, and malaria) specific to the binding spectrum of the TLRs involved.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Hill, A. V. (2006) Aspect of genetic susceptibility to human diseases. Annu. Rev. Genet. 40: 469–86
Takeda, K., Kaisho, T., Akira, S. (2003) Toll-like receptors. Annu. Rev. Immunol. 21: 335–76.
Jurinke, C., van den Boom, D., Cantor, C. R., Koster, H. (2002) Automated genotyping using the DNA MassArray technology. Methods Mol. Biol. 187: 179–92.
Poltorak, A., He, X., Smirnova, I., Liu, M.Y., Van Huffel, C., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., Freudenberg, M., Ricciardi-Castagnoli, P., Layton, B., Beutler, B. (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 282: 2085–8.
Hoshino, K., Takeuchi, O., Kawai, T., Sanjo, H., Ogawa, T.,Takeda, Y., Takeda, K., Akira, S. (1999) Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162: 3749–52
Smirnova, I., Mann, N., Dols, A., Derkx, H.H, Hibberd, M.L., Levin, M., Beutler, B. (2003) Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility. Proc. Natl. Acad. Sci. U. S. A. 100: 6075–80.
Hawn, T.R., Verbon, A., Lettinga, K.D., Zhao, L.P., Li, S.S., Laws, R.J., Skerrett, S. J., Beutler, B., Schroeder, L., Nachman, A., Ozinsky, A., Smith, K.D., Aderem, A. (2003) A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires’ disease. J. Exp. Med. 198:1563–72.
Hawn, T.R., Verbon, A., Janer, M., Zhao, L.P., Beutler, B., Aderem, A. (2005) Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires’ disease. Proc. Natl. Acad. Sci. U. S. A. 102:2487–9.
Hoebe, K., Georgel, P., Rutschmann, S., Du, X., Mudd, S., Crozat, K., Sovath, S., Shamel, L., Hartung, T., Zahringer, U., Beutler, B. (2005) CD36 is a sensor of diacylglycerides. Nature 433: 523–7.
Khor, C.C., Chapman, S.J., Vannberg, F.O., Dunne, A., Murphy, C., Ling, E.Y., Frodsham, A.J., Walley, A.J., Kyrieleis, O., Khan, A., Aucan, C., Segal, S., Moore, C.E., Knox, K., Campbell, S.J., Lienhardt, C., Scott, A., Aaby, P., Sow, O.Y., Grignani, R.T., Sillah, J., Sirugo, G., Peshu, N., Williams, T.N., Maitland, K., Davies, R.J., Kwiatkowski, D.P., Day, N.P., Yala, D., Crook, D.W., Marsh, K., Berkley, J.A., O’Neill, L.A., Hill, A.V. (2007) A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat. Genet. 39: 523–38
Krishnegowda, G., Hajjar, A.M., Zhu, J., Douglass, E.J., Uematsu, S., Akira, S., Woods, A.S., Gowda, D.C. (2005) Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: cell signalling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity. J. Biol. Chem. 280: 8606–16.
Dunne, A., Ejdeback, M., Ludidi, P.L., O’Neill, L.A., Gay, N.J. (2003) Structural complementarity of Toll/interleukin-1 receptor domains in Toll-like receptors and the adaptors TIRAP and MyD88. J. Biol. Chem. 278: 41443–51
Thoma-Uszynski, S., Stenger, S., Takeuchi, O., Ochoa, M.T., Engele, M., Sieling, P.A., Barnes, P.F., Rollinghoff, M., Bolcskei, P.L., Wagner, M., Akira, S., Norgard, M.V., Belisle, J.T., Godowski, P.J., Bloom, B.R., Modlin, R.L. (2001) Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291: 1544–7.
Acknowledgments
The author would like to thank Adrian Hill, Luke O’Neill, Stephen Chapman, and Fredrik Vannberg for their helpful suggestions, encouragement, and support.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Humana Press, a part of Springer Science + Business Media, LLC
About this protocol
Cite this protocol
Khor, CC. (2009). Genotyping Methods to Analyse Polymorphisms in Toll-Like Receptors and Disease. In: McCoy, C.E., O’Neill, L.A.J. (eds) Toll-Like Receptors. Methods in Molecular Biology™, vol 517. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59745-541-1_18
Download citation
DOI: https://doi.org/10.1007/978-1-59745-541-1_18
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-934115-72-5
Online ISBN: 978-1-59745-541-1
eBook Packages: Springer Protocols