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Pro-Inflammatory Responses in Macrophages during Toxoplasma gondii Infection

and *.

* Corresponding Author: Dr. Christopher A. Hunter—Department of Pathobiology, University of Pennsylvania, 3800 Spruce St., Philadelphia, Pennsylvania 19104, U.S.A. Email: chunter@vet.upenn.edu

Toxoplasma gondii is an obligate intracellular parasite that causes an asymptomatic infection in a significant percentage of the world's population. Healthy hosts mount a robust innate response mediated by IL-12, which influences the development of protective cell-mediated immunity by stimulating NK and T cells to produce IFN-γ. Although macrophages can be infected by T. gondii, they are able to limit parasite replication and produce cytokines that contribute to resistance, making them important regulatory and effector cells during toxoplasmosis. A large body of work has focused on the interactions between parasites and these host cells, and contributed to our understanding of the pro-inflammatory activities of macrophages during T. gondii infection.

Introduction

Toxoplasma gondii is an intracellular parasite that causes a persistent infection in 10-80% of the world's population, depending on geographic location.1 Infection is normally asymptomatic in healthy individuals because control of this pathogen results from the host's ability to mount a robust cell-mediated immune response which is dominated by production of Interferon-γ (IFN-γ) by NK cells during the earliest stages of infection, and by parasite specific CD4+ and CD8+ T cells thereafter.2-5 The clinical significance of these events is illustrated by patients with primary or acquired defects in T cell function, in whom a failure to control parasite replication results in overt disease. Thus, in AIDS patients, the decline in T cell numbers correlates with reactivation of latent infection and the development of Toxoplasmic Encephalitis (TE).6,7 Likewise, patients undergoing immunosuppressive therapy or affected by cancers that lead to defects in T cell function are also susceptible to TE.8 Consequently, studies on immunity to T. gondii have focused on the role of T cells in resistance to this organism. However, it is now recognized that Toxoplasma induces a strong innate immune response that provides a mechanism of resistance during acute infection and influences subsequent adaptive responses. Historically, macrophages have been considered important effectors of resistance during toxoplasmosis in large part because of early work that established their ability to kill parasites9-11 and produce chemokines and cytokines like IL-12 and TNF-α, which are critical for the production of IFN-γ.12-14 In the last decade, studies using macrophages and dendritic cells (DC) have significantly advanced our understanding of the parasite-derived factors and host signaling pathways that are involved in the innate recognition of Toxoplasma. Thus, this chapter will review the pro-inflammatory signaling and cytokine responses that are initiated by macrophages in response to T. gondii.

Macrophages Effector Functions

In macrophages, the fate of intracellular T. gondii depends on the mechanism of entry into the cell. Dead or opsonized parasites that are phagocytosed are targeted to lysosomal compartments for degradation15 whereas live parasites that actively invade the host cell become established in a protective nonfusogenic parasitophorous vacuole (PV).16 Macrophages that have been preactivated by IFN-γ are able to limit replication of these intra-vacuolar parasites, and work by several laboratories has focused on the mechanisms by which IFN-γ priming directs this response (Fig. 1). One of its anti-microbial activities in murine cells is to stimulate production of NO17 through upregulation of inducible nitric oxide synthase (iNOS). This occurs in combination with TNF-α, which provides a necessary “second signal” that triggers iNOS-dependent parasite control.18 The significance of NO production during Toxoplasma infection was evaluated using iNOS-/- mice, which survived acute parasite challenge but were highly susceptible to TE.19,20 This finding established a central role for NO in the control of toxoplasmosis in the CNS, but it also indicated that there were NO-independent mechanisms that conferred early resistance. In this regard, human macrophages have been shown to use reactive oxygen species to inhibit parasite replication.10,11 In addition to iNOS, IFN-γ stimulation induces expression of six 47-48 kDa GTPase proteins (p47 GTPases) in mouse macrophages, of which IGTP, LRG47 and IRG47 are essential for acute (IGTP and LRG47) or chronic (IRG47) resistance.21,22 Moreover, IFN-γ stimulated macrophages deficient in IGTP or LRG47 have been shown to be attenuated in their ability to limit parasite growth.23 The mechanisms by which these proteins effect anti-microbial activity are yet to be defined, however recent evidence suggests they may localize to and disrupt the PV.24 Notably, human homologues of mouse p47 GTPases have been identified through genome screening but have yet to be cloned.

Figure 1. Overview of pro-inflammatory responses generated by macrophages during toxoplasmosis.

Figure 1

Overview of pro-inflammatory responses generated by macrophages during toxoplasmosis. Exposure to T. gondii initiates MAPK and NF-κB signaling, leading to synthesis of cytokines, including IL-12, that stimulate production of IFN-γ from (more...)

Although there is broad consensus that IFN-γ is the major mediator of resistance to T. gondii, there is evidence of IFN-γ independent anti-microbial activity in macrophages. This is based in part upon reports of patients with partial defects in IFN-γR1 signaling who exhibit serological evidence of Toxoplasma infection, but are clinically asymptomatic.25 One mechanism of resistance that has been suggested in these patients involves TNF-α, in combination with the CD40/CD40L interaction, which triggers parasite killing independently of IFN-γ or NO.26-28 The significance of this pathway in vivo is illustrated in CD40L-/- mice29 and in human patients with a primary defect in the CD40/CD40L interaction,30 which are susceptible to TE. In addition, a recent report using a forward genetic approach has identified a novel locus in rats, Toxo1, which confers resistance to Toxoplasma infection, apparently through the ability of macrophages to limit parasite replication.31 The function of this locus has yet to be described, but appears to be unique from other resistance mechanisms.

Production of IL-12

The discovery of IL-12 as a major mediator of acute resistance to T. gondii12,14,32 prompted investigation into its sources, and initial studies using inflammatory macrophages indicated that they could respond to T. gondii and make IL-12.12 However, it was also recognized that resting macrophages are poor sources of IL-12 when stimulated with live T. gondii, and host survival depends upon its production during the first three days of infection, before extensive macrophage activation has occurred.32 Thus, it was likely that there were other cell types that could produce this cytokine in response to infection without prior priming. Subsequent work identified that conventional DCs exposed to soluble toxoplasma antigens (STAg) could also make IL-12,33 and that neutrophils contained preformed stores that were released following parasite challenge.34 Consistent with this observation, depletion of neutrophils with anti-GR1 antibody antagonized development of protective T cell responses and had a profound effect on infection-induced activation of DC.35 This finding implicated neutrophils as important sources of IL-12 during acute toxoplasmosis, however it is now appreciated that anti-GR1 not only depletes granulocytes, but also affects other GR-1+ cell populations including certain monocytes, CD8+ T cells and the plasmacytoid subset of DC (pDC). Indeed, recent studies have shown that GR-1+ monocytes are the principal cell type recruited to the site of infection, and these cells not only generate NO and kill parasites directly without prior activation, but also can act as a source of IL-12.36,37 Thus, it appears that there are multiple cell types that can produce IL-12 during acute toxoplasmosis, and future work will likely define the extent to which each of these contributes to the development of protective immunity in infected hosts.

Innate Recognition of T. gondii

Macrophages are a prominent source of proinflammatory cytokines, in particular IL-12, during toxoplasmosis, and the last decade has seen considerable progress in defining the mechanisms by which these cells recognize and respond to live parasites or their products. The Toll-like family of pattern recognition receptors (TLR) plays a critical role in the innate immune response to multiple types of microbial stimuli,38 and several studies have implicated their role in toxoplasmosis. Signaling downstream from TLRs is dependent on the adaptor molecules MyD88 and TRAF6, and studies conducted with knockout mice have associated these factors with resistance to T. gondii. MyD88-/- mice exhibit profound defects in IL-12 production and are highly susceptible to acute infection,39 and TRAF6 deficient macrophages are also deficient in their IL-12 response to T. gondii.40 Subsequent work has attempted to identify the TLRs that may be involved in parasite recognition, with conflicting results. No defect in IL-12 production was noted following infection of DC from either TLR2-/- or TLR4-/- mice,39 and it has been reported that mice lacking TLR1,2,4,6, or 9 are not acutely susceptible to Toxoplasma infection.41 Moreover, the recently identified TLR1142 has been implicated in parasite recognition, however, despite having a major defect in IL-12 production following parasite challenge, TLR11-/- mice are not susceptible to acute infection.43 In contrast to these findings, one study has reported that TLR2-/- mice are acutely susceptible to i.p. challenge, and peritoneal macrophages from these mice make reduced levels of IL-12.44 However these results are complicated by the high dose of parasites that was required to see an effect. In addition, a TLR-independent signaling pathway has been implicated in IL-12 production during toxoplasmosis. In studies using MyD88-/- mice, it was observed that there was a residual IL-12 response in vivo, and from accessory cells in vitro, which was sensitive to treatment with pertussis toxin, an uncoupler of G-protein signaling.39 This result suggested a MyD88-independent, G-protein mediated pathway to IL-12 production, and subsequent work identified a secreted parasite product, C-18, that induced IL-12 synthesis from DC through the chemokine receptor CCR5.45,46 Consistent with this observation, CCR5-/- mice were more susceptible to T. gondii, and produced lower levels of IL-12.47 Despite its prominent function in DC, the role of CCR5 in parasite recognition by other innate immune cells, including macrophages, is at present undefined.

Pro-Inflammatory Signaling Events in Macrophages

Significant progress has been made in understanding the proximal events that facilitate parasite recognition, and several studies have begun to elucidate the downstream signaling pathways that effect the pro-inflammatory response (Fig. 2). In macrophages, parasite challenge initiates at least two prominent innate signaling cascades, Mitogen-activated protein kinases (MAPK) and NF-κB. Macrophages stimulated with STAg activate rapid, TRAF6-dependent phosphorylation of the MAPK family members p38 and ERK1/2.40 Using kinase-specific inhibitors, it has been shown that p38 acts as a positive regulator of IL-12p40 production, whereas activation of ERK1/2 is antagonistic.40,48 Moreover, the MAPK-activated transcription factors c-jun, ATF-2, and MAPKAPK2 are reported to translocate to the nucleus in infected cells,48 however the mechanisms by which MAPK direct transcription of IL-12p40 are unknown, and their role in production of IL-12p35, and hence bioactive IL-12p70, has yet to be investigated. Recent work has started to elucidate the T. gondii-induced mechanisms of MAPK activation, and it appears that the upstream pathways leading to ERK1/2 and p38 activation are divergent. Phosphorylation of p38 occurs by TAB1-dependent autophosphorylation,48 and is dependent on MyD88.49 In contrast, ERK1/2 activation by the upstream kinase MEK1/2 is MyD88 independent, and is sensitive to pertussis toxin and wortmannin, implicating activation by a G-protein coupled pathway and PI3-kinase.49 Notably, CCR5 is a G-protein coupled receptor involved in IL-12 production by DC, however it is dispensable for activation of p38 and ERK1/2 in macrophages,49 which suggests that there are other G-protein coupled receptor pathways that are activated in response to T. gondii.

Figure 2. Signaling events induced by parasites and their products.

Figure 2

Signaling events induced by parasites and their products. Macrophages contacted by T. gondii or parasite-derived products initiate phosphorylation of the MAPK family members p38, ERK1/2 and JNK, which is associated with nuclear translocation of MAPK-dependent transcription (more...)

In addition to MAPK, Toxoplasma initiates rapid activation of the NF-κB pathway in macrophages. This evolutionarily conserved family of transcription factors is involved in many aspects of innate immunity and is ubiquitously expressed in mammalian cells.50 In the inactive state, they are maintained in the cytoplasm through association with an inhibitor protein, IκB, which becomes phosphorylated and then degraded following cellular stimulation. NF-κB homoand hetero-dimers are then free to translocate to the nucleus, where they bind DNA and initiate transcription of pro-inflammatory and anti-apoptotic genes. The upstream signaling events that facilitate NF-κB activation following stimulation with various TLR ligands or TNF-α are well-defined, and involve activation of the IKK complex as a proximal step to IκB phosphorylation and degradation. In macrophages, as well as numerous other cell types, acute infection with Toxoplasma induces robust IKK activation51,52 and phosphorylation and subsequent degradation of IκB.51-55 However, there is conflicting evidence with regard to the mechanism by which Toxoplasma initiates IKK activity in infected cells. A parasite-derived kinase activity that can phosphorylate IκB has been reported at the PV membrane.52 However, work from this laboratory demonstrates that infection of IKK knockout cells does not result in degradation of IκB, implicating only the host's kinase activity in this response.51 Moreover, despite robust IKK activation and IκB degradation, whether NF-κB dimers access the nucleus in infected cells and initiate transcription is also controversial. Several groups have determined that virulent strains of T. gondii block nuclear translocation and DNA binding in infected cells,51,53,54,56,57 whereas another group reports that NF-κB accesses the nucleus and induces transcription of anti-apoptotic genes.55,58 In addition, recent studies indicate that while virulent strains of parasites induce low levels of IL-12 from infected cells and do not activate NF-κB, infection with avirulent, Type II strains of T. gondii leads to low level NF-κB activation, which correlates with increased production of IL-12,57 and survival of challenged mice.59,60 The contribution of NF-κB dependent signaling in the macrophage's pro-inflammatory response to T. gondii, and to the outcome of disease, remains to be precisely defined, and may significantly depend on variations in parasite strain.

It is well recognized that STAg and live tachyzoites induce pro-inflammatory signaling in macrophages, however there are differences in the pathways that become activated by these stimuli. For example, STAg does not induce IκB degradation in macrophages or NF-κB binding to DNA.40 In addition, whereas STAg activates p38 and ERK1/2,40 live infection also initiates phosphorylation of JNK,48,53,61 which may be involved in parasite-induced IL-12 production.48 Moreover, STAg induces significantly more IL-12 from macrophages and DC than live infection, which may be attributed to differences in pro-inflammatory signaling, as well as the ability of live parasites to actively suppress IL-12 production,53,62 through a recently described STAT3-dependent mechanism.63

Despite characterization of the pro-inflammatory signaling events that occur in infected macrophages, there are many questions regarding the downstream factors that effect transcription. The NF-κB family member c-rel is required for IL-12 production in response to multiple microbial stimuli, including LPS and CpG, but it appears to be dispensable in the Toxoplasma system since knockout macrophages treated with STAg make normal levels of IL-12p40 and in vivo cytokine levels are similar to WT following parasite challenge.64 The Interferon Regulatory Factors (IRF) comprise another group of transcription factors that is implicated in induction of IL-12 synthesis by microbial stimuli like LPS. Studies using IRF-8/ICSBP knockout mice have demonstrated that these animals are acutely susceptible to Toxoplasma infection, and this is associated with decreased IL-12p40 production in vivo.65 However, it is now recognized that ICSBP-/- mice have defective maturation and trafficking of CD8α+ DCs,66,67 which may contribute to enhanced susceptibility to acute toxoplasmosis.33 Nevertheless, peritoneal macrophages from ICSBP knockout mice produce low levels of IL-12p40 following challenge with live parasites or STAg in vitro, implicating a role for this transcription factor in the cell's pro-inflammatory response.65 Notably, these studies have begun to shed light on the transcriptional elements involved in production of IL-12p40, however little is known about T. gondii-induced regulation of p35.

Conclusions

Macrophages residing in tissues are among the first defenses against invading microbes, and there is a growing appreciation of their role in determining the outcome of the host-pathogen interaction. This is not only because they act as effectors to kill invading microbes, but also because they can bridge the gap between innate and adaptive immunity by acting as professional APCs, and through production of chemokines and cytokines. With the discovery of the TLR family of pattern recognition receptors, there has been significant progress in our understanding of the molecular mechanisms by which these cells sense bacterial, viral, parasitic, and fungal organisms. It is now clear that macrophages, together with a few other elite cell types such as DC, are crucial to the innate immune response through their unique ability to distinguish and respond to prokaryotic and eukaryotic infections. Microarray analysis, coupled with in vivo and in vitro investigation, has determined that these other accessory cell types share many functions with macrophages, however there are also distinct differences between them. Thus a future challenge will be to define the unique contributions of these cell types that help coordinate a tailored and targeted immune response to distinct classes of pathogens.

Acknowledgements

This work was supported by NIH grants AI46288, T32 AI055400, NIGMS T32-07229 and the State of Pennsylvania.

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