Innate recognition of intracellular bacteria

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The molecular repertoire for innate recognition of bacterial pathogens has expanded rapidly in the past decade. These immunosensors include Toll-like receptors and the more recently defined NOD-like receptors (NLRs): NODs, NALPs, NAIP and IPAF. Toll-like receptors signal from the cell surface or endosome upon ligand binding, whereas NLRs are activated by characteristic bacterially derived molecules, such as peptidoglycan, RNA, toxins and flagellin, in the cytosol. Studies using animal and culture models of bacterial infection indicate a pro-inflammatory role for NLRs, mediated by signaling through nuclear transcription factor κB and activation of caspase-1 by the inflammasome. These data also support a synergistic role for extracellular and intracellular bacterial sensing in regulating inflammation. In humans, NLR mutations are often associated with autoinflammatory syndromes, suggesting a complex role for cytosolic surveillance in systemic innate immunity.

Introduction

Innate immunity plays a crucial role in the survival of diverse organisms such as plants, flies and mammals by controlling microbial infection. Macrophages, dendritic cells and neutrophils, as innate immune effectors, must serve multiple functions: pathogen detection, antimicrobial defense and instruction of the adaptive immune system. The paradigm of mammalian innate immune recognition was proposed more than a decade ago by Medzhitov and Janeway [1] based on elegant genetic experiments in Drosophila that cast the Toll protein as a key regulator of innate immune signaling. Mammalian Toll-like receptors (TLRs) sense a wide array of microbial and self ligands, such as lipopolysaccharide (LPS) and flagellin, at the cell surface or within phagosomes [2]. However, many successful bacterial pathogens, such as Mycobacterium tuberculosis, are intracellular. These pathogens often reside within specialized compartments and might evade or minimize extracellular innate immune signaling, raising the questions of whether infected host cells can distinguish intracellular bacteria from extracellular bacteria, and if such a distinction would have immunological consequences [3]. Specific recognition of intracellular bacterial pathogens could allow the immune response to be tailored for maximum effectiveness in sterilizing intracellular infection, which generally requires a cytotoxic T lymphocyte or a Th1-type response [4].

Recent studies have revealed a large novel protein family, termed the nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs), which have a domain structure similar to the plant cytosolic R protein family that mediates resistance to phytopathogens [5, 6]. Thus, the hypothesis was proposed that NLRs regulate innate immunity in response to recognition of bacterial products in the cytosol [7]. Two cytoplasmic receptors for viral dsRNA, retinoic acid inducible gene I (RIG-I) and melanona differentiation associated gene 5 (MDA-5), which modulate the anti-viral innate immune response were also identified recently [8, 9]. These discoveries suggest that the mammalian cytosol is a rich environment for host–pathogen interactions and is a site of active immune surveillance.

NLRs, like TLRs, sense a variety of characteristic bacterial products, although only some NLRs have known ligands (Figure 1, Table 1). Each family member contains a leucine-rich repeat region (LRR) required for ligand sensing, a NOD domain (also termed NACHT domain), and signaling modules such as the caspase activation and recruitment domain (CARD), pyrin or baculoviral inhibitor of apoptosis repeat (BIR) domains [10]. Activation of NLRs by bacterial products can stimulate two major signaling pathways: the nuclear transcription factor (NF)-κB pathway and the inflammasome. NF-κB, a heterodimeric transcription factor, is a key regulator of the pro-inflammatory response, activating genes that encode cytokines and co-stimulatory factors [11]. NF-κB is also activated by extracellular binding of microbial ligands to TLRs, thus, although NLRs and TLRs can be triggered independently, the signals from both pathways intersect to use common intermediates such as the inhibitor of κB kinase (IKK) complex (Figure 2). NLR proteins can also activate caspase-1 by way of the inflammasome — a multi-protein complex activated by diverse stimuli (Figure 1) [12]. A primary function of caspase-1 and the inflammasome is to process the inflammatory cytokines proIL-1β and proIL-18 to their mature and active forms; caspase-1 can also trigger host cell death. TLR signaling induces the expression of proIL-1β; however, a second signal, such as NLR activation, is needed to activate caspase-1 for cleavage and secretion of mature IL-1β [13]. Thus, cytosolic bacterial detection by NLRs might play a distinct role in amplification of TLR-dependent signaling and modulation of the caspase-1-dependent inflammatory response. TLR and NLR signaling from different cellular compartments could serve to alert the host to immunological ‘danger’ and to protect the organism from inappropriate immune responses to non-pathogenic bacteria [14].

In this review, we present recent advances in our understanding of immune surveillance for bacteria in the mammalian cytosol and how intracellular sensing can impact the innate immune response to infection. Areas of future interest in the field of intracellular surveillance for bacterial pathogens are also discussed.

Section snippets

NOD1 and NOD2 — peptidoglycan sensors

NOD1 and NOD2 are the archetypal members of the NLR family and were originally characterized by Nunez and co-workers [7, 15]. Both proteins respond to components of peptidoglycan (PG), a polymeric structure unique and essential to bacteria that forms the rigid bacterial cell wall. NOD1, which is ubiquitously expressed, senses PG-derived meso-diaminopimelic acid (DAP)-containing muramyl peptides, which are a structural component of the cell wall in Gram-negative organisms [16]. Human NOD1

NALP1 and NALP3 — sensors of bacterial RNA, bacterial toxins, peptidoglycan and endogenous danger signals

Members of the NACHT-, LRR- and PYRIN domain-containing proteins (NALP) subfamily of NLRs have a similar domain structure to NODs, but contain a PYRIN domain instead of, or in addition to, a CARD domain (Figure 1). NALP1b mediates caspase-1 activation and necrosis in response to treatment with anthrax lethal toxin (LeTx), which is composed of protective antigen and lethal factor (LF), in macrophages from inbred mice susceptible to intoxication [27]. The allele of Nalp1b associated with LeTx

NAIP5 and IPAF – sensors of bacterial flagellin

Neuronal apoptosis inhibitory protein 5 (NAIP5) is unique among the NLRs because it has an amino-terminal set of BIR motifs as an effector module, in addition to the NOD and LRR domains [34]. Polymorphisms in the murine Naip5 (also known as Birc1e) locus, found in the A/J mouse strain, result in enhanced susceptibility to infection by the Gram-negative pathogen Legionella pneumophila [35, 36]. Several groups have now demonstrated that wild-type NAIP5 senses bacterial flagellin and initiates

Conclusions

Many exciting discoveries have been made in the area of cytosolic immune surveillance in the past several years. Nevertheless, it is clear that there are still large gaps in our knowledge of the ligands and sensors involved. In this review, we have discussed six NLR proteins that respond to bacterial ligands, but the human NLR family contains more than 30 proteins [6]. It is not yet known if all NLR family members sense microbial ligands or danger signals, or whether some NLRs, such as CIITA, a

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We offer apologies to authors whose work could not be cited owing to space limitations. LMD is supported by the National Institutes of Health (NIH) Genetics Training Program at the University of Michigan (T32 GM07544). This work was funded by the Ellison Medical Foundation and NIH NIAID AI064540 (MXDO).

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