FEMS Immunology and Medical Microbiology 34 (2002) 255^266
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Gram-negative bacteria and phagocytic cell interaction mediated by complement receptor 3 Jose¤ Agramonte-Hevia a
a;
, Aliesha Gonza¤lez-Arenas b , Diana Barrera b , Marco Velasco-Vela¤zquez c
Departamento de Inmunolog|¤a, Instituto de Investigaciones Biome¤dicas, Apartado postal 70228, Ciudad Universitaria, UNAM, 04510 Me¤xico D.F., Mexico b Departamento de Biolog|¤a, Facultad de Qu|¤mica, Universidad Nacional Auto¤noma de Me¤xico, Me¤xico D.F., Mexico c Departamento de Farmacolog|¤a, Facultad de Medicina, Universidad Nacional Auto¤noma de Me¤xico, UNAM, Me¤xico D.F., Mexico Received 22 May 2002; received in revised form 13 August 2002; accepted 27 September 2002 First published online 28 October 2002
Abstract Complement receptor 3 (CR3) is an integrin that recognizes several different ligands. Binding to CR3 in phagocytic cells activates signaling pathways involved in cytoskeleton rearrangement, regulation of cell motility, alteration of gene expression and phagocytosis of complement-opsonized as well as of some non-opsonized particles and pathogenic bacteria. However, CR3-mediated phagocytosis of some Gram-negative bacteria does not induce bacterial clearance. Pseudomonas aeruginosa, Salmonella and Escherichia coli are eliminated after phagocytic cell^bacteria interaction mediated by CR3. However, Bordetella takes advantage of the CR3 function and uses it to enter into macrophages leading to bacterial survival. The final fate of the pathogen is determined by combinations of host and bacterial factors, in which molecular interactions between CR3 and bacterial ligands are involved. 6 2002 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. Keywords : Complement receptor 3; Bacteria ; Phagocytic cells
Integrins are surface receptors involved in cell^cell recognition, cell^extracellular matrix adhesion and binding to complement-derived ligands. Integrins are composed of two transmembrane peptidic chains named alpha (K) and beta (L). The ligand speci¢city is determined by the combination of extracellular domains of both peptide chains [1]. Complement receptor 3 (CR3, KM L2 , CD11b/CD18) belongs to the L2 integrin subfamily which contains three other members that have a common L-chain associated with di¡erent K-chains: KL L2 (CD11a/CD18, LFA-1), p150/95 (CD11c/CD18) and KD L2 [1]. CR3 is expressed on polymorphonuclear leukocytes (PMNs), on monocytes/macrophages and on activated lymphocytes where it is involved in cell^cell adhesion, phagocytosis, chemotaxis, and cell activation [1,2]. CR3 is the principal receptor for the iC3b peptide. iC3b is a fragment generated in the complement cascade when factor I, in the presence of a
* Corresponding author. Tel. : +52 (55) 5622 3834 ; Fax : +52 (55) 5622 3369. E-mail address :
[email protected] (J. Agramonte-Hevia).
co-factor (either factor H or CR1), splits the K-chain of the C3b molecule in two places. It releases a small intervening polypeptide referred to as C3f (iC3b). When iC3b serves as the ligand, CR3 mediates opsonization and phagocytosis of microorganisms (Fig. 1), as well as enhancement of natural killer cell activity for C3-coated targets. CR3 is a promiscuous receptor that recognizes a variety of di¡erent molecules including intercellular adhesion molecule 1 (ICAM-1) [3], ¢brinogen [4], factor X [5], glycophosphatidylinositol (GPI)bK [6], heparin [7], neutrophil inhibitory factor (NIF) [8], and Zymosan (a complex cell wall polysaccharide isolated from yeast, of which a major component is L-glucan) [9]. Binding of CR3 induces di¡erent functions, such as leukocyte extravasation, migration promotion and activation of neutrophils and monocytes (see Table 1). CR3 is an important receptor for opsonic phagocytosis because it binds bacteria coated with iC3b; and through its lectin domain it can also recognize carbohydrates on the surface of bacteria, mediating non-opsonic phagocytosis. CR3 is also capable of interacting physically with GPI-anchored proteins (which lack a cytosolic tail) such as lipopolysaccharide (LPS) receptor (CD14), recep-
0928-8244 / 02 / $22.00 6 2002 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved. PII : S 0 9 2 8 - 8 2 4 4 ( 0 2 ) 0 0 4 0 8 - X
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Fig. 1. iC3b generation. A: Fluid phase C3 is normally hydrolyzed at a slow rate by the ‘C3 tickover’ process to generate C3b. C3b can also be produced at a fast rate by a C3 convertase (a potent protease), which generates massive numbers of C3b fragments from other soluble C3 molecules. C3b possesses a highly reactive thioester group which can covalently attach some C3b molecules to the surface of both pathogens and self (host) cells. iC3b is generated in the complement cascade when factor I, in the presence of a co-factor (either factor H or CR1), splits the K chain of the C3b molecule in two places. It releases a small intervening polypeptide referred to as C3f. B: The C3b and iC3b coat the surface of the microorganisms and act as opsonins to promote phagocytosis using CR3 as the principal receptor on macrophages.
tor type 3B for the Fc IgG portion (FcQRIIIB) and urokinase-type plasminogen activator receptor (uPAR) expressed on the membrane of the phagocytic cell. In these associations, CR3 provides a signal transduction machinery for GPI-anchored receptor ligand recognition [10]. LPS, IgG and plasminogen can be opsonins, and through these receptors CR3 interacts indirectly with Gram-negative bacteria. The signal pathways activated by CR3 are not entirely resolved. Being a promiscuous receptor, the nature of the ligand and the way in which CR3 interacts with the integrin are the principal determinants of the signal that must be transduced into the cell. A schematic representation of the signaling mechanisms is shown in Fig. 2. Septicemia caused by Gram-negative bacteria is a common clinical syndrome. In healthy subjects, Gram-negative bacteria reside primarily in the gut, where intact barriers prevent translocation into the host’s bloodstream [11].
Once the Gram-negative bacteria gain access to the bloodstream, LPS interact directly with leukocytes to induce an in£ammatory cascade [11]. Molecules other than LPS can mediate the interaction of the Gram-negative bacteria with leukocytes. CR3-mediated phagocytosis of pathogenic bacteria is e¡ective, but is probably not enough to trigger complete bacterial clearance. The fate of the pathogen is determined by a combination of host factors, such as the phenotype of the phagocytic cells and the presence or absence of speci¢c antibodies. In this respect, in addition to phagocytosis of opsonized bacteria, the same complement receptors can ingest many pathogens directly, but not as e¡ectively. The leukocyte receptors involved in phagocytosis include the immunoglobulin (Fc) receptors and the complement receptors CR3 and CR4. Complement receptors and Fc receptors generally act in concert to facilitate phagocytosis. The best characterized complement receptor is CR1
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Table 1 Protein and non-protein CR3 ligands Ligand nature
Ligand
Involved domains
Related function
Proteins Extracellular matrix Counter receptor of the immunoglobulin superfamily Blood coagulation proteins
Fibrinogen ICAM-1, ICAM-2 Heparin, Factor X
I-domain I-domain I-domain
Complement pathway product
iC3b
I-domain
Others
CyA NIF FHA HMW WI-1
^ I-domain I-domain ^ ^
cell-matrix adhesion, and migration cell-cell adhesion cell-matrix adhesion, transmigration and monocyte-associated initiation of the coagulation cascade. phagocytosis and cell activation NKC cytotoxicity B. pertussis phagocytosis inhibition of neutrophil migration phagocytosis virulence factor for Haemophilus in£uenzae ^
LPS Zymosan (L-glucan)
Lectin domain Lectin domain
phagocytosis and cell activation
Non-protein
Abbreviations: factor X, coagulation factor X; iC3b, proteolytic fragment of complement protein C3; WI-1, immunodominant cell wall Ag 1; CyA, adenylate cyclase toxin; HMW, high-molecular mass kinogen; NKC, natural killer cell; (^) unknown. Compiled from references [1^10].
which binds C3b. CR1 is expressed on macrophages, monocytes, and PMNs. Binding of C3b to CR1 alone does not stimulate phagocytosis, but it can enhance phagocytosis and microbicidal activity induced by the binding of IgG to the FcQ receptor The binding of C5a (complement molecule 5a) to its receptor on macrophages can activate macrophages to ingest bacteria coated with only complement. This pathway is especially important if bacteria are coated with C3b and IgM. Phagocytes have Fc receptors for IgG but not for IgM. Bacteria coated with IgM and C3b cannot be ingested unless the phagocyte is preactivated by C5a or T-cell-derived interferon-Q [12] (IFN-Q). Thus, if there has been prior infection with the speci¢c bacteria that is causing the current infection, speci¢c IgG will be present and the bacteria is easily coated with speci¢c IgG and C3b; phagocytosis and killing of the bacteria follow. If there is only IgM or C3b opsonization, the phagocyte must ¢rst be activated by IFN-Q or C5a. Bacteria with polysaccharide-rich walls can induce rapid B-cell production of polyclonal IgM independent of T-cell processing of antigen [12]. Bacterial factors, such as the species of bacteria, the nature of CR3-ligand, or the generation of additional modifying signals by the bacteria are also important. CR3-mediated phagocytosis of Pseudomonas aeruginosa, Salmonella and Escherichia coli prevents the establishment of infection. However, virulence factors from such bacteria can alter the normal CR3 signaling pathway. On the other hand, Bordetella takes advantage of CR3 and uses it as a safe portal of entry into macrophages, leading to bacterial survival. Thus, phagocytosis of bacteria is mediated by a combination of interactions, in which CR3 is frequently involved. An almost complete description of the structure and cell expression of CR3, and of the way bacteria can
infect phagocytic cells, has been achieved today. The next step is to understand the principal mechanisms involved in the CR3-mediated interaction of phagocytic cells with bacteria and to determine which biochemical signals could be a¡ected by this interaction in the case of ine⁄cient bacterial clearance. Given that CR3 is a promiscuous receptor, its principal role is to mediate the uptake of infectious microorganisms. P. aeruginosa, E. coli, Salmonella sp. and Bordetella pertussis are Gram-negative bacteria that frequently cause illness. In this review, we describe and discuss the possible molecular interactions of these bacteria with phagocytic cells through CR3, and the di¡erent receptor systems that also cooperate in the interaction and help to de¢ne the clearance or the survival of the pathogen. 1.1. Partnership of CR3 and GPI-anchored receptors in P. aeruginosa clearance P. aeruginosa is a common pulmonary pathogen and a leading cause of nosocomial pneumonia [13]. This Gramnegative bacterium is responsible for 12% of hospital-acquired urinary tract infections [12,14], 8% of surgical wound infections [15], and 10% of bloodstream infections in the United States [16]. In 1996, Qin et al. [17] investigated the function of LFA-1 (KL L2 ), CR3 (KM L2 ) and ICAM-1 in P. aeruginosa-induced neutrophil migration by blocking the function of these adhesion molecules in BALB/c mice. Monoclonal antibodies directed to CD11a and CD11b induced a greater inhibition of neutrophil migration than an anti-ICAM antibody. However, when the function of ICAM-1 was evaluated using ICAM-1 mutant mice, P. aeruginosa-induced neutrophil migration was not prevented, in contrast to wild-type mice [17]. This indicates that L2 integrins present in neutrophils are important
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Fig. 2. CR3 signaling pathways. Binding to CR3 must trigger signaling pathways that activate cytoskeletal rearrangement, gene transcription and the release of ROIs, in order to promote e¡ective phagocytosis and killing of bacteria. CR3/ligand interaction induces the formation of a multi-protein signaling complex that includes non-receptor tyrosine kinases, cytoskeletal proteins and adapter proteins. All CR3 signal transduction pathways are dependent on intracellular tyrosine kinases; but even when several tyrosine kinases are recruited, it seems that Src-family TK (p58Fgr , p59/61Hck , p53/56Lyn ) and Syk are key initiators of cellular responses. These tyrosine kinases phosphorylate cytoskeletal associated proteins, such as K-actinin, paxillin and talin, modulating actin cytoskeleton rearrangement. Activation of tyrosine kinases also leads to activation of phospholipase C (PLC) and PI3 kinase (PI3K) pathways. PLC promotes the release of calcium from intracellular stores and a subsequent calcium in£ux from the extracellular medium ; these events activate actin-severing proteins and, consequently, actin cytoskeleton reorganization. The stimulation of PI3K leads to activation of phospholipase D (an important signal regulating the engulfment of particles and the generation of ROIs) and to the stimulation of the small GTPases Rho and Rac (strongly implicated in cytoskeletal modulation). Additionally, CR3-activated tyrosine kinases may switch on the Ras/ERK signaling pathway, probably by the formation of a Shc^Grb2^Sos complex. Through this pathway, CR3 can direct gene transcription and cell activation [66]. Abbreviations : Ligands, triangles; IP3, inositol (1,4,5) P3; DAG, diacylglycerol; [Ca]i2þ , cytosolic calcium increase ; PKC, protein kinase C; Cbl, cobalamin (cbl proto-oncogene product); PI3K, phosphatidylinositol 3-kinase; PLD, phospholipase D; Shc, SH-2 collagen homology; Grb2, growth-factor receptor binding protein; Sos, mammalian Son of sevenless; Ras, ras protooncogene product (small GTPase); Rac and Rho, small GTPases; Erk1/2, extracellular signal regulated kinase 1/2; Vav, vermicola sporoblast valvogenic (nucleotide exchange factor).
in the in£ammatory response against P. aeruginosa, perhaps by inducing release of proin£ammatory factors after P. aeruginosa-neutrophil interaction. uPAR3 /3 mice demonstrate impaired clearance of P. aeruginosa compared to wild-type mice, and also the blockade of CR3 with antibodies reduces neutrophil recruitment in wild-type mice to the levels seen in uPAR3 / 3 mice. However, anti-CR3 antibodies had no e¡ect on neutrophil recruitment in uPAR3 /3 mice [18]. It has been con¢rmed that the partnering of uPAR with CR3 is involved not only in pathogen clearance, but also in the regulation of other CR3-mediated functions, such as adhesion. Thus, uPAR expression is required for P. aeruginosa clearance by the neutrophil and for CR3-dependent neutrophil recruitment in vivo. Studies with neutrophils and macrophages from CR3de¢cient humans demonstrated that CR3 appears to be the exclusive receptor for non-opsonic phagocytosis of some strains of P. aeruginosa (CR3 strains). Conversely, other strains were ingested through interaction with CD14 (CD14 strains). This ¢nding suggests that phenotypic heterogeneity in P. aeruginosa strains leads to di¡erent mechanisms of non-opsonic phagocytosis. It is also known that the absence of glucose in the phagocytosis bu¡er abrogates ingestion of some P. aeruginosa strains; interestingly, the strains that exhibited this glucose e¡ect are those that are phagocytosed via CR3 [19^22]. These observations suggest that glucose is a requirement for CR3-mediated phagocytosis of P. aeruginosa. Whether glucose is needed as an energy source, perhaps to regulate kinase pathways, remains to be determined. Pulmonary surfactant protein D (SP-D) is a glycoprotein belonging to the collectins family of C-type lectins, which stimulate phagocytosis and other immune cell functions. This protein binds carbohydrates in a calcium-dependent manner and shows monosaccharide speci¢city in the order glucose/mannose s galactose [21,23]. Studies have shown that SP-D speci¢cally recognizes vicinal, equatorial OH groups on monosaccharides equivalent to those present at the 3 and 4 positions of sugars such as mannose and glucose [22,24]. It appears that SP-D recognizes similar OH groups present on the non-reducing terminal carbohydrate residues of polysaccharides [21,23]. SP-D is able to bind P. aeruginosa without induction of bacterial aggregation. Killing of a mucoid strain of P. aeruginosa by alveolar macrophages was enhanced by SP-D. The receptor(s) involved in modulating this event has not been identi¢ed, although previous studies have demonstrated that SP-D binds with high a⁄nity to alveolar macrophages [25,26]. Interestingly, it is known that glucose inhibits the binding of SP-D to alveolar macrophages. Restrepo et al. showed that SP-D can enhance phagocytosis of P. aeruginosa by rat alveolar macrophages in the absence of glucose and it seems as if bacterial killing is even increased under these conditions [26]. All these studies suggest that neutrophil migration dur-
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ing the acute response to P. aeruginosa is mediated through a CR3-dependent pathway. The binding of P. aeruginosa to phagocytic cells appears to be mediated by binding to LPS. In this interaction, CR3 and CD14 work either together or individually, depending on the P. aeruginosa strain. During recruitment of neutrophils to the lung in response to P. aeruginosa, uPAR and CR3 act by a common mechanism, cooperating in the P. aeruginosa clearance. Thus, the strain is not the only factor that determines the dynamics of the interactions ; evidently, the microenvironment is also important. Two more factors are identi¢ed at this time : the glucose level and the presence of SPs in the lung. SP-D has an attached polysaccharide structure (characteristic of the collagen-like lectin family) which could interact with the lectin-binding domain in the CR3 molecule, or SP-D could bind to the bacterial LPS molecule and together interact with the phagocytic cell. If SP-D binds CR3 usually with high af¢nity, high levels of glucose could still block the SP-D/ CR3 interaction. Another possibility could be that glucose induces a conformational change in CR3 leading to a lowa⁄nity state for the P. aeruginosa membrane structure. The receptor(s) involved in modulation of P. aeruginosa phagocytosis has not been clearly identi¢ed. Holmskov and co-workers reported the isolation of a glycoprotein of 340 kDa (gp340) that was localized on alveolar macrophages and contains scavenger receptor domains [27]. Most probably, CR3 participates simultaneously with other receptors in P. aeruginosa recognition and phagocytosis. 1.2. E. coli may modify CR3-induced signaling pathways in phagocytic cells E. coli circulates in the human population, typically without causing symptoms due to the immunity a¡orded by previous exposure, but it may occasionally cause diarrheal disease [24]. Six categories or strains of diarrheagenic E. coli are now recognized : enterotoxigenic (ETEC), enteroinvasive (EIEC), enterohemorrhagic (EHEC), enteropathogenic (EPEC), enteroaggregative (EAggEC) and diffusely adhering (DAEC) [28]. The structurally related human receptors CR3, LFA-1 and p150,95, recognize E. coli in an LPS-dependent manner. The site on LPS that is recognized by CR3, LFA-1 and p150,95 appears to be the lipid A region of the molecule, speci¢cally through the biosynthetic precursor termed lipid IVa [29]. Because LPS is inserted into E. coli membranes, these L2 integrins must bind the hydrophilic portion of the lipid IVa, which is composed of diglucosamine biphosphate [29] (Fig. 3). The mechanism of sugar binding involves the relatively low-a⁄nity binding sites for monosaccharides that are formed at shallow indentations on the protein surface. Selectivity is achieved through a combination of hydrogen bonding to the sugar hydroxyl groups with van der Waals packing, often against aromatic amino acid
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side chains. Coordination with metal ions may occasionally play a role too. Higher selectivity is achieved by extending binding sites through additional direct and water-mediated contacts between the oligosaccharides and protein surface. Dramatically increased a⁄nity for oligosaccharides results from clustering of simple binding sites in oligomers of the lectin polypeptides. The geometry of such oligomers enables the lectins to distinguish surface arrays of polysaccharides and to cross-link glycoconjugates [30^32]. It seems that LPS is the ¢rst molecule involved in the recognition of E. coli by the phagocytic cell. CD14 expression is associated with enhanced phagocytosis of E. coli (opEc) opsonized with serum inactivated by heat. THP-1derived cell lines were stably transfected with constructs encoding GPI-anchored or transmembrane forms of human CD14. Both forms of CD14 support phagocytosis of opEc equally well. CD14-dependent phagocytosis of opEc was inhibited by wortmannin (a PI-3-kinase inhibitor) and a protein tyrosine kinase C inhibitor or a divalent cation chelator. A monoclonal antibody against the LPS binding protein (LBP) did not block cell activation but inhibited ingestion of opEc by THP-1 wild-type CD14 cells. Furthermore, CD14-dependent phagocytosis was not inhibited by anti-CD18 (CR3 and CR4 L-chain) or anti-FcQR monoclonal antibodies [33]. The phagocytic capacity of the PMNs augments after transepithelial migration, and it is well known that the level of CR3 dramatically increases and the superoxide production is conserved concomitantly [34]. Gordon et al. examined CR3 expression by PMNs during E. coli phagocytosis. Kinetic studies indicated a rapid initial fall in CR3 expression after addition of E. coli to PMN, followed by enhanced expression within 5^10 min. The initial fall in CR3 probably represents CR3 internalization rather than receptor destruction. Opsonized E. coli caused an oxidative response from PMN but non-opsonized E. coli did not [35]. Kindzelskii et al. [36] visualized the spatial distribution of membrane receptors during neutrophil phagocytosis. Labeled neutrophils were observed during the phagocytosis of non-opsonized latex beads, E. coli and Staphylococcus aureus. Ligated formyl peptide receptors and, to a lesser extent, CR3, accumulated at the sites of target internalization for all forms of phagocytosis examined. Other receptors, such as FcQR IIIB and uPAR, also polarized during phagocytosis [36]. This fact showed that CR3 is present during E. coli phagocytosis, possibly cooperating with other receptors. E. coli is able to produce exotoxins, including hemolysin A (HlyA). HlyA toxicity on PMN adhesion to cultured endothelial cells (HUVEC) has been examined [37]. The toxin increased CR3 expression and the adherence of human PMN to HUVEC in a dose- and time-dependent manner. The pretreatment of PMN with anti-CD11b/ CD18 monoclonal antibodies reduced HlyA-promoted
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Fig. 3. Schematic representation of probable structures involved in E. coli lipid A and CR3 interaction. A: The ¢ve molecules involved in the recognition are: LPS, CR3 (complement receptor type 3), CD14 (LPS receptor), LBP and TLR 4 (Toll-like receptor 4). B: Tetraacyl lipid A of E. coli is an integral part of LPS. It has a diglucosamine biphosphate backbone that is highly hydrophilic and provides the motif that is recognized by the lectin domain present in the K chain of the CR3 molecule.
cell adhesion [37]; so, CR3 mediates the response to a soluble factor produced by the bacteria increasing the adhesive capacity of the cell. This could be relevant in patients with severe local or systemic bacterial infections. However, it depends on the type of soluble factor and the E. coli strain. Enteropathogenic E. coli can block other phagocytic mechanisms such as PI3-kinase-dependent pathways triggered through the FcQ receptors, but not those activated upon engagement of the complement receptor CR3 [38]. Ficolins belong to a family of proteins that resemble collectins in structure [39], and they are expressed on the monocyte and macrophage surface. As an alternative to CR3, M-¢colin might act as a phagocytic receptor or adapter on circulating monocytes for microorganism recognition. Anti-M-¢colin F(abP)2 antibodies inhibit the phagocytosis of E. coli K-12 by U937 cells [40]. The E. coli structure that binds M-¢colin in the phagocytic cell is not yet known.
The data in the literature clearly demonstrate that many molecules are involved in the interaction of E. coli with phagocytic cells, and the presence or absence of any one of such molecules may alter the bacterium’s attempts to survive (see Table 2). Some of the phagocyte receptors, such as the L2 integrins and CD14/LBP, promote binding, internalization and phagocytosis that result in bacterial clearance. Nevertheless, other molecules mediate interactions that promote the survival of E. coli. HlyA usually causes damage of the epithelial cell using LFA-1 as its receptor, but in the case of phagocytic cells we believe that this interaction promotes the rapid expression of an activated conformational state of CR3 on the membrane by the so-called ‘inside-out’ signal transduction of L2 integrins. This is a term for the molecular mechanism which turns the ligand-binding capacity of integrins on or o¡, i.e. that enables the cell to adhere or to detach. In this particular case, some epitopes appear only after the CR3 acti-
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Table 2 Role of molecules involved in E. coli^phagocytic cell interaction
Abbreviations: CR3, complement receptor type 3; LFA-1, lymphocyte function adhesion molecule; p150,95 (CR4), complement receptor type 4; CD14, LPS receptor; FimH, ¢mbriae H; CD48, mannose-containing GPI-linked molecule ; Tir, translocated intimin receptor. Compiled from references [29,33,37^42].
vation pathway has been triggered [41] and more activated CR3 molecules are expressed at the moment of the interaction (CR3/CD14/LPS/LBP). CR3-mediated interaction triggers an e⁄cient respiratory burst to destroy bacteria after phagocytosis. During this process, NADPH oxidase reduces oxygen to superoxide, and superoxide dismutase converts superoxide to hydrogen peroxide (together, these are referred to as reactive oxygen intermediates (ROIs)). Hydrogen peroxide can then react with newly formed superoxide and produce the highly reactive hydroxyl radical which is toxic for the bacteria. However, in serum-free conditions, E. coli is able to enter into mast cells without loss of viability. CD48, a mannose-containing GPI-linked molecule, localized on cholesterol/glycolipid-enriched microdomains, is the receptor in mouse mast cells for FimH-expressing E. coli. This mechanism of entrance probably occurs in opsonin-de¢cient sites in the body or in immunocompromised hosts with low systemic levels of E. coli-speci¢c antibody [42], demonstrating that E. coli infects the host by di¡erent routes. Enteropathogenic E. coli use a type III secretion system in order to inhibit their uptake by macrophages; the bacterium secretes the translocated intimin receptor (Tir) for its own membrane protein intimin. The intimin/Tir binding promotes damage to the bacterial host, forming a lesion known as a pedestal, which involves the activation of phosphatases and alteration in the actin cytoskeleton of the macrophage [43]. So, even when CR3-mediated signals are trying to trigger bacterial killing, a contrary mechanism is being switched on to ensure bacterial survival.
Fig. 4 summarizes the complex interactions between the major molecules involved in the E. coli-phagocytic cell interaction, with special attention to the participation of CR3. The ¢nal result is a balance between the promotion and avoidance of bacterial clearance factors. The balance depends on the type of E. coli strain and the type of phagocytic cell involved. 1.3. CR3-mediated phagocytosis of Salmonella serovars procures bacterial clearance The pathogenicity of Salmonella serovars is known to be speci¢c for animal species; for example, S. typhi causes a systemic febrile illness known as typhoid fever in humans, but not in mice. In contrast, Salmonella typhimurium causes a typhoid fever-like disease in mice, but less so in humans [44,45]. It appears that opsonization of Salmonella serovars with complement components is required for optimal phagocytosis by host macrophages. Inhibition assays using monoclonal antibodies against the complement receptors demonstrated that human and murine macrophages recognize serum-opsonized Salmonella serovars via di¡erent receptors. CR1 and CR3 on human macrophages contribute to the recognition of S. typhi and S. typhimurium, respectively. Also, it has been shown that the intracellular fate of Salmonella serovars following phagocytosis depends on the type of complement receptors involved in their recognition. CR1- but not CR3-mediated recognition is closely correlated with intracellular survival and is responsible for the host-speci¢c pathogenesis of Salmonella serovars [46]. Grossman et al. have reported
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Fig. 4. Schematic model of the major molecules involved in the interaction between E. coli and phagocytic cells. The interaction can be induced by different cell surface receptors of both cells. FimH, ¢mbriae H ; CD48, mannose-containing GPI-linked molecule ; LFA-1, lymphocyte function adhesion molecule ; CD14, LPS receptor; CR3, complement receptor type 3; Tir ; translocated intimin receptor.
that various Salmonella serovars di¡er neither in the deposition of C3b nor of iC3b on their surfaces [47]. It seems that selective recognition of S. typhi via CR1 may be due to the impaired CR3/iC3b interaction rather than to the enhanced CR1/C3b interaction. In that case, binding of CR1 to iC3b can compensate for the inability of the CR3 to bind iC3b, since iC3b also serves as an important ligand for CR1 [48]. It should be noticed that the impaired interaction of CR3 with surface-bound iC3b can be caused by the secretion of an inhibitory bacterial factor (peptide or sugar-like), capable of blocking the CR3^iC3b interaction. The roles of CR1 and CR3 in phagocytosis and subsequent phagosome fusion in Salmonella-infected murine macrophages have been studied. Anti-murine CR1 antibody suppressed phagocytosis of S. typhimurium by 36%, whereas anti-CR3 antibodies failed to prevent phagocytosis of S. typhimurium, suggesting that CR1 in murine macrophages may only contribute to the recognition of S. typhimurium and may possibly play a minor role. In the case of S. typhi, only anti-CR3 antibodies signi¢cantly inhibited phagocytosis of S. typhi and phagosome^lysosome fusion. The treatment with an inhibitor of the complement cascade factor I, resulted in a marked inhibition of phagosome^lysosome fusion in S. typhi-infected macrophages, although no signi¢cant inhibition was observed on phagocytosis of S. typhi. In response to S. typhimurium infection, RA/VD-di¡erentiated U937 cells developed an oxidative metabolic burst
corresponding to an extracellular production of superoxide anions [49,50]. The investigation of both bacterial and serum factors involved in the triggering of the oxidative burst show the involvement of S. typhimurium O-speci¢c chains. Even though the role of O-antigen in the activation of neutrophils by Salmonella has already been reported [51], the mechanism is not clear. Cha«teau et al. [52] reported that the recognition of S. typhimurium O-antigen by RA/DV-di¡erentiated U937 cells was mediated by the CR3 K chain (CD11b). They also demonstrated that a lectin-like domain is the speci¢c site for binding O-antigen. Recently, Troelstra et al. [53] reported that in contrast to ELPS (Erythrocyte with LPS coat), no reduction in LBPdependent Salmonella minnesota interaction with neutrophils was seen after preincubation with anti-CR3 antibody; neither was LBP-independent binding a¡ected by anti-CR3 antibody. They proposed that structures other than CR3 and CD14 account for the binding of S. minnesota to activated neutrophils, and that this binding is independent of LBP [53]. Our idea is that various receptors involved in Salmonella recognition exist. Even when CR3 is not able to recognize S. typhi, it may trigger a phagocytic signal for it. That means that the signal produced by the S. typhi/CR1 interaction is not enough to kill the bacteria, but is able to activate CR3 integrin. It is known that Salmonella, like E. coli and Shigella, inject cytoskeleton-altering proteins and activators of the Rho family of GTPases into the
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host cell cytoplasm ; these pathogen molecules induce the formation of cell extensions that resemble macropinosomes (‘a trigger mechanism’) rather than the pseudopods characteristic of phagocytosis mediated by other receptors (FcQRs), like the zipper mechanism. The term zipper mechanism has been suggested for the highly selective receptormediated bacterial entry. After phagocytosis, events including pH acidi¢cation and ROI production lead to the formation of a phagolysosome inducing the killing and the digestion of the bacteria. The term trigger mechanism has been proposed for indiscriminate, apparently adhesion-independent uptake. In that process, di¡erent molecules and mechanisms participate in host-cell entry. Interactions between the bacteria and host cells cause ‘membrane ru¥ing’ at the site of attachment, followed by bacterial entry. Ruf£ing induces indiscriminate uptake. This process has been termed macropinocytosis. It may occur in S. typhi endocytosis, which is mediated by CR1, by exploiting the signaling machinery of the host cell, thus inducing cytoskeletal rearrangements. However, this is not possible for S. typhimurium which can be eliminated by the phagocytic cells because the CR3 signal is su⁄ciently powerful. 1.4. CR3-mediated non-opsonic uptake of Bordetella pertussis impairs bacterial clearance B. pertussis is a Gram-negative bacterium that produces a highly contagious disease called ‘whooping cough’. The bacteria attach to ciliated epithelial cells by producing a speci¢c adherence factor called ¢lamentous hemagglutinin (FHA) [54]. Moreover, FHA also interacts with a complex containing the leukocyte response integrin and the integrin-associated protein CD47 that are known to up-regulate the expression of CD11b/CD18 [55]. FHA has been shown to be a B. pertussis virulence factor responsible for binding to CR3; additionally, FHA as well as the most important toxin of B. pertussis (pertussis toxin) have been shown to be involved in the up-regulation of CR3 [56]. So, it could be that pertussis toxin increases CR3 expression, whereas FHA uses the interaction with CR3 in order to colonize more e⁄ciently. In the absence of opsonizing serum, B. pertussis readily binds to phagocyte CR3 and this increases bacterial survival [57]. Currently, it is not known in detail how this happens. However, activation of CR3 by anti-CR3 antibodies results in dose-dependent down-regulation of IL-12 secretion by human monocytes [58]. Indeed, FHA suppresses IL-12 production of a macrophage cell line [59]. Possibly, such a change might facilitate persistence of B. pertussis in the host cells, frustrating the cellmediated immunity. On the other hand, in the presence of opsonizing antibodies, the cross-linking of Fc receptors results in the uptake and killing of bacteria. The e¡ects of B. pertussis uptake via FcQR (FcQRII/III) and CR3 have been compared by targeting both receptors using bi-speci¢c antibodies. The infection of mice with suspensions of one of two isogenic B. pertussis strains (one of which tar-
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geted to CR3 and the other to FcQRII/III) showed that FcQRII/III-mediated clearance was more e⁄cient than CR3-mediated clearance [60]. It seems likely that qualitative di¡erences between the uptake of B. pertussis via FcQRs and the uptake via CR3 may be caused by di¡erences in the signal transduction pathways [60]. After attachment, B. pertussis also produces an extracytoplasmic invasive adenylate cyclase, a tracheal cytotoxin and dermo-necrotic toxin which destroys epithelial tissue. The adenylate cyclase toxin (CyaA) of B. pertussis is a major virulence factor required for the early phase of lung colonization. Recently, it has been shown that the binding and toxic properties of CyA are dependent on its interaction with CR3. A complete inhibition of CyA binding by anti-CD11b monoclonal antibodies and CD18 for human cells suggest that CR3 is the main receptor in the cell line tested. CD11a/CD18 and CD11c/CD18 show an insu⁄cient binding, suggesting that CR3 is the only integrin L2 family involved in the binding of CyA to the phagocytic cell. The interaction of CyA and CR3 is dependent on Ca2þ and independent of Mg2þ , which suggests that the binding occurs independently of the K chain (CD11b) I domain [61]. Monoclonal antibodies against the ¢bronectin receptor (VLA-5, integrin K5 L1 ) and also soluble ¢bronectin inhibit the binding of non-opsonized B. pertussis to monocytes. This suggests an interaction of B. pertussis with monocyte cells via the VLA-5 molecule [62]. Cross-linking of VLA-5 on monocytes by B. pertussis results in activation of CR3mediated protein tyrosine kinases. The phosphorylated proteins detected were around 55^86 and 100^120 kDa, and the phosphorylation was rapid (between 2 and 10 min after cross-linking) and transient [63]. Fibronectin has been shown to control CR3 expression on neutrophils, as well as that of the low-a⁄nity receptor for IgG (CD16) and the cytokine receptors TNFKR, IL-8R, IL-1R type I [64]. To control this expression, ¢bronectin requires integrin signaling via VLA-5 and, in particular, protein tyrosine kinase activation and intracellular calcium in£ux. It partially explains how VLA-5 signaling may ¢nally activate the CR3 molecule in phagocytic cells. We currently think that B. pertussis adheres to human monocytes/macrophages by the interaction of the bacterial surface-associated protein FHA (which has an Arg-GlyAsp site) with CR3. This interaction permits the uptake and persistence of the bacterium into the host cell, probably by inhibition of Th1 cytokine release and the subsequent establishment of an immunosuppressive state. FHA may act ¢rst to bind to cells and facilitate the interaction of CyaA with CR3 [65]. The interaction between CyaA and CR3 could favor the insertion of CyaA into the host cell membrane. Alternatively, CyaA may bind ¢rst to lipids in the membrane, and then CR3 may stabilize this interaction, allowing a more e⁄cient intoxication. Leukocyte integrin VLA-5 can also mediate the interaction, forming a signal transduction complex, involving the
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leukocyte response integrin and even integrin-associated protein CD47 [55]. This complex is known to up-regulate CR3 binding activity ; thus, the bacterial pathogen enhances its own attachment to host cells by co-opting a cell signaling pathway.
leading to actin polymerization, particle internalization and bacterial death; however, Gram-negative bacteria can use it to evade the immune response.
Acknowledgements We thank Dr. Carlos Rosales for his helpful review of this manuscript.
2. Conclusions Recognition, interaction and phagocytosis of bacteria by phagocytic cells is a highly diverse process ; the signals leading to actin polymerization and particle internalization depend on the speci¢c receptors and on additional modifying signals that can be generated by bacteria. Gramnegative bacteria are complex particles that can activate multiple receptors whose signaling pathways may interact in a complex way. Complement receptors can be involved in the ¢rst stage of the infection. CR3 can assist in the ingestion of bacteria utilizing opsonins (C3bi) or by direct recognition processes. For example, CR3 binds directly to B. pertussis FHA and CyaA. In this process, FHA may act ¢rst to bind cells and to induce up-regulation of CR3 membrane expression, and then to facilitate the CyaA interaction with CR3. It can also bind directly to S. typhimurium, P. aeruginosa and E. coli through an LPS^LPB/ CD14^CR3 complex. CR3 can also use other membrane molecules expressed in the phagocytic cell like uPAR (in P. aeruginosa clearance) as well as FcQR IIIB and CD48 (in E. coli clearance). In the case of S. typhi, which CR1 can recognize but is incapable of eliminating, and which CR3 is not able to recognize but may trigger a phagocytic signal against, we believe that CR3 activation could be by a CR3 inside-out signal mechanism mediated by CR1 and dependent on the interaction with S. typhi. The same mechanism could be functioning in the E. coli interaction with the structurally related receptors LFA-1 and p150,95. In addition to the capacity of CR3 to interact with di¡erent molecules on the bacterial surface, or through partnership molecules, di¡erent receptor systems are also cooperating. We have described here LFA-1/HlyA interactions in macrophages, Fim-CD48 in basophils, and VLA-5 interaction with B. pertussis and E. coli through an unidenti¢ed molecule on macrophages. Phagocytosis of Gram-negative bacteria is mediated by the combination of various interactions occurring at the same time. The signal generated by the sum of these interactions rules the fate of the bacteria : survival or death. It is known that Salmonella, E. coli and Shigella inject cytoskeleton-altering proteins and activators of the Rho family of GTPases into the host cell cytoplasm, inducing the formation of cell extensions. These are distinct from pseudopods and needed for e⁄cient phagocytosis. The participation of CR3 in these events is frequent and also important. The signaling pathways activated by CR3 could be a¡ected at di¡erent levels. CR3 is one of the main molecules on phagocytic cells that trigger signals
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