Mice, men and the relatives: cross-species studies underpin innate immunity

Abstract

The innate immune response is the first line of defence against infection. Germ-line-encoded receptors recognize conserved molecular motifs from both exogenous and endogenous sources. Receptor activation results in the initiation of a pro-inflammatory immune response that enables the resolution of infection. Understanding the inner workings of the innate immune system is a fundamental requirement in the search to understand the basis of health and disease. The development of new vaccinations, the treatment of pathogenic infection, the generation of therapies for chronic and auto-inflammatory disorders, and the ongoing battle against cancer, diabetes and atherosclerosis will all benefit from a greater understanding of innate immunity. The rate of knowledge acquisition in this area has been outstanding. It has been underpinned and driven by the use of model organisms. Information obtained from Drospohila melanogaster, knock-out and knock-in mice, and through the use of forward genetics has resulted in discoveries that have opened our eyes to the functionality and complexity of the innate immune system. With the current increase in genomic information, the range of innate immune receptors and pathways of other species available to study is rapidly increasing, and provides a rich resource to continue the development of innate immune research. Here, we address some of the highlights of cross-species study in the innate immune field and consider the benefits of widening the species-field further.

Keywords: toll-like receptor, NLR, pattern recognition receptor, species immunity, immune evolution.

Figure 1.

Timeline of TLR ectodomain structural characterization. The list to date of current structures of TLR ectodomains from humans, mice and zebrafish are shown in conjunction with their Protein Data Bank (PDB) identifies. Murine and zebrafish structures are presented in ribbon format and images were generated using the PyMOL molecular graphics system, v. 1.3, Schrödinger, LLC. Years highlighted in bright blue (2006, 2010, 2011) correspond to those in which no TLR ectodomain structures were published. PDB files are associated with the following references: PDB 1ziw [35]; PDB 2a0z [36]; PDBs 2z62, 2z63, 2z64, 2z65, 2z66 [37]; PDBs 2z80, 2z81, 2z82, 2z7x [38]; PDB 3ciy [39]; PDB 3fxi [40]; PDBs 3a79, 3a7b, 3a7c [41]; and PDBs 3v44, 3v47 [42]. VLR, variable lymphocyte receptor.

Figure 2.

Murine and human TLR ectodomain structures are nearly identical. (a) Overlay of the ectodomains of murine TLR3 (PDB 3ciy, red) and both human TLR3 structures (PDB 2a0z, orange; PDB 1ziw, blue). (b) Overlay of the human (PDB 2z63, blue) and murine (PDB 2z64, red) ectodomains of TLR4. Structures are shown in a ribbon representation. Images were generated using the PyMOL molecular graphics system, v. 1.3, Schrödinger, LLC.

Figure 3.

Predicted domain organization of NAIP proteins from different species. Red oval, BIR domain; blue rectangle, NACHT domain; lilac diamonds, LRR domain. Domain information derived from Ting et al. [57] and Romanish et al. [58].