Activation Of Pattern Recognition Receptors Research Articles

Antigen archiving and management by lymphatic endothelial cells. (INC1P.363)

Abstract Antigen derived from virus infections such as influenza and Vesicular Stomatitis Virus (VSV) can persist well beyond the natural rise and fall of the adaptive immune response against the infection. Antigen can similarly persist following both viral Vaccinia challenge and subunit vaccination. Surprisingly, persisting antigen from either Vaccinia or subunit vaccination is captured and maintained by a stromal cell subset: Lymphatic Endothelial Cells (LECs). The duration of antigen persistence is directly correlated with antigen dose and pattern recognition receptor (PRR) activation. PRR induced inflammation leads to LEC proliferation followed by antigen persistence in the lymph node. The coupling of LEC proliferation and antigen capture identifies a novel mechanism by which the secondary lymphoid stroma stores, or “archives”, antigens for extended periods of time after antigen challenge. Consistent with the idea that viral antigen persistence impacts the function of circulating memory T cells, we find that vaccine elicited antigen archiving on LECs has a significant impact on the fate of circulating memory T cells. As such, antigen archiving on LECs leads to increased production of interferon gamma and interleukin 2 by antigen specific CD8 T cells and protection against secondary infection. These findings may broadly impact our understanding of how lymph node stroma, specifically LECs, are involved in i) managing antigen and ii) protecting against re-infection.

Drugs to block cytokine signaling for the prevention and treatment of inflammation-induced preterm birth.

Preterm birth (PTB) at less than 37 weeks of gestation is the leading cause of neonatal morbidity and mortality. Intrauterine infection (IUI) due to microbial invasion of the amniotic cavity is the leading cause of early PTB (<32 weeks). Commensal genital tract Ureaplasma and Mycoplasma species, as well as Gram-positive and Gram-negative bacteria, have been associated with IUI-induced PTB. Bacterial activation of Toll-like receptors and other pattern recognition receptors initiates a cascade of inflammatory signaling via the NF-κB and p38 mitogen-activated protein kinase (MAPK) signaling pathways, prematurely activating parturition. Antenatal antibiotic treatment has had limited success in preventing PTB or fetal inflammation. Administration of anti-inflammatory drugs with antibiotics could be a viable therapeutic option to prevent PTB and fetal complications in women at risk of IUI and inflammation. In this mini-review, we will discuss the potential for anti-inflammatory drugs in obstetric care, focusing on the class of drugs termed “cytokine suppressive anti-inflammatory drugs” or CSAIDs. These inhibitors work by specifically targeting the NF-κB and p38 MAPK inflammatory signaling pathways. Several CSAIDs are discussed, together with clinical and toxicological considerations associated with the administration of anti-inflammatory agents in pregnancy.

Differential adjuvant activities of TLR7 and TLR9 agonists inversely correlate with nitric oxide and PGE2 production.

Activation of different pattern recognition receptors causes distinct profiles of innate immune responses, which in turn dictate the adaptive immune response. We found that mice had higher CD4+ T cell expansion to an immunogen, ovalbumin, when coadministered with CpG than with CL097 in vivo. To account for this differential adjuvanticity, we assessed the activities of CpG and CL097 on antigen-specific CD4+ T cell expansion in vitro using an OT-II CD4+ T cell/bone marrow-derived dendritic cell (DC) co-culture system. Unexpectedly, ovalbumin-stimulated expansion of OT-II CD4+ T cells in vitro was potently suppressed by both TLR agonists, with CL097 being stronger than CpG. The suppression was synergistically reversed by co-inhibition of cyclooxygenases 1 and 2, and inducible nitric oxide (NO) synthase. In addition, stimulation of OT-II CD4+ T cell/DC cultures with CL097 induced higher levels of CD4+ T cell death than stimulation with CpG, and this CD4+ T cell turnover was reversed by NO and PGE2 inhibition. Consistently, the co-cultures stimulated with CL097 produced higher levels of prostaglandin E2 (PGE2) and NO than stimulation with CpG. CL097 induced higher PGE2 production in DC cultures and higher IFN-γ in the OT-II CD4+ T cell/DC cultures, accounting for the high levels of PGE2 and NO. This study demonstrates that the adjuvant activities of immunostimulatory molecules may be determined by differential induction of negative regulators, including NO and PGE2 suppressing clonal expansion and promoting cell death of CD4+ T cells.

Melatonin attenuates carbon tetrachloride–induced liver fibrosis via inhibition of necroptosis

We investigated the protective mechanisms of melatonin (MLT) associated with necroptosis signaling and damage-associated molecular patterns, which are mediated by the activation of pattern recognition receptors in liver fibrosis. Rats were given an intraperitoneal injection of carbon tetrachloride (CCl4) dissolved in olive oil (1:3, vol/vol) twice a week (0.5 mL/kg) for 8 weeks. During this period, MLT was administered orally at 2.5, 5, and 10 mg/kg once a day. Chronic CCl4 administration increased hepatic hydroxyproline content and hepatocellular damage. MLT attenuated these increases. The expression levels of transforming growth factor β1 and α-smooth muscle actin that were increased by chronic CCl4 exposure were attenuated by MLT. CCl4 significantly increased receptor-interacting protein 1 (RIP1) expression, the formation of the RIP1 and RIP3 necrosome complex, and the level of mixed lineage kinase domain-like protein in liver tissue, which were attenuated by MLT. MLT also attenuated CCl4-induced increases in serum high-mobility group box 1 (HMGB1) and interleukin 1α, as well as the interaction between HMGB1 receptors for advanced glycation end products (RAGE). The increases in toll-like receptor 4 expression, p38, c-Jun N-terminal kinases phosphorylation, and nuclear factor κB translocation were suppressed by MLT. MLT attenuated the overexpression of RAGE, increased level of early growth response protein 1, and increased messenger RNA level of macrophage inflammatory protein 2. Our findings suggest MLT may prevent liver fibrosis by inhibiting necroptosis-associated inflammatory signaling.

Chronic Activation of Pattern Recognition Receptors Suppresses Brown Adipogenesis of Multipotent Mesodermal Stem Cells and Brown Preadipocytes

Brown adipose tissue (BAT) holds promise to combat obesity through energy‐spending, non‐shivering thermogenesis. Understanding of the regulation of BAT development can lead to novel strategies to increase BAT mass and function for obesity treatment and prevention. Here, we report the effects of chronic activation of pattern recognition receptors on brown adipogenesis of multipotent mesodermal stem C3H10T1/2 cells and immortalized brown preadipocytes derived from classical interscapular BAT of mice. Activation of NOD1, TLR4, or TLR2 by their respective synthetic ligand suppressed brown marker gene expression and lipid accumulation during differentiation of brown‐like adipocytes of C3H10T1/2. Surprisingly, activation of the PRR only during the commitment was sufficient to suppress the differentiation. PRR activation suppressed PGC‐1alpha mRNA, but induced PRDM16 mRNA at the commitment. Consistently, PRR activation suppressed the differentiation of immortalized brown preadipocytes. Activation of PRR induced NF‐κB activation in both cell types, which correlated with their abilities to suppress PPARgamma transactivation, a critical event for brown adipogenesis. Taken together, our results demonstrate that chronic PRR activation suppressed brown adipogenesis of multipotent mesodermal stem cells and brown preadipocytes, possibly through suppression of PPARgamma transactivation. The results suggest that anti‐ inflammatory therapies targeting PRRs may be beneficial for the BAT development.

International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease.

Since the discovery of Toll, in the fruit fly Drosophila melanogaster, as the first described pattern recognition receptor (PRR) in 1996, many families of these receptors have been discovered and characterized. PRRs play critically important roles in pathogen recognition to initiate innate immune responses that ultimately link to the generation of adaptive immunity. Activation of PRRs leads to the induction of immune and inflammatory genes, including proinflammatory cytokines and chemokines. It is increasingly clear that many PRRs are linked to a range of inflammatory, infectious, immune, and chronic degenerative diseases. Several drugs to modulate PRR activity are already in clinical trials and many more are likely to appear in the near future. Here, we review the different families of mammalian PRRs, the ligands they recognize, the mechanisms of activation, their role in disease, and the potential of targeting these proteins to develop the anti-inflammatory therapeutics of the future.

Involvement of neutrophil hyporesponse and the role of Toll-like receptors in human immunodeficiency virus 1 protection.

ObjectivesNeutrophils contribute to pathogen clearance through pattern recognition receptors (PRRs) activation. However, the role of PRRs in neutrophils in both HIV-1-infected [HIV-1(+)] and HIV-1-exposed seronegative individuals (HESN) is unknown. Here, a study was carried out to evaluate the level of PRR mRNAs and cytokines produced after activation of neutrophils from HIV-1(+), HESN and healthy donors.MethodsThe neutrophils were stimulated with specific agonists for TLR2, TLR4 and TLR9 in the presence of HIV-1 particles. Pro-inflammatory cytokine production, expression of neutrophil activation markers and reactive oxygen species (ROS) production were analyzed in neutrophils from HESN, HIV-1(+) and healthy donors (controls).ResultsWe found that neutrophils from HESN presented reduced expression of PRR mRNAs (TLR4, TLR9, NOD1, NOD2, NLRC4 and RIG-I) and reduced expression of cytokine mRNAs (IL-1β, IL-6, IL-18, TNF-α and TGF-β). Moreover, neutrophils from HESN were less sensitive to stimulation through TLR4. Furthermore, neutrophils from HESN challenged with HIV-1 and stimulated with TLR2 and TLR4 agonists, produced significantly lower levels of reactive oxygen species, versus HIV-1(+).ConclusionsA differential pattern of PRR expression and release of innate immune factors in neutrophils from HESN is evident. Our results suggest that lower neutrophil activation can be involved in protection against HIV-1 infection.

Increased serum levels of LL37, HMGB1 and S100A9 during exacerbation in COPD patients

Chronic obstructive pulmonary disease (COPD) is a severe and progressive lung disease characterised by destruction of lung parenchyma and chronic airway inflammation [1]. A major cause of COPD is chronic exposure to noxious gases and particles, including cigarette smoke. During exacerbation, COPD patients experience a worsening of symptoms that coincides with increased inflammation and accelerated decline in lung function, resulting in a decrease in quality of life and increased healthcare costs. Approximately half of the COPD exacerbations causing hospitalisation are associated with respiratory viral and/or bacterial infections [2]. However, the underlying mechanisms causing COPD exacerbations are unknown [3]. Molecules derived from viruses and bacteria during airway infection can trigger the activation of pattern recognition receptors (PRRs) on lung structural and innate immune cells, and may thus contribute to the aggravation of inflammation during COPD exacerbations [1]. Interestingly, damage-associated molecular patterns (DAMPs) released from damaged or necrotic cells are also known to activate PRRs, including Toll-like receptors (TLRs) and the receptor for advanced glycation end-products (RAGE) [4]. A role for DAMPs has been proposed in the pathogenesis of COPD, as various DAMPs have been found to be increased in lung fluids and serum of COPD patients [5, 6]. Furthermore, Ager , the gene encoding RAGE, has been identified by genome-wide association studies as a susceptibility gene for COPD [7, 8]. Moreover, the serum levels of soluble RAGE (sRAGE), a decoy receptor for RAGE, were shown to be significantly lower in COPD patients, while the RAGE ligand EN-RAGE (also known as S100 calcium-binding protein (S100)A12) was significantly higher in COPD patients compared with smoking and nonsmoking controls [9]. It is currently unknown, however, whether DAMPs play a role in COPD exacerbations. Here, we hypothesised that the release of DAMPs is increased during exacerbations of COPD. Serum levels of the RAGE-activating DAMPs LL37, HMGB1 and S100A9 are increased during exacerbation in COPD patients http://ow.ly/Idh3r

The many interactions between the innate immune system and the response to radiation

The role of the immune system in the protection of the organism against biological aggressions is long established and well-studied. A new role emerged more recently in the protection from – and the response to – physical trauma such as exposure to ionizing radiation. A pre-existing inflammation, induced by administration of an inflammatory cytokine or of a Toll-like receptor agonist, is indeed able to mitigate the toxic effects of acute radiation exposure. Conversely, it appears that the innate immune system can be activated during the course of the cellular response to radiation. Activation of different sensors and pattern recognition receptors by intra-cellular molecules such as HMGB1 or DNA released in the extra-cellular milieu or in the cytosol by irradiated cells induces the production of inflammatory and anti-viral cytokines. In addition, in human monocytes and macrophages, the expression of inflammatory cytokine genes can be directly induced by p53- and ATM-dependent mechanisms. This last finding establishes a direct link between radiation-induced DNA damage response and radiation-induced inflammation.

Chronic activation of pattern recognition receptors suppresses brown adipogenesis of multipotent mesodermal stem cells and brown pre-adipocytes.

Brown adipose tissue (BAT) holds promise to combat obesity through energy-spending, non-shivering thermogenesis. Understanding of regulation of BAT development can lead to novel strategies to increase BAT mass and function for obesity treatment and prevention. Here, we report the effects of chronic activation of PRR on brown adipogenesis of multipotent mesodermal stem C3H10T1/2 cells and immortalized brown pre-adipocytes from the classical interscapular BAT of mice. Activation of NOD1, TLR4, or TLR2 by their respective synthetic ligand suppressed brown marker gene expression and lipid accumulation during differentiation of brown-like adipocytes of C3H10T1/2. Activation of the PRR only during the commitment was sufficient to suppress the differentiation. PRR activation suppressed PGC-1α mRNA, but induced PRDM16 mRNA at the commitment. Consistently, PRR activation suppressed the differentiation of immortalized brown pre-adipocytes. Activation of PRR induced NF-κB activation in both cells, which correlated with their abilities to suppress PPARγ transactivation, a critical event for brown adipogenesis. Taken together, our results demonstrate that chronic PRR activation suppressed brown adipogenesis of multipotent mesodermal stem cells and brown pre-adipocytes, possibly through suppression of PPARγ transactivation. The results suggest that anti- inflammatory therapies targeting PRRs may be beneficial for the BAT development.

Implication of pattern-recognition receptors in cardiovascular diseases.

Pattern-recognition receptors (PRRs) are a family of receptors that are used to detect pathogen-associated molecular patterns or damage-associated molecular patterns, which initiate immune responses to resolve infections and repair damaged tissues. Abnormalities in PRR activation will unavoidably lead to excessive inflammation. Although multiple pathophysiological processes are involved in cardiovascular disease, recent studies have highlighted the importance of innate PRRs, in particular, Toll-like receptors and nucleotide-binding oligomerization domain-like receptors, in mediating inflammatory responses and cardiovascular function. The functional roles and regulatory mechanisms of PRRs in cardiovascular diseases are still largely unknown. In particular, controversies exist on the certainty of these detrimental or beneficial effects of some PRRs in different diseased states or different experimental animal models. Considering that the molecular mechanisms for individual PRR to regulate cellular function are complex and multiple PRRs are activated simultaneously or synergistically, a better understanding of the function of individual PRRs and the interplay of PRRs will provide unexpected opportunities to develop new therapies for cardiovascular disease by modulation of an innate immune system.

Pattern Recognition Receptors in Cancer Progression and Metastasis.

The innate immune system is an integral component of the inflammatory response to pathophysiological stimuli. Toll-like receptors (TLRs) and inflammasomes are the major sensors and pattern recognition receptors (PRRs) of the innate immune system that activate stimulus (signal)-specific pro-inflammatory responses. Chronic activation of PRRs has been found to be associated with the aggressiveness of various cancers and poor prognosis. Involvement of PRRs was earlier considered to be limited to infection- and injury-driven carcinogenesis, where they are activated by pathogenic ligands. With the recognition of damage-associated molecular patterns (DAMPs) as ligands of PRRs, the role of PRRs in carcinogenesis has also been implicated in other non-pathogen-driven neoplasms. Dying (apoptotic or necrotic) cells shed a plethora of DAMPs causing persistent activation of PRRs, leading to chronic inflammation and carcinogenesis. Such chronic activation of TLRs promotes tumor cell proliferation and enhances tumor cell invasion and metastasis by regulating pro-inflammatory cytokines, metalloproteinases, and integrins. Due to the decisive role of PRRs in carcinogenesis, targeting PRRs appears to be an effective cancer-preventive strategy. This review provides a brief account on the association of PRRs with various cancers and their role in carcinogenesis.

Can a synergistic activation of pattern recognition receptors by plant immunomodulators enhance the effect of oncologic therapy? Case Report of a patient with uterus and ovary sarcoma

Can a synergistic activation of pattern recognition receptors by plant immunomodulators enhance the effect of oncologic therapy? Case Report of a patient with uterus and ovary sarcoma

Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives.

The inflammasome is a molecular platform formed by activation of an innate immune pattern recognition receptor seed, such as NLRP3. Once activated, NLRP3 recruits the adapter ASC (apoptosis-related speck-like protein containing a caspase recruitment domain), which in turn recruits procaspase-1. Procaspase-1 autocatalyzes its cleavage and activation, resulting in maturation of the precursor forms of interleukin (IL)-1β and IL-18 into active proinflammatory cytokines and initiation of pyroptotic cell death. The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of diseases, including genetically inherited autoinflammatory conditions as well as chronic diseases in which NLRP3 is abnormally activated. The NLRP3 inflammasome has been linked to diseases such as Alzheimer’s disease, atherosclerosis, metabolic syndrome, and age-related macular degeneration. In this review, we describe the NLRP3 inflammasome complex and its activation in disease, and detail the current therapies that modulate either the NLRP3 inflammasome complex itself or the two cytokines it is responsible for activating, ie, IL-1β and IL-18.

Recognition of Specified RNA Modifications by the Innate Immune System.

Microbial nucleic acids have been described as important activators of human innate immune responses by triggering so-called pattern recognition receptors (PRRs) that are expressed on innate immune cells, including plasmacytoid dendritic cells and monocytes. Although host and microbial nucleic acids share pronounced chemical and structural similarities, they significantly differ in their posttranscriptional modification profile, allowing the host to discriminate between self and nonself. In this regard, ribose 2'-O-methylation has been discovered as suppressor of RNA-induced PRR activation. Although 2'-O-methylation occurs with higher frequencies in eukaryotic than in prokaryotic RNA, the immunosuppressive properties of 2'-O-methylated nucleotides may be misused by certain bacteria as immune evasion mechanism. In the course of identifying inhibitory RNA modifications, our groups have synthesized and comparatively analyzed a series of differentially modified RNAs, so-called modivariants, for their immune stimulatory capacities. In this chapter, we will detail the protocols for the design and synthesis of RNA modivariants by molecular cut-and-paste techniques (referred to as molecular surgery) and describe testing of their immune stimulatory properties upon transfection into peripheral blood mononuclear cells.

Prostaglandin pathways in duodenal chemosensing.

Acid-sensing pathways, which trigger mucosal defense mechanisms in response to luminal acid, involve the rapid afferent-mediated "capsaicin pathway" and the sustained "prostaglandin (PG) pathway." Luminal acid quickly increases protective PG synthesis and release from epithelia, although the mechanism by which luminal acid induces PG synthesis is still mostly unknown. Acid exposure augments purinergic ATP-P2Y signaling by inhibition of intestinal alkaline phosphatase activity. Since P2Y activation increases intracellular Ca2+, we further hypothesized that ATP-P2Y signals increase the generation of H2O2 derived from dual oxidase, a member of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family activated by Ca2+. Our recent studies suggest that acid exposure increases H2O2 output, followed by phospholipase A2 and cyclooxygenase activation, increasing PG synthesis. Released prostaglandin E2 augments protective HCO3- and mucus secretion via EP4 receptor activation. Thus, the PG pathway as a component of duodenal acid sensing consists of acid-related intestinal alkaline phosphatase inhibition, ATP-P2Y signals, dual oxidase 2-derived H2O2 production, phospholipase A2 activation, prostaglandin E2 synthesis, and EP4 receptor activation. The PG pathway is also involved in luminal bacterial sensing in the duodenum via activation of pattern recognition receptors, including Toll-like receptors and nucleotide-binding oligomerization domain 2. The presence of acute mucosal responses to luminal bacteria suggests that the duodenum is important for host defenses and may reduce bacterial loading to the hindgut using H2O2, complementing gastric acidity and anti-bacterial bile acids.

Inflammation increases plasma angiopoietin-like protein 4 in patients with the metabolic syndrome and type 2 diabetes

BackgroundAngiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase and associates with dyslipidemia. The expression of ANGPTL4 is regulated by free fatty acids (FFA) that activate lipid-sensing peroxisome proliferator-activated receptors (PPARs), but...

Abstract 13855: The Impact of Plasma Levels of Receptor for Advanced Glycation End-products and High Mobility Group Box 1 in Patients With Pulmonary Hypertension

Background: In pulmonary hypertension (PH), the increase of pulmonary artery pressure by vasoconstriction, remodeling of small pulmonary arteries, and chronic pulmonary thromboembolism result in right ventricular failure and ultimately death. Nuclear protein, high mobility group box 1 (HMGB1), stabilizes nucleosome, and on release into extracellular environment, HMGB1 acts as a pro-inflammatory cytokine by activating pattern recognition receptors including receptor for advanced glycation end-products (RAGE). HMGB1 is one of endogenous ligands of RAGE, and HMGB1 and RAGE are ubiquitously expressed in various organs. Several reports have recently revealed that RAGE is expressed in pulmonary artery in patients with PH, and HMGB1 contributes to migration of vascular smooth muscle cells in PH patient. The purpose of this study was to examine the clinical significance of circulating levels of HMGB1 and RAGE in patients with PH. Methods and Results: Plasma levels of HMGB1 and soluble RAGE were measured in 33 patients with PH (9 in idiopathic PH, 7 in PH related to collagen disease, 9 in chronic thromboembolic PH (CTEPH), 8 in others) and 30 normal subjects as control. Plasma levels of HMGB1 were not difference between PH patients and control subjects, however, plasma levels of soluble RAGE were significantly higher in patients with PH than in control (1464.2 vs. 831.7 pg/ml, P=0.008). Plasma soluble RAGE levels were higher in idiopathic PH (P&lt;0.001), PH related to collagen disease (P=0.050), and CTEPH (P=0.002) than control. In addition, there was statistically significant positive correlation between pressure gradient of tricuspid valve and plasma level of soluble RAGE (R=0.403, P=0.019). Conclusions: Plasma levels of soluble RAGE, but not HMGB1, might be a novel marker which reflects the pathological conditions in patients with PH.

S-1: Regnase-1, a ribonuclease involved in the inflammatory and immune responses

Gene expression is controlled at multiple points, including signal transduction, transcription and mRNA stability. So far, transcriptional regulation has been extensively studied. However, recent studies have revealed that control of gene expression at the mRNA level is as important as transcriptional control in the immune response. The innate immune system is an evolutionally conserved host defense mechanism against pathogens. Innate immune responses are initiated by activation of pattern recognition receptors (PRRs), which recognize microbial components. Among them, Toll-like receptors (TLRs) are capable of sensing organisms ranging from bacteria to fungi, protozoa and viruses, and play a major role in innate immunity. Individual TLRs recognize different microbial components, activate different signaling pathways via selective usage of adaptor molecules, and give rise to different patterns in gene expression. We are now focusing on the role of genes induced in response to TLR stimulation, particularly the genes that are rapidly induced in a MyD88-dependent manner within 30 min after LPS stimulation. Among them, we have recently identified a novel gene named Zc3h12a which has a CCCH-type zinc finger domain. The knockout mice developed spontaneous autoimmune diseases accompanied by splenomegaly and lymphadenopathy. Subsequent studies showed that Zc3h12a is a nuclease involved in destabilization of IL-6 and IL-12mRNA via the stem loop structure present in the 3’UTR of these genes. We renamed it Regulatory RNase-1 (Regnase-1) based on the function. I would like to discuss the role of Regnase-1 in the immune response.

Scaling of immune responses against intracellular bacterial infection.

Macrophages detect bacterial infection through pattern recognition receptors (PRRs) localized at the cell surface, in intracellular vesicles or in the cytosol. Discrimination of viable and virulent bacteria from non-virulent bacteria (dead or viable) is necessary to appropriately scale the anti-bacterial immune response. Such scaling of anti-bacterial immunity is necessary to control the infection, but also to avoid immunopathology or bacterial persistence. PRR-mediated detection of bacterial constituents in the cytosol rather than at the cell surface along with cytosolic recognition of secreted bacterial nucleic acids indicates viability and virulence of infecting bacteria. The effector responses triggered by activation of cytosolic PRRs, in particular the RIG-I-induced simultaneous rapid type I IFN induction and inflammasome activation, are crucial for timely control of bacterial infection by innate and adaptive immunity. The knowledge on the PRRs and the effector responses relevant for control of infection with intracellular bacteria will help to develop strategies to overcome chronic infection.