http://informahealthcare.com/mby ISSN: 1040-841X (print), 1549-7828 (electronic) Crit Rev Microbiol, Early Online: 1–12 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/1040841X.2014.929563

REVIEW ARTICLE

Innate immunity networks during infection with Borrelia burgdorferi Marije Oosting1,2, Kathrin Buffen1,2, Jos W. M. van der Meer1,2, Mihai G. Netea1,2, and Leo A. B. Joosten1,2 Department of Internal Medicine, and 2Nijmegen Institute of Infection, Inflammation and Immunity (N4i), Radboud University Medical Centre, Nijmegen, The Netherlands

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Abstract

Keywords

The recognition of Borrelia species represents a complex process in which multiple components of the immune system are involved. In this review, we summarize the interplay between the host innate system and Borrelia spp., from the recognition by pattern recognition receptors (PRRs) to the induction of a complex network of proinflammatory mediators. Several PRR families are crucial for recognition of Borrelia spp., including Toll-like receptors (TLRs) and Nucleotide Oligomerization Domain (NOD)-like receptors (NLRs). TLR-2 is crucial for the recognition of outer surface protein (Osp)A from Borrelia spp. and together with TLR8 mediates phagocytosis of the microorganism and production of type I interferons. Intracellular receptors such as TLR7, TLR8 and TLR9 on the one hand and the NLR receptor NOD2 on the other hand, represent the second major recognition system of Borrelia. PRR-dependent signals induce the release of pro-inflammatory cytokines such as interleukin-1 and T-helper-derived cytokines, which are thought to mediate the inflammation during Lyme disease. Understanding the regulation of host defense mechanisms against Borrelia has the potential to lead to the discovery of novel immunotherapeutic targets to improve the therapy against Lyme disease.

Cytokines, Lyme disease, pattern recognition receptors, recognition

Introduction Lyme disease is one of the most frequently occurring zoonoses. The disease is mainly encountered in the Northern hemisphere with high occurrence in Europe and America. The Centers for Disease Control and Prevention reported over 300 000 cases of confirmed Lyme disease patients in 2013 in the United States of America, whereas already 22 000 cases of erythema migrans (EM) where reported in 2010 in the Netherlands. The disease is caused by Borrelia species and transmitted by ticks. This review focuses on Lyme-causing Borreliae, since other Borrelia spp. are described to cause relapsing fever (Miller et al., 2013). Since the original description of the disease by Steere and co-workers in 1975 (Steere et al., 1977) and the discovery of the causative pathogen by Burgdorfer et al. (1982), our knowledge of the etiology and pathogenesis of Lyme disease has increased tremendously. Research into Lyme disease has been triggered by its increasing incidence. Although clinicians still have difficulties making the diagnosis, signs and symptoms of the infection are nowadays better recognized, and this results in early antibiotic treatment in many patients. In a small percentage of the patients, symptoms may persist, despite

Address for correspondence: Leo A. B. Joosten, PhD, Department of Internal Medicine (463), Radboud University Medical Centre, Geert Grooteplein Zuid 8, 6525 GA, Nijmegen, The Netherlands. Tel: 00-31-24-3613283. Fax: 00-31-24-3541734. E-mail: [email protected]

History Received 21 February 2014 Revised 22 May 2014 Accepted 27 May 2014 Published online 23 June 2014

antibiotic treatment, but in most of the patients, clinical symptoms completely disappear after treatment (Steere et al., 2004). To what extent the prolonged illness is due to persistent infection, persistent non-infectious inflammation or neither is controversial. Thus more insight into the pathogenesis of Lyme disease and its sequelae will help in the management of patients to develop novel treatment modalities in the future. This review gives an update on Borrelia recognition by the host defense system, the downstream signaling pathways, cytokine production and effector mechanisms.

Borrelia characteristics and early host defense Borrelia burgdorferi, Borrelia afzelii, and Borrelia garinii are stained as Gram-negative bacteria with specific morphology, but are neither true Gram-positive or Gram-negative. The spirochetal flat-waved body of Borrelia is similar to that of Treponema spp., but differs from other members of the family of Leptospiraceae (Charon et al., 2012). Borrelia has a typical coiled spiral shape, with lengths ranging from 3 to 500 mm and a diameter ranging from 0.09 to 0.75 mm (Olson, 2013). This variation in diameter might be dependent on the environment from which the spirochetes originate, but not crucial for their pathogenic behavior. For example, the typical coiled shape Borrelia was detected in biopsies from kidney or EM, whereas straightened bacteria were found in solid tissues (Macdonald, 2013). Flagellin-lacking spirochetes could be detected in myocardial infection in macaques (Cadavid et al., 2000).

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At least three genospecies of the B. burgdorferi sensu lato complex can cause Lyme disease in humans; B. burgdorferi, B. garinii and B. afzelii. B. burgdorferi sensu stricto is mainly found in the northern part of the United States, causing predominantly flu-like illness but also Lyme arthritis, whereas B. garinii and B. afzelii occur in Eurasia, where they can lead to neurological and skin complications (Radolf et al., 2012). Borrelia has a complex, but relatively small, genome displaying a linear chromosome as well as several circular and linear plasmids (Fraser et al., 1997). Borrelia has 21 plasmids, of which nine are circular and the others linear, thereby expressing the most plasmids of all prokaryotes (Olson, 2013). In contrast to Gram-negative bacteria, lipopolysaccharide (LPS) is not expressed by this bacterium, as the relevant genes are absent (Takayama et al., 1987). When injected into the bloodstream of the host by the tick, Borrelia is sensitive to proteases that are released by the host defense system (Fraser et al., 1997; Guyard et al., 2006; Kumru et al., 2011). Borrelia spirochetes express a variety of proteins on their outer surface that modulates the defense system of the host. One family of proteins expressed by Borrelia belongs to the OSP family, of which OspA and OspC are best known. OspC is expressed during early stages of infection and has recently been described to bind host plasminogen and thereby support dissemination of the Borrelia bacterium (Figure 1) (Onder et al., 2012). When OspC is bound to plasminogen, it is more difficult for the host defense system to recognize the pathogen. Other OSPs of Borrelia (such as decorin-binding proteins and complement regulator proteins) also contribute to protection of the bacterium against degradation by the host defense system. The immune system of the host is able to react to pathogenic bacteria in a short timeframe with a wide range of different immune cells. Already in 1984, it was described that Borrelia could be recognized and phagocytosed by

Figure 1. Borrelia expressed OspC can be recognized through complement receptor 3. Borrelia spirochetes express linear as well as plasmid DNA structures that encode immune evasion genes. Borrelia binds to host plasminogen, subsequently inhibiting the capacity of the host immune system to recognize it. After transmission of Borrelia, outer surface protein (Osp) C on the surface of Borrelia is upregulated, which can be recognized by receptors of the host white blood cells (WBC), such as complement receptors (CR). Borrelia-directed immune responses and production of cytokines are initiated after activation of complement receptors on host cells.

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neutrophils and macrophages (Benach et al., 1984). Phagocytosis of Borrelia by human neutrophils has been demonstrated by electron microscopy (Peterson et al., 1984). In conjunction with phagocytosis, neutrophils are capable of eliminating Borrelia by oxidative burst and release of lysosomal hydrolytic enzymes. Chemoattractants for polymorphonuclear (PMN) leukocytes have been detected in human synovial fluids from Borrelia-infected knee joints (Georgilis et al., 1991). Recently, Borrelia was shown unable to inhibit the formation of neutrophil extracellular traps (NETs). Furthermore, the proteins found in the tick saliva, which are known to have immune inhibitory capacities, were incapable of influencing the formation of NETs by human neutrophils (Menten-Dedoyart et al., 2012). T helper 1 (Th1) cells seem to be among the main players in both the innate and the adaptive immune responses against Borrelia. OspC molecules are able to induce a strong Th1-like immune response (Strle et al., 2011), leading to the production of Interferon (IFN)-g and sizable amounts of interleukin (IL)-1b, IL-6 and IL-8 (Strle et al., 2009). This is the rationale why OspC has been proposed as a vaccine candidate. Indeed, an experimental recombinant OspC vaccine in mice-induced protective Th1 responses and a strong anti-OspC IgG2 response (Krupka et al., 2012). Although this study demonstrates a strong antibody response, protection against Borrelia infection and development of clinical signs were not studied.

Complement activation and Borrelia killing The complement system is an important component of the innate immune response and able to respond within minutes. The complement system can be activated in three different ways; through the classical pathway, the lectin pathway and the alternative pathway. All three activation pathways can be activated in Borrelia infection (De Taeye et al., 2013). Complement factor C1q binds to IgG or IgM antibodies attached to the bacterial surface after which the complement cascade is activated leading to activation of C2 and C4 via the classical pathway (De Taeye et al., 2013). Activation of the lectin pathway is initiated by binding of mannose binding lectin to carbohydrates on the surface of Borrelia, and the alternative pathway is initiated by spontaneous activation of C3 on the bacterial surface. All three pathways lead to the formation of C3 and C5 convertases and finally cell lysis by formation of the membrane attack complex (Schuijt et al., 2011). The C3 molecule binds covalently to proteins expressed by Borrelia, and this results in opsonization of this pathogen. The opsonized Borrelia is recognized by complement receptor (CR)1, CR2 and CR3 on phagocytic cells. CR1 and CR2 are not the major CRs involved in Borrelia recognition, although mice lacking CR1 and CR2 showed less production of antibodies against Borrelia compared to wild-type animals (Jacobson et al., 2007). Nevertheless, the severity of Borreliainduced arthritis after intradermal injection of live B. burgdorferi was similar in CR1/CR2 gene-deficient mice and wild-type mice (Jacobson et al., 2007). Borrelia induces increased expression of CR3 on PMN neutrophils (Cinco et al., 2000). Binding of Borrelia to CR3, which also occurs directly through ligation of OspA and

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DOI: 10.3109/1040841X.2014.929563

OspB, induces the oxidative burst and phagocytosis as demonstrated in THP-1 cells and freshly isolated human neutrophils (Garcia et al., 2005; Suhonen et al., 2000). Opsonization of Borrelia is dependent on CD14. In mice lacking CR3, the phagocytosis of Borrelia is diminished, and the latter leads to dissemination of the spirochetes after subcutaneous injection of live B. burgdorferi (Hawley et al., 2012). Carditis with elevated numbers of infiltrating macrophages and increased levels of chemoattractants is a manifestation of the dissemination (Hawley et al., 2012). The complement system is able to kill several strains of Borrelia (so-called serum-sensitive strains). Borrelia species differ in their susceptibility to complement activation. Most isolates of B. afzelii are complement resistant, while most B. garinii strains are complement sensitive. B. burgdorferi sensu stricto is generally intermediate in terms of complement sensitivity (Breitner-Ruddock et al., 1997; Kraiczy et al., 2001; Van Dam et al., 1997). Of high interest, several Borrelia family members, including B. burgdorferi B31, are able to survive the action of complement. The formation of the membrane attack complex is not induced by these strains (De Taeye et al., 2013). These particular Borrelia strains are able to interfere with both complement activation and complement-mediated lysis in a number of ways. Complement regulator acquiring surface proteins (CRASPs) are lipoproteins on the cell surface of Borrelia, which are able to bind factor H, factor H-like protein 1 and factor H-related proteins of the complement system, which are described to inhibit overactivation of the complement system (Kraiczy et al., 2001, 2004; Siegel et al., 2010). CRASP-3, -4 and -5 (Hammerschmidt et al., 2012; Steere et al., 2004) and OspE (Kenedy & Akins, 2011), expressed on the outer surface of Borrelia, are able to interfere with complement activation. CRASP-1 and CRASP-2 were described to confer resistance against complement activation and killing by components from the serum (Kenedy et al., 2009). Borrelia was also found to bind to C4-binding protein, an inhibitor of the classical pathway that binds to C4b, thereby preventing C2 binding and formation of the C3 convertase C4b2a (Pietikainen et al., 2010). In addition, Borrelia utilizes the complement-regulator proteins present in the salivary glands of the ticks (salivary proteins, Salp8 and Salp15), to inhibit the complement system (Schuijt et al., 2008, 2011).

Pattern recognition receptors involved in Borrelia recognition Cells of the immune system need to be activated before cytokines or chemokines can be produced. These activation mechanisms can be induced after the recognition of highly specific microbial ligands, so-called pathogen-associated molecular patterns (PAMPs), by pattern recognition receptors (PRRs). Several families of PRRs have been described, including TLRs, Nucleotide Oligomerization Domain (NOD)-like receptors (NLRs), C-type lectins (CTLs) and RigI-helicases. Toll-like receptors The TLR-family comprises 11 human and 13 murine receptors. TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 are

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mainly found on the surface of cells, whereas TLR3, TLR7, TLR8 and TLR9 are located intracellularly. TLR11 is nonfunctional in humans due to an early stop codon in the coding gene (Lauw et al., 2005). Each of the TLRs recognizes a specific set of microbial ligands. TLR1/TLR2 heterodimers recognize triacetylated bacterial peptides, whereas TLR2/TLR6 complexes recognize mainly diacetylated bacterial peptides (Takeuchi et al., 2001, 2002). TLR3 recognizes double-stranded RNA as found in viruses, whereas TLR7 and TLR8 recognize viruses through single stranded RNA. TLR9 recognizes bacterial DNA structures with a CpG motif (Kawai & Akira, 2009), whereas the ligands for TLR10 are not yet known. Role of TLR1, TLR2 and TLR6 for Borrelia recognition and the pathogenesis of Lyme disease By recognizing lipopeptides (e.g. OspA) from Borrelia species (Figure 2) (Akira & Takeda, 2004; Lien et al., 1999), TLR2 represents a key recognition receptor present on immune cells (Hirschfeld et al., 2000). Blockade of TLR2 leads to an abrogated immune responses induced by Borrelia exposure in human primary cells (Oosting et al., 2010). Furthermore, variations in the human TLR2 gene appear to result in different clinical outcomes in Lyme disease (Wooten et al., 2002). TLR2 forms either homodimers or heterodimers with TLR1 or TLR6. By interacting with co-receptors, TLR2 is able to recognize a broad range of microbial ligands, including peptidoglycans, lipopeptides and fungal polysaccharides (Oliveira-Nascimento et al., 2012). Until recently, it was unclear whether Borrelia was recognized by either TLR2/ 6 or TLR1/2 heterodimers. By using RNA silencing approaches, it was shown that both TLR1 and TLR2 are important (Dennis et al., 2009); after silencing of either TLR1 or TLR2, reduced amounts of the pro-inflammatory cytokines IL-6 and tumor necrosis factor (TNF)-a were produced by a human monocytic cell line (THP-1) exposed to live Borrelia. We corroborated this study using human peripheral blood mononuclear cells (PBMCs) bearing single nucleotide polymorphisms (SNPs) in TLR genes leading to dysfunctional TLR molecules. Individuals carrying SNPs in the TLR1 gene displayed abrogated cytokine responses after Borrelia stimulation, whereas a specific SNP in the TLR6 gene did not affect cytokine induction by Borrelia (Oosting et al., 2011a). Moreover, in TLR2-transfected human endothelial cells, it was demonstrated that additional transfection of TLR6 inhibited the response after OspA stimulation (Bulut et al., 2001). TLR6 gene expression was downregulated after stimulation of human monocytes with live Borrelia (Salazar et al., 2009). Cells isolated from mice lacking TLR6 displayed the same cytokine response to OspA exposure as wild-type animals (Takeuchi et al., 2001). Taken together, TLR1, rather than TLR6, is important for the recognition of Borrelia by the host defense system. There is additional evidence that TLR1 and TLR2 are important in a murine model of Lyme disease. Wooten et al. demonstrated that higher spirochetal numbers were found in joints of TLR2-deficient mice eight weeks after intradermal infection with live B. burgdorferi (Wooten et al., 2002).

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Figure 2. Recognition and function of specific pattern recognition receptors. Borrelia spirochetes can be recognized by several different PRRs. Each of these PRR will induce different immune responses against Borrelia. In addition, Toll-like receptor family members, C-type lectin and NOD-like receptor family members are described to play a role in Borrelia-induced immune responses.

Higher amounts of Borrelia were also observed in skin and bladder of TLR1/2 deficient mice after transmission of Borrelia via tick bites (Fikrig et al., 2009). In addition, Borrelia-induced Lyme arthritis was significantly enhanced in mice missing TLR1 or TLR2, as demonstrated by increased local cell influx after OspA immunization or intradermal Borrelia injection (Alexopoulou et al., 2002; Wang et al., 2008). TLR1/2 heterodimers are therefore crucial for the recognition and for controlling the outgrowth of Borrelia in vivo, as well as for Borrelia-induced inflammation. TLR3 TLR3 is a receptor for double-stranded viral RNA and induces production of type I IFNs (Shin et al., 2009). Although it is currently not known whether Borrelia PAMPs are recognized by TLR3, type I IFN transcription and production by human monocytes or bone-marrow derived macrophages induced by Borrelia species has been described (Figure 2) (Salazar et al., 2009; Shin et al., 2009). As discussed below, TLRs other than TLR3, such as TLR7 and TLR8, are able to induce Borrelia-dependent type I IFN production (Cervantes et al., 2011). TLR4 Borrelia spirochetes lack LPS on their membrane, due to the fact that Borrelia misses the DNA sequence for enzymes necessary for synthesis of the polysaccharide tail of LPS (Fraser et al., 1997; Takayama et al., 1987). Hence they miss a major TLR4 ligand and as expected, no differences in cytokine response could be observed between murine TLR4-deficient cells and normal murine cells exposed to live Borrelia spirochetes (Oosting et al., 2010). However, a different study suggested that mice lacking TLR4 developed less Lyme arthritis, and macrophages isolated from these mice produced less IL-12 and TNF-a after live Borrelia exposure in vivo (Glickstein & Coburn, 2006). In contrast, the

mRNA expression for TLR4 in human PBMCs is even downregulated by in vitro exposure to Borrelia, pointing to a minor role for this PRR in the recognition of Borrelia (Petzke et al., 2009). CD14 is the well-known co-receptor for TLR4 and known to exhibit its own pathogen-recognizing capacity by interacting with bacterial cell wall components (Pugin et al., 1994). CD14 on human cells recognizes intact Borrelia organisms and more specifically OspA (Figure 2) (Giambartolomei et al., 1999). OspA not only signals through CD14 but also upregulates the CD14 gene expression in human primary cells (Cabral et al., 2006; Sellati et al., 1998). The relevance of CD14 activation in host defense against Borrelia is exemplified by experiments using CD14-deficient mice. These mice produce more cytokines after Borrelia injection, display more severe joint inflammation and displayed a prolonged duration of Lyme disease (Sahay et al., 2009). This is due to the fact that activated CD14 is able to upregulate the suppressor of cytokine signaling; thus in the absence of CD14, this inhibitory loop is not activated leading to exaggerated TNF-a and IFN-g production. CD14 is also linked to the influx of neutrophils into infected tissues (Sahay et al., 2011), and hence a reduced neutrophil influx is seen in the CD14-deficient mice after infection with Borrelia, resulting in a higher spirochetal load in the inflamed joints (Sahay et al., 2011). TLR5 TLR5 recognizes flagellin, the major component of flagella. Although Borrelia spirochetes possess flagella responsible for their motility, these flagella are present in a cytoplasmic cylinder, unlike in most other flagellated bacteria (Radolf et al., 2012). This probably explains why TLR5 does not play a major role in the recognition of Borrelia by the human defense system (Dennis et al., 2009). This became clear in RNA-silencing experiments with THP-1 cells: there is no difference in production of pro-inflammatory cytokines

DOI: 10.3109/1040841X.2014.929563

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between TLR5 silenced cells and control cells after exposure to live Borrelia spirochetes (Dennis et al., 2009). Still, it was proposed that degradation of phagocytosed Borrelia bacteria unmasks flagella and expose them for TLR5 sensing or that other components similar to flagellin may be recognized by this particular PRR (Shin et al., 2008). However, by using genetically modified live Borrelia lacking flagellin, it was demonstrated that TLR5 is not important for the recognition of this bacterium and subsequent cytokine production by human cells (Salazar et al., 2009). In humans with a polymorphism in the TLR5 gene leading to an altered function, no differences were observed in recognition of Borrelia between PBMCs isolated from these individuals and controls bearing the wild-type TLR5 allele after stimulation with live B. burgdorferi (Strle et al., 2012). TLR7, TLR8 and TLR9 TLR7, TLR8 and TLR9 are TLRs that are located intracellularly (Figure 2). TLR7 was formally known to selectively recognize single-stranded viral RNA. However, in 2009, Mancuso et al. demonstrated that phagocytosed bacteria are also recognized by TLR7, leading to production of type I IFNs (Mancuso et al., 2009). RNAse treatment of Streptococcus pneumoniae or Lactococcus lactis almost entirely blocked IFN-b production by human dendritic cells. It is now well established that bacterial RNA induces a strong type I IFN response that is dependent on TLR7, TLR8, TLR3 and possibly TLR9 (Kariko et al., 2005). Furthermore, IL-1b production seems to be partially dependent on recognition of bacterial RNA via TLR7 (Eberle et al., 2009). It was long assumed that only the proteins on the outer surface of Borrelia cell wall are responsible for the induction of inflammatory mediators (Wooten et al., 2002). Moore et al. (2007), however, demonstrated that phagocytosis of live Borrelia by THP-1 cells also contributes to production of proinflammatory mediators. The signaling pathways triggered by the phagocytosis of complete live B. burgdorferi by human monocytes and the exposure to the intracellular TLRs differ from those induced by OspA interacting with TLR2 on the cellular surface (Salazar et al., 2009). Exposure of bone marrow-derived macrophages to live Borrelia resulted in upregulation of IFN-regulating genes, independent of MyD88 TRIF, the co-stimulatory molecules of surface TLRs (Miller et al., 2008, 2010). It revealed that 50% of the upregulated genes after exposure of human PBMCs to live B. burgdorferi were found to be inducible by the type I IFN family (Figure 2) (Petzke et al., 2009). The precise role of TLR9 for Borrelia recognition is not known. Although some studies could not find a role for TLR9, others proposed involvement of TLR9 in induction of type I IFNs after internalization of bacteria by mouse bone-marrowderived dendritic cells or macrophages (Mancuso et al., 2009; Miller et al., 2008). While the induction of type I IFNs by live B. burgdorferi was not affected in TLR9-deficient murine BMDMs (Miller et al., 2008), recent studies with human white blood cells show involvement of TLR9 in the type I IFN induction after exposure to either heat-killed or live B. burgdorferi (Petzke et al., 2009). Blocking TLR9 with specific inhibitors almost completely abrogated production of

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IFN-a. Whether TLR7 and TLR9 require cooperation with other PRR for proper downstream signaling is unknown. Cervantes et al. (2011) recently showed that cooperation between TLR2 and TLR8 is needed for the induction of type I IFNs in human mononuclear cells (Figure 2). To this end, Borrelia-activated TLR2 has to establish a link with TLR8 intracellularly. TLR2/8 heterodimer is responsible for nuclear factor-kappaB (NFkB)-dependent cytokines, whereas TLR8 alone is responsible for the induction of type I IFNs after phagocytosis of live B. burgdorferi and recognition of borrelal RNA (Cervantes et al., 2013). These studies indicate that the type I IFNs are important mediators during Borrelia infection. It should be noted, however, that type I IFNs might enhance the inflammatory component after Borrelia infection, since it was found that treatment with antibodies against type I IFNs strongly attenuated Lyme arthritis in mice after intradermal injection of live B. burgdorferi (Miller et al., 2008). NOD-like receptors Nucleotide-binding and leucine-rich repeats (NLR) family members are a separate class of intracellular PRR. The major PRRs within this family are the NOD members 1 and 2, as well as the NLRP; Nod-like receptor family, pyrin domain containing receptors that are involved inflammasome activation. NOD1 is activated by muramyltripeptide (MTP), derived from Gram-negative bacteria, while NOD2 is activated by muramyldipeptide from Gram-positive bacteria. After activation of either NOD1 or NOD2 by these bacterial moieties, activation of the adaptor molecule RICK; rip-like interacting caspase-like apoptosis-regulatory protein kinase finally leads to transcription of NFiB and production of pro- and antiinflammatory cytokines. It has been shown that NOD2 is involved in Borreliainduced cytokine responses of human PBMCs (Oosting et al., 2010). Individuals bearing a genetic polymorphism leading to a dysfunctional NOD2 molecule display a decreased cytokine production. In line with these data, murine BMDCs lacking NOD2 also produced less cytokines after live B. burgdorferi exposure (Petnicki-Ocwieja et al., 2011). In addition, the production of cytokines by synovial tissue explants of NOD2deficient mice that were injected intraarticularly with live B. burgdorferi was reduced (Oosting et al., 2012). However, the inhibition of cytokine production was not complete, indicating that NOD2-independent signaling pathways are relevant. The NOD2-deficient BMDMs exposed to Borrelia also exhibit a downregulated type I IFN response (PetnickiOcwieja et al., 2011), but the role of NOD2 for the type I IFN production is largely redundant (Miller et al., 2010). Despite the suppressive effects on the production of type I IFNs and other proinflammatory cytokines, NOD2 did not play a major role for the development of Borrelia-induced inflammation after local injection in knee joints in mice (Oosting et al., 2012). The influx of inflammatory cells in the joint cavity of NOD2-deficient mice was similar to that of wild-type animals. These data are discrepant with the study of Petnicki-Ocwieja et al. (2011) showing that mice lacking NOD2 develop more severe Lyme arthritis than wild-type mice. An explanation for these differences may be the experimental models used. The first study exploring the local

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development of Lyme arthritis after intra-articular injection, whereas Petnicki-Ocwieja et al. studied dissemination of the infection after a local injection of live B. burgdorferi. The role of the adaptor molecule RICK has also been studied in the context of Lyme borreliosis. When RICK was blocked with a specific inhibitor, primary human cells exposed to Borrelia resulted in abrogated cytokine responses (Oosting et al., 2010). In contrast, RICK was not important in a murine model of Borrelia inflammation in knee joints (Oosting et al., 2012).

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CTL receptors CTL receptors (CLRs) are a family of pattern-recognition receptors that recognize polysaccharide structures of microorganisms. The most studied members of the CLR family are Dectin-1, Dectin-2, mannose receptor (MR), mincle and DC-SIGN; dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin. Some of the CLR family members can be activated directly through ligand binding, while others require additional signaling adaptor molecules (Vautier et al., 2010). Dectin-1 is expressed on a variety of immune cells, including monocytes and macrophages, and is upregulated by stimulation with pathogens or specific ligands including b-glucans (Reid et al., 2009). Dectin-1 synergizes with TLRs for the production of cytokines and chemokines, including IL-1b. After activation of Dectin-1, Syk or Raf-1-proteins are recruited, followed by binding to CARD9 and activation of NFkB pathway (Gringhuis et al., 2009). It is unknown whether Dectin-1 is involved in the recognition of Borrelia species. Although Borrelia spirochetes do not express beta-glucans, the typical ligands for Dectin-1, they possess lectins such as galactopyranosides, which might interact with lectin receptors present on immune cells (Lee et al., 1990; Stubs et al., 2011). Individuals carrying mutated Dectin-1 or CARD9 proteins display a disturbed cytokine production when PBMCs were stimulated with Candida albicans (Ferwerda et al., 2009; Rosentul et al., 2011). Dectin-1 also mediates Th17 responses after C. albicans recognition (Vautier et al., 2010). Although IL-17 seems to play a role in Lyme disease, it is unknown whether Dectin-1 is involved in its production (Henningsson et al., 2011; Nardelli et al., 2010). Dectin-2 was also described to be involved in Th17 responses (Robinson et al., 2009). Dectin-2 contributes to the production of pro-inflammatory cytokines, including IL-1b, after exposure to C. albicans and recognition of mannans on the fungal surface. It is still unknown whether Dectin-2 plays a role in Borrelia recognition or in the pathogenesis of Lyme disease. Ongoing studies regarding the role of Dectin-2 indicate a possible inhibitory role in Borrelia-induced immune responses (unpublished data, Oosting et al.). Not much is known about the recognition of bacteria by the MR, but a recent study shows that B. burgdorferi surface components bind to MR (Figure 2) (Cinco et al., 2001). No data are available on the function of MR in host defense against Borrelia. Some DNA sequences encoding for mannose structures are present in the Borrelia genome, but whether these structures bind to MR or other mannanrecognizing CLRs is unknown.

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Borrelia antigens, injected into the skin of healthy volunteers, led to increased transcription of TLR1 and TLR2, as well as to upregulation of DC-SIGN on dendritic cells, monocytes and macrophages (Salazar et al., 2005). A direct interaction between Borrelia spirochetes and DC-SIGN could, however, not be demonstrated. A role for DC-SIGN in the interaction with tick salivary protein Salp15 of Borrelia was suggested (Hovius et al., 2008). Salp15 was shown to inhibit the production of pro-inflammatory cytokines induced by Borrelia in human DCs, and it has been proposed that the latter mechanism enhances the survival of Borrelia shortly after transmission to the host. RIG-I like receptors A fourth family of PRRs are the RIG-I like receptors, consisting of three members, RIG-I, MDA5 and LGP2 (Yoneyama et al., 2005). These receptors mainly play a role in the recognition of viral RNA. Cells without these receptors were described to be incapable of type I IFN production upon viral challenge (Kato et al., 2011). A role for RIG-I like receptors in Borrelia has not been described so far.

Inflammasomes The inflammasome is a protein complex that is formed out of several proteins, including NLRP3, ASC and pro-caspase-1. Activation of the inflammasome leads to autocleavage and activation of pro-caspase-1. In turn, caspase-1 cleaves inactive pro-IL-1b and pro-IL-18 to generate bioactive IL-1b and IL-18, respectively. Indeed, caspase-1 is important for the Borrelia-induced production of IL-1b and IL-18 (Oosting et al., 2011c). ASC was found to be of key importance in the formation of Borrelia-induced IL-1b in mice and for the development of murine Lyme arthritis. Unexpectedly, NLRP3, which is considered as the key component of the NLRP-inflammasome, was not essential for the production of IL-1b upon Borrelia stimulation. In addition, the severity of B. burgdorferi-induced local joint inflammation in mice lacking this NLR member was not affected (Oosting et al., 2012). The upregulation of ASC and NLRP3 appeared to be dependent on caspase-1 (61). AIM2 and NLRC4 are also known to form inflammasome complexes together with ASC and pro-caspase-1. AIM2 recognizes double-stranded DNA from Gram-negative intracellular bacteria, whereas NLRC4 can be activated through Gram-negative bacteria expressing type III or IV secretion systems (Schroder & Tschopp, 2010). To date, no studies have investigated the role of AIM2 or NLRC4 inflammasomes in the pathogenesis of Lyme disease. A role for AIM2 in caspase-1 cleavage after Borrelia recognition might be present, since Borrelia is described to express a broad range of plasmids with variable DNA structures (Stewart et al., 2005). A role for NLRC4 is unlikely since type III or IV secretion systems are not present in this bacterium (Kerr, 1999).

Signaling pathways induced by Borrelia After recognition of Borrelia by immune cells, phagocytosis and intracellular signaling pathways are activated. Which

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signaling cascades are activated depends on the type of PRR engaged. TLR8 and TLR2 are critical receptors in phagosomal signaling to Borrelia (Cervantes et al., 2011). Next to that, the intracellular kinase PI3K is involved in the uptake of live B. burgdorferi, whereas the MAP kinases JNK, ERK and the components of the JAK/STAT pathway do not seem to be involved in phagocytosis by mouse bone-marrow-derived macrophages (Shin et al., 2009). MyD88 is the adaptor molecule used by almost all TLR family members and is crucial for induction of cytokine production. MyD88 forms a signaling complex called the Myddosome (Lin et al., 2010); this complex includes proteins such as mitogen-activated protein kinases (MAPK), IRAK; interleukin-1 receptor-associated kinase and IRAK4. MyD88 signaling results in activation of NFkB followed by gene transcription of proinflammatory mediators, such as cytokines and chemokines. MyD88-deficient mice are highly susceptible to the development of Lyme arthritis after intradermal injection of B. burgdorferi with spirochetal loads in the joints that are 100 times higher than in wild-type mice (Bolz et al., 2004; Liu et al., 2004). These findings point to insufficient killing of Borrelia in MyD88-deficient mice. This is compatible with the finding that phagocytes from MyD88-deficient mice are incapable of phagocytosing live B. burgdorferi (Shin et al., 2009), as will be discussed in more detail in the subsequent sections. In humans, the role of MyD88 in the development of Lyme disease is not established. Individuals with primary immunodeficiencies for MyD88 or IRAK4 suffer from severe infections with pyrogenic bacteria (Picard et al., 2011). SNPs in MyD88 leading to functional defects in the response against pathogens have not been described, but SNPs in genes encoding for proteins downstream of MyD88 are known to result in different infection rates for several pathogens. For example, a polymorphism in MyD88-adaptor like (Mal/TIRAP) was described to decrease the risk to develop complicated infections in HIV patients fourfold (Papadopoulos et al., 2012). The influence of SNPs in the adaptor molecules, TRIF or Mal/TIRAP on Lyme disease have not been studied. The role of MyD88 in Borrelia-induced activation of immune cells in vitro has been well studied (Behera et al., 2006; Oosting et al., 2012). Silencing of MyD88 mRNA in the human cell line THP-1 abrogated cytokine production after Borrelia exposure (Dennis et al., 2009). In contrast, MyD88-deficient mouse macrophages incubated with live B. burgdorferi exhibited normal type I IFN production (Miller et al., 2010), pointing to differences in signaling between mice and humans. Borrelia is able to activate the MAPK pathways dependent on JAK-STAT and p38 signaling as demonstrated by stimulating murine macrophages with Borrelia extracts and human primary chondrocytes with live B. burgdorferi (Anguita et al., 2002; Behera et al., 2004). The role of p38 was also established in vivo; mice lacking p38 kinase developed significantly less Borrelia-induced arthritis after intradermal injection than wild-type mice (Anguita et al., 2002). This effect lasted eight weeks after onset of arthritis, indicating that p38 is not only involved in the early recognition phase of Borrelia but also in the control of arthritis. The paradox that MyD88-deficient mice

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suffer from Lyme arthritis with high bacterial counts (see above) and lack of the downstream p38 is associated with attenuated arthritis is probably explained as follows. In MyD88 deficiency, the phagocyte defect leads to uninhibited growth of the organism (Shin et al., 2009). However, unlike MyD88, the downstream kinases like p38 are not required for phagocytosis of live B. burgdorferi by mouse bonemarrow-derived macrophages (Shin et al., 2008). In fact, when p38 is missing, the other MAPK pathways may take over the activation of NFiB, thereby inducing cytokines that will probably enhance bacterial killing and hence lead to less arthritis. Interestingly, the phagocytic defect in MyD88-deficient mice can be bypassed. MyD88-deficient mouse macrophages are pre-treated with poly I:C, a TLR3 ligand; phagocytosis of live Borrelia by these cells is restored (Shin et al., 2009), because TLR3 is able to transduce signals through the adaptor molecule TRIF, independent of MyD88. Likewise, phagocytosis of Borrelia by MyD88-deficient cells can be restored by transfecting CR3 (Hawley et al., 2012), underlining that several pathways are activated by Borrelia to induce downstream signaling (Hawley et al., 2012). Borrelia also induces IFN regulatory factors (IRFs) in a MyD88independent fashion in mice (Miller et al., 2008). Borrelia exposure of human PBMCs resulted in a strong upregulation of type I IFN-regulating genes (Petzke et al., 2009). Borrelia is capable of activating IFN-regulating genes thereby inducing IRFs, leading to a type I IFN response in both human and mouse cells (Cervantes et al., 2011). At least in the mouse, this signaling is MyD88 and TRIF independent (Miller et al., 2010), but dependent on STAT1 and IRF3.

Borrelia-induced cytokines and clinical relevance for Lyme disease Proinflammatory cytokines play an important role in the pathogenesis of Lyme disease (Figure 3). Early during the infection, monocytes and macrophages, which encounter live Borrelia, produce several pro-inflammatory cytokines, such as TNF-a, IL-6, IL-8 and IL-1b (Miller et al., 1992; Oosting et al., 2011c; Petzke et al., 2009; Porat et al., 1992; Salazar et al., 2009). The mRNA coding for IL-1b can be detected as early as 1 h after exposure to Borrelia in human cells. These cytokines activate phagocytes for the killing of the pathogens after recognition, and in addition attract other immune cells to the site of infection. The monocyte-derived cytokines also induce T lymphocyte polarization leading to production of IFN-g (by Th1 lymphocytes) and IL-17 (by Th17 cells). In skin biopsies taken from patients presenting with an EM, high levels of pro-inflammatory cytokines, including IFN-g, could be detected (Mullegger et al., 2007). IL-1b is one of the cytokines that is produced in high concentrations by both murine and human monocytes/ macrophages after exposure to Borrelia species (Bachmann et al., 2010; Beck et al., 1986; Oosting et al., 2010; Porat et al., 1992). Interestingly, IL-1b was detected in synovial fluid of Lyme arthritis patients at early time points (Shin et al., 2007). Peptidoglycan from the cell wall of Borrelia is the main inducer of the production of IL-1b by murine

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Figure 3. Borrelia-induced cytokines. After recognition of Borrelia by host immune cells, induction of early (upper part) as well as late (lower part) cytokines is induced. Each cytokine has different function in the host immune response against this bacterium.

macrophages (Beck et al., 1990). Mice susceptible for the development of Lyme disease (C3H/HeN strain) were found to respond with high cytokine production when challenged with Borrelia spirochetes (Isogai et al., 1997). The development of murine Lyme arthritis is critically dependent on IL-1b as demonstrated in IL-1R deficient mice (Figure 3) (Oosting et al., 2012). In patients with Lyme arthritis, whose arthritis was reactivated after antibiotic treatment, it was shown that IL-1b concentrations were higher in synovial fluid and tissue than in patients that recovered after the antibiotic treatment (Shin et al., 2007). Still, the exact role of IL-1b in the development of persistent Lyme disease is not fully understood. It is likely that at least part of the pathogenic role IL-1b in Lyme disease is mediated via the induction of a proper IL-17/Th17 response against Borrelia spirochetes, with subsequent production of IL-22 (Bachmann et al., 2010). IL-17 is a cytokine that plays an important role in the Th17-mediated responses and can amplify immune activation upon microbial recognition (Bachmann et al., 2010). Human monocytes exposed to B. burgdorferi OspA and intact spirochetes also produce large amounts of the antiinflammatory cytokine IL-10 (Figure 3) (Giambartolomei et al., 1999). IL-10 inhibits the function of monocytes, macrophages and Th1 cells (Lisinski & Furie, 2002). In the presence of Borrelia, IL-10 decreases human monocyte migration through endothelial cells in vitro (Lisinski & Furie, 2002). In accordance with this finding, more spirochetes are found in joints of mice deficient of IL-10, albeit with a less severe Lyme arthritis score after intradermal injection with live B. burgdorferi (Brown et al., 1999). When IL-10-deficient mice with Lyme arthritis are treated with antibodies against IFN-g, disease severity reduces significantly, indicating that absence of IL-10 leads to a disturbed Th1 response (Sonderegger et al., 2012). In addition, several

chemokines, including IL-8, are downregulated in human endothelial cells exposed to live B. burgdorferi and IL-10 (Lisinski & Furie, 2002). The role of IFN-g, IL-17, IL-22 and IL-23 IFN-g, IL-23 and IL-22 are produced after exposure of Borrelia to human PBMCs (Bachmann et al., 2010; Salazar et al., 2009). The balance between Th1 and Th2 responses has been investigated in many studies and they have unambiguously shown a predominant Th1 response most pronounced within the target organ (Ekerfelt et al., 1997). IL12 and IL-18 that are secreted by APCs and induce Th1 has been found to be elevated in cerebrospinal fluid from patients with neuroborreliosis (Grusell et al., 2002). A study by Kang et al. (1997) showed that Borrelia-infected mice with a strong and rapid IFN-g response and a subsequent IL-4 response had a more beneficial outcome than mice with a slower onset of the IFN-g response and no IL-4 regulation. These findings were also corroborated in a study on humans with neuroborreliosis and clinical outcome (Widhe et al., 2004) and suggest that a Th1 response is important for spirochetal eradication but can contribute to tissue damage and persistent inflammation if unregulated. Production of IL-22 and IL-17 is under control of IL-1b, and the naturally occurring IL-1 receptor antagonist (IL-1Ra) inhibits the Th17-derived cytokine response (Bachmann et al., 2010). In line with these data, IL-1b-deficient mice have a defective Th17 response (Oosting et al., 2011c). IL-17 is important in the development of the Borrelia antigeninduced arthritis model (mice were immunized with B. burgdorferi and challenged with B. burgdorferi) as shown by experiments of Burchill et al., in which IL-17 blockade resulted in diminished joint inflammation (Burchill et al., 2003; Kuo et al., 2011). IFN-g, and IL-22 were detected in

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skin biopsies from individuals with EM (Figure 3) (Jones et al., 2008), and IL-17 production was found in synovial cells from Lyme arthritis patients (Codolo et al., 2008). Patients with proven late neuroborreliosis exhibited higher IL-17 concentrations in the cerebrospinal fluid than patients with earlier stages of neuroborreliosis (Henningsson et al., 2011). However, in this study, no correlations were detected between the IL-17 levels and clinical parameters (e.g. age, gender and duration of symptoms prior to or after treatment). IL-23 signaling is needed for optimal Th17 development, and PBMCs isolated from healthy subjects bearing a SNP in IL-23R showed a significantly decreased IL-17 production when exposed to Borrelia. The presence of this IL-23R SNP was associated with a trend toward a lower frequency of chronic clinical symptoms in a cohort of Lyme patients (Oosting et al., 2011b).

Summary In recent years, the knowledge of the Borrelia spirochete and Lyme disease has greatly increased. Considerable insight has been gained into how the encounter between the microorganism and the host leads to disease. The inflammatory response is initiated by OSPs of Borrelia that activate the complement system. CR 3 and CD14, both independently and in conjunction with members of the TLR family, mediate the response of the host. A first step in this process could be phagocytosis of Borrelia after initial recognition. The recognition of Borrelia by TLR2/TLR1 heterodimers leads to a robust proinflammatory cytokine production. After that, TLRs, known for the recognition of nucleic acids such as TLR7, TLR8 and TLR9, might also recognize Borrelia RNA or DNA, leading to production of type I IFNs. Additional recognition of Borrelia by NLRs, in particular NOD2, contributes to the type I IFN signature. The role of CLR seems to be limited in the host defense against Borrelia; however, DC-SIGN might play a role when Borrelia is bound to the tick protein SALP-15. Among the various cytokines induced by Borrelia, IL-1b, IFN-g and IL-17 seem to be the most important in the pathogenesis of Lyme disease. IL-1b is associated with the acute and chronic inflammatory processes seen in Lyme disease, whereas the role of IL-17 remains to be further elucidated. Since the precise mechanisms leading to chronic or late stages of Lyme disease are still not known, more research is required to unravel the pathogenesis of this inflammatory disease. A series of relevant questions emerge from this research, such as which molecules derived from Borrelia drive the chronic infection or inflammation? Are live bacteria needed for the chronic inflammation seen in Lyme disease? Which host factors are responsible for the establishment of chronic inflammation? May neutralization of IL-1b, IFN-g or IL-17 be beneficial for patients with persistent Lyme disease? Future research is warranted to unravel these relevant questions.

Declaration of interest K. B. was supported by a grant of the Dutch Arthritis Foundation (NR-10-3-301). M. G. N. was supported by a Vici grant of the Netherlands Organization for Scientific Research.

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