CROSSTALK BETWEEN CRP AND FICOLINS REGULATES INNATE IMMUNITY 2

4.2 CRP:L-ficolin interaction connects the classical and lectin complement pathways and boost the antimicrobial activity Local acidosis, mild hypocalcaemia and high CRP level are charact

Chapter 4 Discussion

176

CHAPTER 4: DISCUSSION

Local infection is caused by a wide range of pathogenic microbial agents including

pathogenic viruses (Liu et al 2007), bacteria (Markley 1968), fungi (Marina et al 2008), protozoa and multicellular parasites (Osnas et al 2004), imposing great challenges to

healthcare management While this may manifest as a hot-tub rash, failure to limit such localized inflammation may cause life-threatening septic shock to ensue, leading to multiple organ failure and possibly death These pathogens pose a great challenge to diagnosis and treatment The corollary of severe infection-inflammation response syndrome, due to an attempt to clear pathogens during an overwhelming systemic infection is the over-activation of the immune system, which can backfire and damage the host’s own tissues Therefore, therapeutic intervention of the cellular and molecular pathways, particularly, targeting the custodian protein:protein or protein:ligand interaction is clinically valuable, providing a powerful rationale for future drug design and development

Innate immunology has been a fast-growing field in the last two decades with the discovery of the PAMPs and PRRs With PAMPs and PRRs defined, most of the innate immune molecules that have been isolated can now fit into the functional groups as PRRs Extensive research efforts have been invested into characterizing the roles of these PRRs with regards to the microbial group that they each PRR targets, and the downstream

effectors that they recruit (Holmskov et al 2003; Leclerc et al 2004; Takeda et al 2005)

However, most of the studies have been done with an isolated focus on the role of

individual PRRs Therefore, the potentials that could come from the ensemble of PRRs through PRR:PRR collaborations have been neglected With the individual PRRs characterised, it is therefore timely to study the interactive roles of these PRRs acting in concert CRP and ficolins represent two main families of such PRRs and they each trigger and regulate seminal antimicrobial pathways in infection and injury It is conceivable that insights gained from this PRR:PRR interaction mechanism will offer fresh perspectives

on the potential development of complement immune therapies to enhance the eradication of the invading pathogen

4.1 The functional divergence of L- and M-ficolins in evolution

Ficolins constitute a family of secretory C-type lectins, which play critical roles as pattern-recognition receptors in host defense Patients with ficolin disorder are

susceptible to inflammation brought about by respiratory infections (Atkinson et al 2004), Behçet's disease (Chen et al 2006), rheumatoid arthritis (Vander Cruyssen et al 2007) and necrotizing enterocolitis (Schlapbach et al 2009) Being structurally and functionally conserved (Zelensky et al 2005), all three ficolins were shown to bind to

GlcNAc which is the sugar moieties of PAMPs displayed on microbes (van Kooyk

2008) This liaison between ficolin:GlcNAc activates complements (Frederiksen et al 2005; Zhang et al 2009) and promotes phagocytosis (Jack et al 2005)

Although belonging to the same family, L- and M-ficolins have high homology

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(42%), which determines the different binding behaviors among three ficolins (Figure

4.1) Among three ficolins, L- and H- ficolins are secreted into the serum by lung and

liver and they circulate in the blood (Matsushita et al 1996; Andersen et al 2009) In

contrast, M-ficolin is the only ficolin isoform secreted by immune cells such as

monocytes (Teh et al 2000), neutrophils (Rorvig et al 2009) and alveolar epithelial cells (Liu et al 2005) suggesting the crucial and fundamental roles of M-ficolin in immune responsive cells Whereas the mouse homologue of L- ficolin was identified to

be ficolin A (Endo et al 2004) and mouse homologue of M-ficolin gene is ficolin B (Endo et al 2004), the mouse H-ficolin gene was identified to be a pseudogene and orthologous to mouse ficolins A/B and human L-/M- ficolins This might explain the lack

of bindings between CRP and H-ficolin The dramatic difference between H-ficolin and

L-, M-ficolin proteins and the completely different in vivo locations of L- and M-ficolins

implies that they have different functions and also explains their non-redundancy and the necessity to conserve all three ficolin isoforms through evolution

Figure 4.1: The alignment of three ficolin isoforms using Bioedit Sequence Alignment Editor L- and M- ficolin sequences show high homology with each other while L- and H-

ficolin sequences show low homology to H-ficolin

4.2 CRP:L-ficolin interaction connects the classical and lectin complement pathways and boost the antimicrobial activity

Local acidosis, mild hypocalcaemia and high CRP level are characteristic of local inflammation By defining a typical infection-inflammation condition (pH 6.5 and 2 mM calcium) and normal physiological condition (pH 7.4 and 2.5 mM calcium), we demonstrated crosstalk between CRP and L-ficolin, which resulted in two new autonomous amplification pathways leading to a synergistic level of C3-deposition on the bacteria This serves to boost the bactericidal activity in the serum under local

infection-inflammation condition

L-ficolin was identified to interact with CRP via its fibrinogen-like domain Here,

we showed that the recombinant rL-FBG interacts avidly with CRP at KD of 1.26 x 10-8

M under infection-inflammation condition compared to 1.11 x 10-6 M under normal condition This represents a 100-fold increase in affinity between the two proteins A positional preference was evident, where prior anchorage of CRP resulted in a more

efficient recruitment of the rL-FBG Low pH dramatically enhanced CRP:L-ficolin

interaction, showing that inflammation-induced acidosis promoted stronger crosstalk between CRP and L-ficolin Furthermore, lower level of calcium enhanced the

CRP:L-ficolin interaction, thus indicating that calcium is a main regulator of the

molecular crosstalk between L-ficolin and CRP Co-IP experiments confirmed that the

CRP:L-ficolin complex formation was induced in the serum by infection-inflammation

condition (low pH, low calcium level and high CRP level) and ELISA demonstrated that

180

binding to CRP when the latter was anchored first to bacteria Taken together, our findings explain why and how a typical infection-inflammation condition provokes crosstalk between CRP and the L-ficolin, which might boost the complement system This key mechanism is further confirmed by the fact that in infection-inflammation

condition, the CRP:L-ficolin amplification pathway caused more C3-deposition

Hitherto, two independent complement pathways involving CRP-activated

classical pathway and L-ficolin-mediated lectin pathway are well-established (Kaplan et

al 1974; Fujita et al 2004) Here, we provide evidence for the inflammation-induced

crosstalk between CRP and L-ficolin which impels two new amplification pathways:

(1) Amplification pathway 1 PC-beadsÆCRPÆL-ficolinÆMASPsÆC4ÆC3ÆMAC

(2) Amplification pathway 2 GlcNAc-beadsÆL-ficolinÆCRPÆC1q,r,sÆC4ÆC3ÆMAC

The cleavage of C4 demonstrated that these two amplification pathways were functional only under infection-inflammation condition but are negligible in normal physiological condition The opsonized particles generated by these amplification pathways were recognized and removed by the immune cells indicating the autonomy and effectiveness

of the two new pathways which were further confirmed by quantification of the phagocytic efficiency Competition assays showed that the amplification pathways do not compete against the classical and lectin pathways, but rather, they boost these two well-known complement pathways The complement system becomes a major microbicidal force in the infection-inflammation condition mediated by the synergistic effect of CRP and ficolins We showed that CRP interacts with L-ficolin under

infection-inflammation condition, enhancing the complement-activated killing of the P

aeruginosa Although it was shown that purified CRP and L-ficolin did not bind to P aeruginosa, the presence of serum factors enabled CRP to bind to bacteria indirectly and

the bound CRP recruited L-ficolin (Figure 4.2)

Thus far, we have provided evidence that local infection-inflammation elicits new

Figure 4.2: A model to illustrate the mechanism of enhanced antimicrobial activity of the serum in infection and localized inflammation CRP recruited to the bacterial surface by serum

factors activates the classical complement pathway The infection-inflammation condition triggers the CRP:ficolin interaction, resulting in the immobilization of ficolins to the bacterial surface and the activation of the lectin pathway to amplify the complement response By crosstalk between CRP:ficolin, two autonomous amplification pathways emerge to boost antimicrobial activity of the classical (black upward arrow) and lectin-mediated (bold black upward arrow) complement pathways:

(1) Amplification pathway 1: PC-beads ÆCRPÆL-ficolinÆMASPsÆC4ÆC3ÆMAC

(2) Amplification pathway 2: GlcNAc-beads ÆL-ficolinÆCRPÆC1qÆC1r,sÆC4ÆC3ÆMAC

182

invading pathogen This novel antimicrobial mechanism is particularly effective against

the P aeruginosa, an opportunistic pathogen which causes mortality in critically ill and immuno-compromised patients (Goldman et al 2008) Both the immunoevasive nature (Kharazmi 1991) of P aeruginosa as well as its acquisition of multi-drug resistance (Zaborina et al 2008) makes elimination of this microorganism a particular challenge To date, no effective therapy against P aeruginosa infection has been found However,

insights gained into the mechanisms of complement amplification shown in the present work are crucial in understanding the host defense to counter the immune evasion by the pathogen, which will contribute to the development of complement-immune therapies

unclear, although other C-type lectins like galectin (Nieminen et al 2005) and MBL (Ip

et al 2008) were reported to sense danger signals and boost the proinflammatory

immune response We demonstrated that M-ficolin, a representative soluble CL, mediates NF-κB activation and IL-8 secretion upon challenge by pathogens/PAMPs/GlcNAc, which was confirmed by abrogation of the effect in M-ficolin- cells, as well as cells pretreated with M-ficolin antibody We showed that M-ficolin performs this key role by being localized on the monocyte surface through

interaction with its cognate transmembrane receptor partner, GPCR43 Through this liaison, the M-ficolin:GPCR43 complex probably alerts the host cell of microbial invaders, by transducing an infection signal via the activation of NF-κB (Figure 4.3)

Although M-ficolin expression in macrophages was significantly lower, it can be

upregulated in monocyte/macrophage lineage upon LPS stimulation (Frankenberger et al

2008), indicating its critical function in immune cells during infection Interestingly, such interplay of proteins leading to signal transduction was also observed in other membrane-associated molecules such as angiopoietins which coincidentally also contain

an FBG domain (personal communications with Dr N.S Tan, Nanyang Technological University, Singapore), implying the fundamental significance of such a phenomenon

The conformational change of C-type lectins upon pH or ligand-/ protein-

binding, is universal (Zelensky et al 2005; Menon et al 2009), although the biological

consequence remains unclear We found that under infection-mediated local acidosis condition, the binding of CRP to M-ficolin:GPCR43 complex was enhanced whereas under normal condition, they associate weakly As yeast two hybrid has shown M-ficolin

to interact with itself to form a homopolymer, it is also possible that CRP and GPCR43 may bind to the same M-ficolin molecule or to two different M-ficolin molecules in the polymer/dimer The detailed binding pattern between CRP, M-ficolin and GPCR43 needs to be further studied in future CRP plays a dual reciprocal role in M-ficolin mediated IL-8 secretion: under normal condition, CRP promoted M-ficolin mediated

184

secretion These results clearly support a refined regulatory mechanism where environmental perturbation at the later phase of infection induces the conformational change of M-ficolin and CRP, which regulates its pathogen recognition and IL-8 production

Overall, we have shown how the host exercises plasticity in its immune function-cum-regulation via monocyte-secreted M-ficolin, which exploits its extracellular interacting partners to form a trio-complex to act bidirectionally: (a) to transduce infection signal via GPCR43 into the host cell and (b) to regulate the immune response to restore homeostasis through the reciprocal role of CRP which modulates the

M-ficolin to downregulate IL-8 secretion We envisage that the host can expand its

repertoire of immune function-cum-regulation mechanisms by promiscuous protein networking amongst members of the families of soluble C-type lectins, pentraxins and transmembrane proteins, where cues from the infection-mediated environmental perturbation induce the protein complex to immunomodulate and attain homeostasis Furthermore, our elucidation of the binding interface and the infection-inflammation sensitive regulatory region of the M-ficolin provides insights into the bioactive centre of the M-ficolin molecule Such insights will be useful for future drug development of immunomodulators

Figure 4.3: A model to illustrate the mechanism for M-ficolin-mediated signal transduction GlcNAc moieties in bacterial PAMPs are recognized by M-ficolin, which leads

to induction of IL-8 secretion via NF-κB pathway M-ficolin performs its role as an immune sentinel through its association with a transmembrane protein, GPCR43, which stabilizes the M-ficolin (a C-type lectin) as a receptor complex on the monocyte membrane Infection at different stages (early or late) is accompanied by perturbations of the microenvironmental pH and calcium level, which induce conformational changes in the M-ficolin molecule This weakens or enhances the collaboration between M-ficolin and CRP, which in turn regulates IL-8 secretion: (i) at the early stage of infection (green zone), the pH is still physiological, where CRP binds to FBG weakly This protein-protein interplay exposes the GlcNAc-binding region (pink) of M-ficolin for interacting with PAMP-GlcNAc (thick arrow), which upregulates IL-8; (ii) at the later stage of infection (red zone), local acidosis strongly enhances the interaction between CRP and M-ficolin thus, blocking the GlcNAc-binding site on the

microenvironment This will lead to changes in PRR:PRR or PRR:ligand binding

patterns Therefore, a detailed understanding of the structural changes of PRRs and their corresponding binding interfaces, particularly in targeting the protein-protein interaction

is clinically valuable

Here, we employed HDMS to characterize the dynamic structural changes in

solution of the CRP:M-ficolin interaction, and their contact points We found that a low

pH-induced region (249-255) became embedded into the M-ficolin molecule, while the C-terminal region (284-326) was exposed to the solvent and to the CRP We observed that the presence of calcium led to a generally lower deuterium incorporation of rM-FBG, implying global compaction of the protein structure and this regulatory effect is more dramatic under physiological condition Notably, under infection-inflammation condition but not normal physiological condition, the CRP binding interface on rM-FBG is translocated to the C-terminal region (284-326) Therefore, the low pH and low calcium induces a structural expansion and consequently, greater solvent accessibility to the C-terminal region (284-326) of rM-FBG This observation explains the enhanced

interaction between CRP:M-ficolin Although low pH and low calcium compacts the structure of CRP, the interaction between CRP:M-ficolin is enhanced, suggesting that the

flexible structure of M-ficolin plays a dominant role in controlling the CRP:M-ficolin

interaction Interestingly, we also note that the compacting effect of calcium on rM-FBG structure is only dramatic under normal physiological condition but not under normal

condition implying that in vivo under infection-inflammation condition, there is a need to

switch on the interaction between the M-ficolin and its PRR partners via the flexible C-terminal domain of the FBG, and it must be turned off under physiological condition This would agree with a homeostatic role of M-ficolin in partnership with CRP

The critical function of histidine residues in M-ficolin has been identified to

regulate the pH-sensitive binding of M-ficolin to GlcNAc (Garlatti et al 2007) Here, we

pinpointed to His 284 as the determinant for the low pH- and low calcium- induced

interaction of CRP:rM-FBG under infection-inflammation condition This site is

conserved in most of M-ficolin homologues, and it is absent in H-ficolin This possibly explains our previous observation of the lack of interaction between CRP and H-ficolin,

regardless of pH and calcium shift (Zhang et al 2009) It is reported that the conserved

PAMP/sugar binding pocket is also located in the region 282-285 and under acidic condition, rM-FBG will present as an inactive form for PAMP/sugar-binding Therefore,

we envisage that the stronger binding of CRP to the rM-FBG His 284 will further dissociate the PAMP/sugar and shift the protein’s structure-activity towards downregulation of the antimicrobial immune response in order to restore homeostasis This was supported by the experimental evidence that CRP inhibited M-ficolin mediated

188

and the infection-inflammation sensitive regulatory region of the M-ficolin provide insights into the bioactive centre of the M-ficolin molecule, which might be useful for future drug development for immunomodulation.

Overall, we have found that as a pathogen-recognition receptor, the M-ficolin exploits its flexible structure and modifies its binding pattern to its interacting acute phase partner, CRP, under different pathophysiological conditions This will result in different pathogen recognition activity and regulation of the host immune response

Chapter 5 General Conclusion and

Future Perspectives

markedly However, the Pseudomonas aeruginosa is a persistent opportunistic pathogen

prevalent at the site of local inflammation, and its acquisition of multiple antibiotic-resistance poses grave challenges to patient healthcare management Using

blood samples from infected patients, we demonstrate that P aeruginosa is effectively

killed in the plasma under defined typical local “infection-inflammation condition”, where slight acidosis and reduced calcium level (pH 6.5, 2 mM calcium) prevails We showed that this powerful antimicrobial activity is provoked by crosstalk between two

plasma proteins; CRP:L-ficolin interaction led to communication between the

complement classical and lectin pathways from which two amplification events emerged Assays for C4 deposition, phagocytosis and protein competition consistently proved the functional significance of the amplification pathways in boosting complement mediated antimicrobial activity We conclude that the infection-induced local inflammation

condition triggers strong interaction between CRP:L-ficolin, eliciting

complement-amplification pathways which are autonomous, co-exist with and reinforce the classical and lectin pathways Our findings provide new insights into the host immune

response to P aeruginosa infection and the potential for development of new therapeutic

strategies against bacterial infection

The “infection-inflammation” condition also induced CRP:M-ficolin interaction

in the nanomolar range Since the M-ficolin is monocyte membrane-associated, its crosstalk with CRP implies subsequent cellular immune response to clear the bacteria Here we found that M-ficolin, a conserved soluble CL of monocyte origin, overcomes its lack of membrane-anchor domain by docking constitutively onto a monocyte transmembrane receptor, GPCR43, to form a pathogen sensor-cum-signal transducer On

encountering microbial invaders, the M-ficolin:GPCR43 complex activates the NF-κB

cascade to upregulate IL-8 production We showed that mild acidosis at the local site of infection induces conformational changes in the M-ficolin molecule which provokes a

strong interaction between the CRP and the M-ficolin:GPCR43 complex The ternary collaboration amongst CRP:M-ficolin:GPCR43 under acidosis curtails IL-8 production

thus preventing immune over-activation Therefore, we propose that other soluble C-type lectin members may become membrane-associated through interaction with a transmembrane protein, whereupon infection, collaborates with other plasma proteins to transduce the infection signal and regulate host defense Our finding implies a possible mechanism where the host might expand its repertoire of immune function-cum-regulation tactics by promiscuous protein-protein networking

The underlying mechanism for low pH- and low calcium- triggered interaction between CRP and ficolins were studied By HDMS, we delineated the precise motifs on M-ficolin that bind CRP The M-ficolin undergoes dramatic conformational change under

191

physiological level of calcium compacts the M-ficolin structure to downregulate its interaction with CRP In contrast, the CRP structure remains relatively immutable under

both conditions In silico analyses showed that under infection-inflammation condition,

the CRP binding site on M-ficolin overlaps with the conserved pathogen sugar-ligand binding pocket whereas under physiological condition, they are separate Our findings support that the initial conformation of M-ficolin binds pathogen sugar-ligand, and boosts the immune response The simultaneous pathophysiological perturbations act as a molecular switch to transform the conformation of the M-ficolin for binding CRP This avid molecular crosstalk between M-ficolin and CRP diverts the M-ficolin from pathogen recognition, and restores homeostasis Our elucidation of the binding interface and the infection-inflammation sensitive regulatory region of the M-ficolin provide insights into the bioactive centre of the M-ficolin molecule, which might be useful for future development of immunomodulators

It is clear that innate immunity constitutes an important immune defense mechanism and that numerous innate immune molecules such as CRP and ficolins are evolutionarily conserved structurally or functionally Through the crosstalk of a diverse range of PRRs, the innate immune system is boosted in a timely manner and in a well-regulated mode, and it is not random as was previously thought Therefore, the findings in this thesis offer new avenues for the study of innate immunity through instant protein-protein interactions Furthermore, the arena of complements is far from saturation and there are still intriguing forward and reverse defense mechanisms awaiting

elucidation and understanding

Taken together, the differential interactions between (a) L-ficolin:CRP, (b) M-ficolin:CRP and (c) CRP:M-ficolin:GPCR43 under normal and infection-inflammation conditions regulate both the extracellular and intracellular immune responses These molecular events which culminate in the secretion of IL-8 further trigger cellular chemotactic responses resulting in monocyte recruitment to the

site of infection (Figure 5.1)

5.2 Future perspectives

Based on the findings in this thesis, there are several interesting directions for future work in the areas of CRP and ficolin crosstalk To gain a wider understanding of the

intricacy of CRP:FBG interaction and their crosstalk induced by infection-inflammation,

further studies are proposed as follows

(1) Co-crystallization of rM-FBG:CRP complex

As both rL-FBG and rM-FBG show high affinity to the CRP, to increase the resolution of the FBG:CRP interaction, and to confirm the accuracy and specificity of HDMS experiments, structure determination of the co-crystallized complex would enable us to investigate the exact contacting residues Different pH and different calcium concentrations may be applied during the co-crystallization to reveal the structural change of the individual proteins and the effects on the binding pattern

(2) Elucidation of the detailed mechanism of M-ficolin:GPCR43 mediated signal transduction of IL-8

As M-ficolin:GPCR43 interaction shows synergistic effect on the IL-8 secretion, it is

imperative for us to uncover the role of GPCR43 GPCR43 is a relatively new molecule, currently known to be involved in chemoattraction induced by short chain fatty acid (Sina

et al 2009) However its alternative role in immune response awaits further studies, and thus mapping out the downstream pathway of GPCR43 is crucial As Protein Kinase C

195

(PKC), which is downstream of GPCR43, was indicated to connect to NF-κB activation,

it is reasonable to test whether PKC also mediates the signal transduction initiated from M-ficolin to upregulate IL-8 This can be done by either using the PKC inhibitor or knocking out PKC or GPCR43 Further downstream effectors and signalling components can be mapped using PLA technology.

(3) Does CRP interact with other FBG domain-containing proteins under normal

be perturbed Since the FBG domain is highly conserved, it will be imperative for us to investigate whether CRP will interact with other FREPs such as angiopoietins The corresponding biological consequence will also be studied Towards this goal, proteins with intact FBG domains will be selected from the protein database and a sequence alignment to M-ficolin FBG will be carried out The proteins showing conserved calcium binding sites and a His284 equivalent, and which have high homology to M-ficolin FBG

may be candidates for this study Their binding to CRP will be investigated by protein binding assays such as ELISA, surface plasma resonance or co-immunoprecipitation Whether the binding of CRP affects the pathogen recognition of these FREPs will be tested by incubating the FREPs with bacteria in the presence of CRP Such study might provide fundamental insights into the interaction between FREPs family and CRP

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