1. ¹Innate Immunity and Signalisation, Institut Pasteur, 28, Rue du Dr. Roux, 75724 Paris Cedex 15, France
2. ²Unité de Pathogénie Microbienne Moléculaire, INSERM U389, Institut Pasteur, 28, Rue du Dr. Roux, 75724 Paris Cedex 15, France
3. ³Groupe Inserm Avenir 'Peptidoglycan and Innate Immunity,' Institut Pasteur, 28, Rue du Dr. Roux, 75724 Paris Cedex 15, France
4. ⁴Current address: Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada H551A8
5. ⁵Current address: Department of Immunology, University of Toronto, Toronto, Ontario, Canada H551A8. Tel: 416 978 7527; Fax: 416 978 1938; E-mail: dana-philpott@utoronto.ca

Correspondence: DJ Philpott, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris, France. Tel: +33-1-45-68-89-93; Fax: +33-1-45-68-89-53; E-mail: philpott@pasteur.fr

Received 30 November 2005; Revised 24 January 2006; Accepted 26 January 2006; Published online 10 March 2006.

Abstract

Innate immunity to microorganisms in mammals has gained a substantial interest during the last decade. The discovery of the Toll-like receptor (TLR) family has allowed the identification of a class of membrane-spanning receptors dedicated to microbial sensing. TLRs transduce downstream signaling via their intracellular Toll–interleukin-1 receptor (TIR) domain. More recently, the role of intracellular microbial sensors has been uncovered. These molecules include the Nod-like receptors Nod1, Nod2, Ipaf and Nalps, together with the helicase domain-containing antiviral proteins RIG-I and Mda-5. The intracellular microbial sensors lack the TIR domain, but instead transduce downstream signals via two domains also implicated in homophilic protein–protein interactions, the caspase activation and recruitment domain (CARD) and PYRIN domains. In light with these recent findings, we propose that TIR, CARD and PYRIN domains represent the three arms of innate immune detection of microorganisms in mammals.