Pattern recognition receptors: doubling up for the innate immune response

Antigen presenting cells (macrophages and dendritic cells) express pattern recognition molecules that are thought to recognize foreign ligands during early phases of the immune response. The best known of these are probably the Toll-like receptors, but a number of other receptors are also involved. Several of these recognize endogenous as well as exogenous ligands, suggesting that they play a dual role in normal tissue function and host defense.     

Pattern recognition molecules and innate immunity to parasites

Recent pioneering advances in understanding how plants, insects and worms eliminate pathogens has led to the realization that innate immunity plays a vital role in protecting humans from infection. This comprehensive review examines the molecules involved in innate immune responses, how they act to control parasites and if their engagement can explain many immune features characteristic of parasitic infections.     

Clara cells impact the pulmonary innate immune response to LPS

Airway epithelial cells secrete proinflammatory mediators in response to LPS, but cytokine production by a prominent nonciliated bronchiolar epithelial cell, the Clara cell, specifically, is unknown. To investigate Clara cell cytokine production in response to LPS, we used a transformed murine Clara cell line, C22, and isolated Clara cells from C57Bl/6 mice. Stimulation of both cell types with LPS resulted in significant upregulation of keratinocyte-derived chemokine (KC) and monocyte chemoattractant protein-1, but did not induce TNF-alpha production. To determine whether LPS induces cytokine production by Clara cells in vivo, LPS was instilled intratracheally into mice. KC was expressed by Clara cells, alveolar type 2 cells, and alveolar macrophages, 2 h after LPS administration, as determined by in situ hybridization. TNF-alpha, although not expressed in airway epithelial cells, was expressed primarily in alveolar macrophages in response to LPS. To assess the impact of Clara cells on KC and TNF-alpha production in the lung in the early response to LPS, mice were treated with naphthalene to selectively induce Clara cell injury before LPS stimulation. KC expression in the airways and the lung periphery, and KC and TNF-alpha levels in the bronchoalveolar lavage fluid, were significantly reduced in naphthalene-treated vs. vehicle-treated mice after LPS stimulation. Furthermore, transwell cocultures of C22 cells and RAW264.7 macrophages indicated that C22 cells released a soluble factor(s) in response to LPS that enhanced macrophage production of TNF-alpha. These results indicate that Clara cells elaborate cytokines and modulate the lung innate immune response to LPS.     

Invariant NKT cells amplify the innate immune response to lipopolysaccharide

NKT cells are thought of as a bridge between innate and adaptive immunity. In this study, we demonstrate that mouse NKT cells are activated in response to Escherichia coli LPS, and produce IFN-gamma, but not IL-4, although activation through their TCR typically induces both IL-4 and IFN-gamma production. IFN-gamma production by NKT cells is dependent on LPS-induced IL-12 and IL-18 from APC. LPS induced IFN-gamma production by NKT cells does not require CD1d-mediated presentation of an endogenous Ag and exposure to a combination of IL-12 and IL-18 is sufficient to activate them. In mice that are deficient for NKT cells, innate immune cells are activated less efficiently in response to LPS, resulting in the reduced production of TNF and IFN-gamma. We propose that in addition to acting as a bridge to adaptive immunity, NKT cells act as an early amplification step in the innate immune response and that the rapid and complete initiation of this innate response depends on the early production of IFN-gamma by NKT cells.     

Roles for T and NK cells in the innate immune response to Shigella flexneri

Shigella flexneri, an enteroinvasive Gram-negative bacterium, is responsible for the worldwide endemic form of bacillary dysentery. The host response to primary infection is characterized by the induction of an acute inflammation, which is accompanied by polymorphonuclear cell (PMN) infiltration, resulting in massive destruction of the colonic mucosa. However, PMN play a major role in the recovery from primary infection, by restricting the bacterial infection at the intestinal mucosa. In this study, we assessed the roles for T and NK cells in the control of primary S. flexneri infection, using an alymphoid mouse strain (Rag null gamma(c) null) devoid of B, T, and NK cells. Using the mouse pulmonary model of Shigella infection, we showed that alymphoid Rag null gamma(c) null mice were highly susceptible to S. flexneri infection in comparison with wild-type (wt) mice. Whereas PMN recruitment upon infection was similar, macrophage recruitment and production of proinflammatory cytokines were significantly decreased in Rag null gamma(c) null mice compared with wt mice. Upon selective engraftment of Rag null gamma(c) null mice with polyclonal alphabeta T cells, but not with alphabeta T cells from IFN-gamma null , S. flexneri infection could be subsequently controlled. Rag null mice devoid of B and T cells but harboring NK cells could control infection. Local IFN-gamma production by T and NK cells recruited to the lung was demonstrated in S. flexneri-infected wt mice. These data demonstrate that both alphabeta T cells and NK cells contribute to the early control of S. flexneri infection through amplification of an inflammatory response. This cellular lymphocyte redundancy assures IFN-gamma production, which is central to innate immunity against Shigella infection.     

Introduction: innate recognition of bacteria and protozoan parasites

Major advances have recently been achieved in the area of microbial recognition by the innate immune system. In this Forum, we discuss important issues related to innate recognition of bacteria and protozoan parasites. In particular, we highlight the structural characterization of pathogen-associated molecular patterns (PAMPs); the definition of the receptors required for recognition of PAMPs, especially the Toll-like receptors (TLRs); the signaling pathways triggered by PAMPs/PAMPs receptor interaction; and the functional consequences of these interactions for pathogenesis during microbial infection.     

Fish immune responses to experimental and natural infection with helminth parasites

Selected features of the responses by fish to helminth parasites are discussed and comparison is made where appropriate with mammals. These include: (i) Factors influencing host specificity and consideration of the mechanisms that underpin the restriction of some parasites in their host spectrum, (ii) How fish leucocytes kill helminth larvae, with emphasis on the role of released oxygen (ROS) and nitrogen (RNS) free radicals from macrophages, (iii) Immune evasion strategies used by fish helminths, including invasion of immunologically privileged sites, encystment, adsorption of host proteins on the parasite surface, and high surface membrane turnover, (iv) Potential immunogens for vaccination and use for immunodiagnosis of infection, and (v) Natural and induced protection against helminths, with emphasis on the potential for future vaccination strategies.     

Evaluation of an innate immune reaction to parasites in earthworms

Encapsulation is an essential process of the invertebrate immune system and includes the prophenoloxidase (proPO) cascade. We present an assay for evaluating this immune response, now newly adapted to earthworms. Coelomic fluid is withdrawn and coelomocytes are stained with l-Dopa. We studied assay repeatability and the correlation between number of PO-active cells and infection level of the parasitic protozoan Monocystis sp. in the earthworm Lumbricus terrestris. Our study showed high assay repeatability although the expected negative relationship between PO-active coelomocytes and parasite load was not observed; yet a suggestion toward a positive relationship was detected. This finding is contrary to previous assumptions that presume coelomocyte concentrations to be the independent variable determining parasite load.     

Fish immune response to Myxozoan parasites

Myxozoan parasites are responsible for important economic losses among fisheries and aquaculture industries, and hence the high interest in studying the immune response of fish against them. The most important data available concerning the immune response of fish against myxosporeans are reviewed, with emphasis on the different innate and adaptive immune mechanisms, their relationship with natural and acquired resistance and the strategies to control and prevent myxosporoses. Cellular effectors (lymphocytes, granulocytes, phagocytes, non-specific cytotoxic cells, rodlet cells) and humoral factors (lysozyme, peroxidades, antiproteases, complement, specific antibodies) have been examined for several myxosporoses, and some immune relevant genes have been studied. This information will be crucial for the future development of vaccines and other preventive strategies such as immunomodulation and selection of disease-resistant strains     

Avian genomics and the innate immune response to viruses

Viral diseases pose a significant threat to the poultry industry. However, there is currently a lack of antivirals and suitable vaccine adjuvants available to the poultry industry to combat this problem. The innate immune system is now recognised to be essential in the response to viral infection. However, in contrast to mammals, the innate immune response in chickens is relatively uncharacterised. The release of the full chicken genome sequence has accelerated the identification of genes involved in the immune response. The characterisation of these genes, including Toll-like receptors and cytokines has led to the identification of potential alternate antivirals and adjuvants.     

Iron metabolism and the innate immune response to infection

Host antimicrobial mechanisms reduce iron availability to pathogens. Iron proteins influencing the innate immune response include hepcidin, lactoferrin, siderocalin, haptoglobin, hemopexin, Nramp1, ferroportin and the transferrin receptor. Numerous global health threats are influenced by iron status and provide examples of our growing understanding of the connections between infection and iron metabolism.     

Apoptosis: an innate immune response to virus infection

Viruses can induce apoptosis of infected cells either directly, to assist virus dissemination, or by inadvertently triggering cellular sensors that initiate cell death. Cellular checkpoints that can function as 'alarm bells' to transmit pro-apoptotic signals in response to virus infections include death receptors, protein kinase R, mitochondrial membrane potential, p53 and the endoplasmic reticulum.     

Humoral immune response to flagellin requires T cells and activation of innate immunity

Bacterial flagellin, the primary structural component of flagella, is a dominant target of humoral immunity upon infection by enteric pathogens and in Crohn's disease. To better understand how such responses may be regulated, we sought to define, in mice, basic mechanisms that regulate generation of flagellin-specific Igs. We observed that, in response to i.p. injection with flagellin, generation of flagellin-specific Ig required activation of innate immunity in that these responses were ablated in MyD88-deficient mice and that flagellin from Helicobacter pylori, which is known not to activate TLR5, also did not elicit Abs. Mice lacking alphabeta T cells (TCRbeta(null)) were completely deficient in their ability to make flagellin Abs in various contexts indicating that, in contrast to common belief, generation of flagellin-specific Ig is absolutely T cell dependent. In contrast to Ab responses to whole flagella (H serotyping), responses to flagellin monomers displayed only moderate serospecificity. Whereas neither oral nor rectal administration of flagellin elicited a strong serum Ab response, induction of colitis with dextran sodium sulfate resulted in a MyD88-dependent serum Ab response to endogenous flagellin, suggesting that, in an inflammatory milieu, TLR signaling promotes acquisition of Abs to intestinal flagellin. Thus, acquisition of a humoral immune response to flagellin requires activation of innate immunity, is T cell dependent, and can originate from flagellin in the intestinal tract in inflammatory conditions in the intestine.     

Skin innate immune response to flaviviral infection

Skin is a complex organ and the largest interface of the human body exposed to numerous stress and pathogens. Skin is composed of different cell types that together perform essential functions such as pathogen sensing, barrier maintenance and immunity, at once providing the first line of defense against microbial infections and ensuring skin homeostasis. Being inoculated directly through the epidermis and the dermis during a vector blood meal, emerging Dengue, Zika andWest Nile mosquito-borne viruses lead to the initiation of the innate immune response in resident skin cells and to the activation of dendritic cells, which migrate to the draining lymph node to elicit an adaptive response. This literature review aims to describe the inflammatory response and the innate immune signalization pathways involved in human skin cells during Dengue, Zika and West Nile virus infections.     

Phosphatidylserine externalization by apoptotic cells is dispensable for specific recognition leading to innate apoptotic immune responses

Surface determinants newly expressed by apoptotic cells that are involved in triggering potent immunosuppressive responses, referred to as “innate apoptotic immunity (IAI)” have not been characterized fully. It is widely assumed, often implicitly, that phosphatidylserine, a phospholipid normally cloistered in the inner leaflet of cells and externalized specifically during apoptosis, is involved in triggering IAI, just as it plays an essential role in the phagocytic recognition of apoptotic cells. It is notable, however, that the triggering of IAI in responder cells is not dependent on the engulfment of apoptotic cells by those responders. Contact between the responder and the apoptotic target, on the other hand, is necessary to elicit IAI. Previously, we demonstrated that exposure of protease-sensitive determinants on the apoptotic cell surface are essential for initiating IAI responses; exposed glycolytic enzyme molecules were implicated in particular. Here, we report our analysis of the involvement of externalized phosphatidylserine in triggering IAI. To analyze the role of phosphatidylserine, we employed a panel of target cells that either externalized phosphatidylserine constitutively, independently of apoptosis, or did not, as well as their WT parental cells that externalized the phospholipid in an apoptosis-dependent manner. We found that the externalization of phosphatidylserine, which can be fully uncoupled from apoptosis, is neither sufficient nor necessary to trigger the profound immunomodulatory effects of IAI. These results reinforce the view that apoptotic immunomodulation and phagocytosis are dissociable and further underscore the significance of protein determinants localized to the cell surface during apoptosis in triggering innate apoptotic immunity.     

Peptidoglycan recognition proteins of the innate immune system

Peptidoglycan (PGN) is the major component of bacterial cell walls and one of the main microbial products recognized by the innate immune system. PGN recognition is mediated by several families of pattern recognition molecules, including Toll-like receptors, nucleotide-binding oligomerization domain-containing proteins, and peptidoglycan recognition proteins (PGRPs). However, only the interaction of PGN with PGRPs, which are highly conserved from insects to mammals, has so far been characterized at the molecular level. Here, we describe recent structural studies of PGRPs that reveal the basis for PGN recognition and provide insights into the signal transduction and antibacterial activities of these innate immune proteins.     

The innate immune response to Trypanosoma cruzi infection

Trypanosoma cruzi infection is a major public health problem in Latin America. The host innate immune system plays a pivotal role in the recognition of T. cruzi infection and the subsequent development of adaptive immunity. In this review, we focus on the TLR-dependent and -independent innate immune responses to T. cruzi.     

固有免疫细胞及其模式识别受体与表观遗传学调控研究进展

固有免疫细胞是机体抵御病原微生物的首道防线,亦是机体有效启动和维持免疫反应的重要参与者,而模式识别受体是固有免疫细胞发挥免疫功能的重要免疫分子,因此,机体对固有免疫细胞及其模式识别受体的精细调控尤为重要。表观遗传学是近年研究热点,其在固有免疫调节中的作用逐渐受到重视。就近年表观遗传学中的DNA甲基化、组蛋白共价修饰及非编码RNA等在调节固有免疫细胞分化发育及其模式识别受体的相关研究作一简述,以期为感染、炎症、自身免疫病等研究与防治提供新的思路和策略。