Innate immunity to pathogens: diversity in receptors for microbial recognition

Eukaryotes are constantly exposed to the threat of microbial species including viruses, bacteria, and parasites. In mammals, the protection against invading pathogens is mediated by two different immune systems: the evolutionarily conserved innate immune system, which is essential for the first line of host defense, and the acquired immune system, which is critical for immunological memory. The acquired immune system generates a highly diverse repertoire of antigen receptors, the T and B-cell receptors, via DNA rearrangement. After encountering a pathogen, the lymphocytes bearing the appropriate high-affinity antigen receptors for that pathogen expand and eliminate the pathogens in the late stage of infection. In contrast, innate immunity discriminates self and non-self by a limited number of germline-encoded receptors. These receptors are called pattern recognition receptors (PRRs), as they recognize molecular patterns of components specific to microbial organisms. Some PRRs are secreted to plasma as humoral proteins, some are present on the cell membrane, and some localize in the cytoplasm as sensors for any type of pathogens. In this volume, we review the roles of PRRs involved in innate immunity and the relationship between the innate PRRs and the adaptive immune system. Various PRRs present in the plasma are involved in detection of pathogens in the body fluid and their opsonization for facilitating phagocytosis. A well-known system is the lectin-complement pathway, which is mediated by carbohydrate-recognizing lectins and complement proteins secreted into the extracellular space. Binding of lectin to a microorganism triggers a chain of reactions on the surface of that microorganism, leading to its destruction or opsonization. Mantovani and colleagues (1) present the function of prototypic long pentraxin 3 (PTX3) as an example of humoral PRRs. Scavenger receptors are transmembrane receptors present on the surface of phagocytes, and they facilitate phagocytosis by recognizing negatively charged ligands and other ligands with lipid moieties such as lipoproteins and lipopolysaccharides. Bowdish and Gordon (2) discuss the role of class A scavenger receptors by focusing on their evolutionary aspects. The receptors described above do not induce production of proinflammatory cytokines by themselves. Toll-like receptors (TLRs) are comprised of leucine-rich repeats, a transmembrane domain, and a cytoplasmic Toll/interleukin-1 (IL-1) receptor (TIR) homology domain. Mammals have approximately 10 TLRs, and each TLR recognizes different microbial components. TLR activation triggers intracellular signaling pathways leading to the expression of a variety of genes involved in inflammatory and immune responses. TLR1, TLR2, TLR4, TLR5, and TLR6 are present on the plasma membrane, whereas TLR3, TLR7, and TLR9 are localized on the endoplasmic reticulum (ER) membrane and move to the endolysosome upon stimulation. TLR3 recognizes double-stranded RNA (dsRNA), whereas TLR7 and TLR9 recognize single-stranded RNA (ssRNA) and DNA with CpG motifs, respectively. The localization of TLRs is important for efficient recognition of microbial components as well as prevention of self-nucleotide recognition. Saito and Miyake (3) discuss the molecular mechanisms of TLR trafficking via chaperone proteins gp96 and protein associated with TLR4 A (PRAT4A) as well as UNC93b, a membrane protein essential for TLR3, TLR7, and TLR9 signaling. PRAT4A and UNC93b control the ligand-induced trafficking of TLR7 and TLR9 from the ER to the endolysosome. TLRs are evolutionarily conserved from insects and worms to mammals. Seya et al. (4) explored fish TLRs and found that fish have two mammalian TLR3 counterparts, TLR3 and TLR22, for dsRNA recognition. In fish, TLR3 localizes in the endosome, whereas TLR22 is present on the cell surface. The authors discuss the evolutionary aspect of vertebrate TLRs, taking advantage of human and fish TLRs. Nucleic acids are the major viral components recognized by the immune system. A cytoplasmic protein family, retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), plays a critical role in the recognition of viral RNAs. RIG-I and melanoma differentiation-associated gene 5 (MDA5) are comprised of two caspase-recruitment domains, a helicase domain, and a C-terminal repressor domain. RLRs recognize viral RNAs in the cytoplasm leading to the production of type I interferons (IFNs). Four reviews discuss the role of RLRs in the recognition of RNA viruses. Yoneyama and Fujita (5) review the roles of RIG-I and MDA5 in RNA recognition and their signaling pathways. The authors present the importance of the C-terminal domain of RIG-I in ligand recognition based on structural analysis data. Hartmann and colleagues (6) review RNA structures recognized by RIG-I. Although ssRNA with a 5′-triphosphate end and dsRNA without triphosphate are reported as RIG-I ligands, the structure recognized by RIG-I remains an enigma. They summarize all reports concerning RIG-I ligands and discuss RIG-I ligands. Takeuchi and Akira (7) discuss the difference between RIG-I and MDA5 ligands. RIG-I recognizes relatively short dsRNA in addition to 5′-triphosphate ssRNA, whereas MDA5 recognizes long (more than 2 kb) dsRNA. McCartney and Colonna (8) discuss the diversity of RLRs and TLRs in the responses to infection with various viruses. RLRs are responsible for type I IFN production in various cell types except for plasmacytoid dendritic cells, where TLRs play an essential role for viral recognition. Nucleotide oligomerization domain (NOD) protein-like receptors (NLRs) are another class of cytoplasmic PRRs characterized by a nucleotide-binding oligomerization domain and leucine-rich repeats. Except for NOD1 and NOD2, which are involved in activation of inflammatory gene expression, NLRs are involved in the activation of caspase-1-activating complexes called inflammasomes. Following bacterial infection or exposure to asbestos and uric acid crystals, inflammasome activation leads to the maturation of IL-1β and IL-18 by processing of their pro-forms. Dixit (9) and Nunez and colleagues (10) review NOD1- and NOD2-mediated recognition of bacterial components as well as mechanisms of inflammasome activation by NLR proteins. The relationships of genetic mutations in NLRs and autoinflammatory disorders are also discussed. Natural killer (NK) cells are innate cytotoxic lymphocytes that are able to kill host cells infected with viruses or tumor cells. NK cells directly recognize viral components via a set of receptors. Simultaneously, NK cells harbor inhibitory receptors recognizing molecules constitutively expressed on host cells such as major histocompatibility complex class I. Vivier and colleagues (11) review roles of activating and inhibitory receptors in controlling innate immune responses. Lanier (12) discusses roles of DAP12 or DAP10, which were originally identified as adapter molecules for activating NK receptors. However, DAP12 and DAP10 are found to associate with another set of receptors present on various innate immune cells. Structural analysis of PRRs and their signaling molecules is rapidly advancing, and molecular details of interaction between some TLRs and their ligands have been clarified. Gay and colleagues (13) review the structures of intracellular signaling molecules for TLRs, NLRs, and RLRs. The molecular basis of the homotypic receptor/adapter interaction and its role in signaling are also discussed. RNA silencing refers to mechanisms guided by small RNAs such as small interfering RNA (siRNA) and microRNA. siRNAs for viruses are generated by Dicer family RNases from viral dsRNA. Ding (14) shows the importance of RNA silencing in eliminating viruses in Drosophila and plants. The role of viral microRNA in mammalian immunity is also discussed. Autophagy is an intracellular homeostatic pathway that degrades organelles such as mitochondria. Deretic and colleagues (15) discusses the involvement of autophagy in the activation of innate immune responses. Autophagy degrades microbes or their products as well as modulates TLR and other PRR signaling. Green and colleagues (16) show that TLR stimulation recruits the autophagic machinery to the surface of phagosome. Intriguingly, the autophagic machinery is required for phagosome maturation leading to elimination of pathogens by the lysosomal pathway. The innate immune system is essential for the development of the adaptive immune system. Palm and Medzhitov (17) review how PRR-induced signals control adaptive immunity by showing multiple checkpoints. These include initiation of a response, the type of response, the magnitude and duration of the response, and the production of long-term memory. Dendritic cells recognize pathogen infection via PRRs and instruct acquired immune cells by presenting antigens as well as by expression of costimulatory molecules and cytokines. Reis e Sousa and colleagues (18) show that dendritic cells activated by proinflammatory cytokines are not equivalent to those activated by PRRs. The authors speculate that dendritic cells activated by cytokines induce tolerance rather than protective immunity. Innate immunity is also involved in the development of autoimmune diseases. Beutler (19) discusses that endogenous DNA may trigger specific immune responses that beget further responses in a TLR-dependent autoamplification loop. Some of this notion was developed through mouse forward genetics, which is a powerful tool contributed with the identification of genes involved in the mammalian innate immune system. Accumulating knowledge regarding PRRs and their signaling make it difficult to depict the entire picture of innate immunity. Zak and Aderem (20) discuss the application of systems biology in the research of innate immunity. The authors describe emerging technologies for this approach by showing identification of IFN regulatory factor 3 (IRF3) as the negative regulator of TLR signaling as an example of the application of transcriptome analysis. In recent years, the research efforts into the host innate immune system and the knowledge gained have rapidly progressed. Articles in this volume of Immunological Reviews highlight the diversity of PRRs and their coverage to sense broad spectrum of microorganisms. The innate PRRs are critical for mounting appropriate acquired immune responses, and aberrant activation of PRR signaling can cause autoimmune diseases. The interaction between PRRs and novel pathogen recognition systems, including RNA silencing and autophagy, is intriguing to explore, and huge amounts of information will be integrated by taking advantage of novel techniques such as systems biology.