Innate immunity to Legionella pneumophila

Review Article published: 16 May 2011 doi: 10.3389/fmicb.2011.00109 Innate immunity to Legionella pneumophila Liliana M. Massis and Dario S. Zamboni* Department of Cell Biology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil Edited by: Carmen Buchrieser, Pasteur Institute, France Reviewed by: Thomas Rudel, University of Wuerzburg, Germany Elizabeth L. Hartland, The University of Melbourne, Australia *Correspondence: Dario S. Zamboni, Department of Cell Biology, School of Medicine, University of São Paulo, Av. Bandeirantes, 3900, Ribeirão Preto, SP 14049-900, Brazil. e-mail: Innate immune cells, such as macrophages, are highly adapted to rapidly recognize infections by distinct pathogens, including viruses, bacteria, fungi, and protozoa. This recognition is mediated by pattern recognition receptors (PRRs), which are found in host cell surface membranes and the host cell cytoplasm. PRRs include protein families such as the toll-like receptors, nod-like receptors, RIG-I-like receptors, and sensors of cytosolic DNA. The activation of these PRRs by pathogen-associated molecular patterns leads to transcriptional responses and specific forms of cell death. These processes effectively contribute to host resistance to infection either via cell-autonomous processes that lead to the intracellular restriction of microbial replication and/ or by activating pathogen-specific adaptive immune responses. Legionella pneumophila, the causative agent of Legionnaires’ disease, is a Gram-negative bacterium that triggers responses by multiple PRRs. Here, we review a set of studies that have contributed to our specific understanding of the molecular mechanisms by which innate immune cells recognize and respond to L. pneumophila and the importance of these processes to the outcome of infection. Keywords: Legionella pneumophila, innate immunity, pattern recognition receptors, nod-like receptors Introduction Activation of innate immune cells is critical for the initiation of adaptive immune responses. This process relies mostly on the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). Among the canonical PAMPs are molecules such as lipopolysaccharide, peptidoglycan, bacterial lipoproteins, flagellin, and nucleic acids derived from viruses, bacteria, fungi, and protozoa (Janeway and Medzhitov, 2002; Akira et al., 2006; Gazzinelli and Denkers, 2006). Upon direct or indirect ligand recognition, toll-like receptors (TLRs) dimerize and trigger a signaling cascade leading to the activation of proinflammatory responses (Uematsu and Akira, 2006). TLRs are transmembrane proteins containing an extracellular leucine-rich repeat (LRR) domain that facilitates PAMP recognition and an intracellular domain that mediates intracellular signaling via four different adaptor proteins: TRAM, MAL/TIRAP, MyD88, and TRIF (O’Neill, 2008). Depending on the nature of their specific ligands, TLRs are embedded in either the extracellular membrane (TLR-1, -2, -4, -5, -6, -10, -11) or in the membranes of endocytic vacuoles (TLR-3, -7, -8, -9). In addition to TLRs, other PRR families have already been described; these include DNA/RNA-sensing proteins such as the RIG-I-like receptor (RLR) family and sensors of membrane damage and intracellular PAMPs such as the nod-like receptors (NLRs; Creagh and O’Neill, 2006). The RNA helicase domain-containing proteins retinoic acidinducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) comprise a group of cytoplasmic receptors important for the recognition of viral nucleic acids. PAMP recognition by RIG-I and MDA5 triggers the activation of IRF3 via MAVS (IPS-1), culminating in the production of type I interferons (IFN). Recent studies have demonstrated that these receptors also induce type I IFN production upon recognition of nucleic acids from intracellular bacteria (Cao, 2009). In addition, some studies have www.frontiersin.org shown that the recognition of DNA by RIG-I/MDA5 is dependent on cytosolic RNA polymerase III (Pol III; Ablasser et al., 2009; Chiu et al., 2009). The NLRs comprise a PRR family that can be classified into three sub-groups. The first sub-group is composed of receptors that trigger intracellular signaling pathways leading to the activation of transcriptional factors mediating the expression of inflammatory response genes. Both NOD1 and NOD2 are members of this first group, and they signal via RIP2, a kinase that ubiquitinates NEMO to induce the activation of NF-κB and MAPK (Shaw et al., 2008). The second sub-group comprises NLRs that do not require ASC to trigger caspase-1 activation. Among these proteins are NAIP5 (BIRC1e) and NLRC4 (IPAF), which have been suggested to assembly a unique inflammasome (hereafter referred to as the NLRC4 inflammasome). Activation of this inflammasome triggers a specific form of host cell death called pyroptosis (Lightfield et al., 2008; Case et al., 2009; Broz et al., 2010; Silveira and Zamboni, 2010; Whitfield et al., 2010). The third sub-group of NLRs comprises those that trigger caspase-1 activation via the adaptor protein ASC. These proteins assemble into a multimeric molecular platform known as the “classical” inflammasome. Among the NLRs that trigger the ASC-dependent inflammasome is NALP3, which has been extensively characterized and shown to be important for the recognition of danger-associated molecular patterns (DAMPs) reviewed by Schroder and Tschopp (2010). In addition to TLRs, NLRs, and RLRs, previous studies have described a class of proteins that recognize cytoplasmic DNA (Ishii and Akira, 2006; Stetson and Medzhitov, 2006). These multiple protein families include DNA-dependent activators of IFN-regulatory factors (DAI; Takaoka et al., 2007), RNA polymerase III, which induces type I IFN production through the RIG-I pathway (Ablasser et al., 2009; Chiu et al., 2009), and the recently described protein absent in melanoma (AIM2), which activates May 2011 | Volume 2 | Article 109 | 1 Massis and Zamboni inflammasomes in an ASC-dependentmanner (Burckstummer et al., 2009; Fernandes-Alnemri et al., 2009; Hornung et al., 2009; Roberts et al., 2009). Legionella pneumophila, a Gram-negative bacterial pathogen that evolved infecting unicellular protozoa in freshwater reservoirs, may not have encountered strong selective pressure to avoid recognition by mammalian PRRs. Consequently, L. pneumophila triggers multiple PRR and has been a useful model for understanding the biology of PRRs and the induction of appropriate adaptive immune responses against intracellular pathogens. The successful use of L. pneumophila as a tool for studying immunology has been reviewed elsewhere (Vance, 2010). Here, we will review the salient findings that have contributed to our understanding of the molecular mechanisms underlying innate immune cell recognition and response to L. pneumophila infection (Figure 1). Furthermore, w (...truncated)