Published online before print February 3, 2006
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,1
* Department of Biomedical Sciences, College of Medicine, University of Illinois at Chicago;
Virus and Immunity Group in the Department of Virology, Institut Pasteur, France;
Department of Microbiology and Immunology, Division of Infectious Diseases, Walther Oncology Center, Indiana University School of Medicine, Indianapolis; and
Molecular Epidemiology, Enteric Diseases Research Program, U.S. Naval Medical Research Unit-3, Cairo, Egypt
1Corresponding author: Enteric Diseases Research Program, U.S. Naval Medical Research Unit-3, PSC452, Box 154, FPO AE 09835, Cairo, Egypt. E-mail: KlenaJ{at}namru3.med.navy.mil
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: Escherichia coli • dendritic cells • CEACAM1 (CD66a)
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Unlike lipopolysaccharides (LPS) from enteric bacteria (Fig. 1A
), GC expresses LOS, which lacks the somatic O-antigen sugar residues. Several laboratories have identified the genes encoding the glycosyltransferases responsible for addition of sugar residues to GC LOS [10
, 11
], and the lgtA to lgtE genes are responsible for the synthesis of the 
-chain of GC LOS (Fig. 1B)
. LOS antigenic diversity in GC can be achieved by phase variation. For example, Schneider and co-workers [12] challenged human volunteers with GC strain MS11 variant A (equivalent to an lgtD mutant) and found that the majority of the variants recovered expressed variant C {equivalent to wild-type (WT) [6
]}.
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Figure 1. The structures of core region of Escherichia coli K12 LPS (A) and the -chain of LOS in GC and Neisseria meningitidis (B). Genes involved in the biosynthesis of core LPS are shown at their approximate site of action (italic), and their corresponding mutants are shown on the top of each epitope. GalNAc, N-Acetylgalactosamine; Gal, galactose; GlcNAc, N-acetylglucosamine; Glc, glucose; Hep, L-glycero-D-mannoheptose; KDO, 2-ketp-3-deoxyoctonate. It should be noted that here, only the chain is shown, and Neisseria strains do not possess O-antigen.
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Dendritic cells (DCs) from mice express CEACAM1 [19
], a member of the CEA family. Furthermore, DCs can interact with microorganisms by using the distinct C-type lectin, DC-specific intercellular adhesion molecule-grabbing nonintegrin (SIGN; CD209). Bacteria such as Helicobacter pylori and certain strains of Klebsiella pneumonia interact with DC-SIGN through LPS structures that contain Lex [Galß1_4(fucose1_3)GlcNAcß] or mannose [20
21
22
23
]. Mycobacterium tuberculosis uses its mannose-capped cell-wall component to interact with DC-SIGN to promote the internalization of this microorganism [20
, 24
]. DC-SIGN also serves as a receptor for the gp120 antigen of human immunodeficiency virus type 1 (HIV-1) and acts as a carrier for HIV-1 viruses to deliver them to the target cells such as CD4 lymphocytes [25
26
27
]. Although cell-signaling mechanisms demonstrating how DC-SIGN mediates the uptake of microorganisms are not yet defined clearly, the immunoreceptor tyrosine-based activation motif (ITAM)-like motif on the cytoplasmic domain might play a role in the uptake of bacteria or viruses [23
]. However, internalization of M. tuberculosis mediated by DC-SIGN inhibits DC functions [24
].
In this study, we investigated the role CEACAM1 and DC-SIGN in mediating adherence and phagocytosis of Opa-expressing or nonexpressing GC during infection of DCs. We also assessed the importance of LOS in the interaction of GC with DC-SIGN.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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3, I3, 2, and 4, isogenic LOS mutants of GC F62 WT (provided by Emil Gotschlich, The Rockefeller University, New York, NY), contain mutations within the lgtD, lgtB, lgtA, and lgtE genes, respectively [10
] (Fig. 1)
. In these F62 strains (WT or LOS-defective), only Opa– and pilus– variants were used. Recombinant opa genes from GC strain MS11 were expressed in E. coli K12 hybrid strain HB101 [14
], a rough and avirulent strain, which does not contain the O-antigen polysaccharide as part of its LPS. Expression of OpaI by GC and E. coli was routinely monitored by Western blot using the Opa cross-reactive monoclonal antibody (mAb) 4B12 [14
, 31
]. E. coli, harboring the vector, pGEM, is designated as Opa– E. coli. The cDNAs of CEACAM1 (CD66a) and CEACAM6 (CD66c) were obtained from Drs. John Shively (Beckman Research Institute of the City of Hope, Duarte, CA) and Wolfgang Zimmermann (University of Munich, Germany), respectively. Anti-CD209 mAb, specific for DC-SIGN, was purchased from PharMingen (San Diego, CA). YTH71.3, a rat antibody that recognizes CEACAM1, CEACAM6, and CEACAM3 (CD66d), was purchased from Roche Molecular Biochemicals (Indianapolis, IN). The anti-rat secondary antibody conjugated with fluorescein isothiocyanate (FITC) was purchased from Roche Molecular Biochemicals. Mannan, the ligand antagonist of human mannose receptor, was purchased from Sigma Chemical Co. (St. Louis, MO).
HeLa-DC-SIGN cells were constructed by transfecting HeLa cells with human DC-SIGN cDNA and were selected for surface antigen expression as described previously [32 , 33 ]. For construction of transfectants, the tyrosine (Y) residue in the WT cytoplasmic domain of human DC-SIGN was changed to an alanine residue (A), giving rise to the mutant: DC-SIGN-Y/A, which was then stably transfected in HeLa cells (HeLa-DC-SIGN-Y/A) [33 ].
Preparation of DCs
Peripheral blood mononuclear cells (PBMC) were isolated from buffy coats obtained from the Indiana Blood Center (Indianapolis) by density gradient centrifugation over FicollPaqueplus (1.077 g/ml, Pharmacia, Piscataway, NJ). The Institutional Review Board and Study Committees at Indiana University School of Medicine (Indiana University-Purdue University Indianapolis and Clarian Health Partners) approved of the acquisition of human blood. Buffy coats were diluted 1:4 with phosphate-buffered saline (PBS) and loaded in a 1:1 (v:v) ratio on Ficoll and centrifuged without braking for 30 min. PBMC were washed four times with PBS, and monocytes were purified from PBMC using CD14 microbeads (Miltenyi Biotec, Auburn, CA) as described previously [34
]. To increase purity, cells were passed over a second CD14 microbead column. The final purity of the isolated monocytes was >98%, as assessed by labeling with CD14 FITC antibody (Caltag, Burlingame, CA) and flow cytometric analysis. Purified CD14+ monocytes (5x105 cells/ml) were cultured for 6 days to promote differentiation of immature monocyte-derived DCs in culture medium consisting of RPMI 1640 (BioWhittaker, Walkersville, MD), 10% heat-inactivated fetal bovine serum (Hyclone, Logan, UT), 100 U/ml penicillin, and 100 µg/ml streptomycin in the presence of 20 ng/ml recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF; Immunex, Seattle, WA) and 10 ng/ml rh interleukin (IL)-4 (Peprotech, Rocky Hill, NJ). The DCs derived from these cultured monocytes display typical dendrites and in mixed lymphocyte cultures, promote activation of alloreactive T cells. The phenotypes of these cells are human leukocyte antigen-DR+, CD1a+, CD86+, CD40+, CD14– [34
]. Upon LPS stimulation, these DCs express CD83 [35
, 36
].
Adherence and phagocytosis assays
The assays for adherence and phagocytosis have been described previously [16
, 17
, 37
]. Briefly, DCs and HeLa cells were plated in 24-well plates, in which each well contained a coverslip. DCs were suspended in RPMI with 2% fetal calf serum (FCS) at a concentration of 4 x 105/ml. These cell suspensions (1/2 ml each) were added to 24-well plates, and after addition of 50 µl bacterial suspensions at a concentration of 4 x 107 colony-forming units (CFU)/ml, the cells were allowed to incubate for 2.5 h at 37°C in the presence of 5% CO2. For the inhibition assay, the antibodies were added 20 min prior to the addition of bacteria. The DC monolayers were washed twice with PBS using cytospin and fixed with 2% paraformaldehyde in PBS containing Giemsa stain. The number of associated bacteria (adherent and internalized) per DCs was determined by microscopy by counting the bacteria associated with 100 cells on the coverslips. For the HeLa cells, the associated bacteria were quantified by washing three times with RPMI containing 2% FCS and plating the culture after the cells were lysed by 0.5% saponin (Calbiochem Corp., La Jolla, CA).
To determine the internalization of bacteria, gentamicin, which kills extracellular bacteria but cannot penetrate into host cells, was added to each well at a final concentration of 100 µg/ml, and the cultures were incubated for 90 min. The cells were diluted in PBS containing 0.5% saponin and plated on GC or Luria-Bertani plates. The level of internalization of bacteria in DCs and HeLa cells was calculated by determining the CFU recovered from lysed cells.
Determination of phagocytosis by flow cytometry
The following method was used to supplement the survival-based phagocytosis assay described above, as DCs kill the phagocytosed GC. The phagocytosis rate of GC by DCs was performed as follows. Briefly, GC was suspended in RPMI medium containing 5- and 6-carboxyfluorescein diacetate-succinimidyl ester (Molecular Probes, Eugene, OR) [38
] for 40 min and washed twice with RPMI to remove the excess dye. Labeled bacteria were added to DC cultures for 2.5 h. The cell cultures were washed twice to remove unbound bacteria. DCs plus adherent GC were fixed with 2% paraformaldehyde. Before flow cytometry, a 1:10 dilution of Trypan blue (0.4%, Sigma Chemical Co.) was added to the fixed cell cultures, and the mixture was incubated at ambient temperature for 10 min [39
] to quench the fluorescence from extracelluar-labeled bacteria. Trypan blue blocks the fluorescence but cannot penetrate host cells; therefore, fluorescence from internalized bacteria will not be influenced by addition of Trypan blue. The rate of bacterial internalization was determined by comparing the percentage of fluorescence-positive DCs and unlabeled DCs. The phagocytosis of GC by DCs was determined using flow cytometry to alleviate the concern that the measurement of phagocytosis, based on the survival of bacteria in DCs, does not accurately represent the natural processes of the bacteria-DC interaction. As shown in Figure 2C
, a limited number of GC were recovered from DCs after gentamicin killing.
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Figure 2. The main interaction of GC and E. coli in human DCs is not mediated by Opa. (A) GC and (B) E. coli (EC) adhere to DCs, regardless of expression of Opa protein. Opa– and OpaI bacteria were allowed to interact with host cells; the number of bacteria associated with 100 cells was scored by microscopic examination. HeLa and HeLa-CEACAM1 cells served as negative and positive controls for the adherence assay, respectively. (C) DCs internalize a limited number of GC but phagocytose a large number of E. coli, regardless of Opa expression. (D) Phagocytosis of E. coli and GC by DCs was confirmed by transmission electronic microscopy. The diameter of E. coli is usually  1 µm. Phagocytosis of WT GC and the lgtB mutant by DCs, as determined by flow cytometry, is shown (E). Phagocytosis of E. coli is used here as a positive control.
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Reverse transcriptase-polymerase chain reaction (RT-PCR) of CEACAM1 and CEACAM6
RT-PCR for CEACAM1 and CEACAM6 from human DCs followed the procedures described for mouse DCs [19
]. Briefly, total mRNA was isolated from 2 x 106 DCs and used for cDNA synthesis by RT using the RT system (Promega, Madison, WI). The RT product was amplified by PCR for 25 cycles with Taq DNA polymerase (Qiagen, Valencia, CA). Oligonucleotide primers for CEACAM1 were (forward) 5'-GCAACAGGACCACAGTCAAGACGA and (reverse) 5'-GTGGTTGGAGACTGAGGGTTTG, and the oligonucleotide primers for CEACAM6 were (forward) 5'-GTTCTTCTACTCGCCCACAAC and (reverse) 5'-CGTTCCTTTTGACGCTGAGTAG [40
]. The expected sizes of the PCR amplicons for CEACAM1 and CEACAM6 using these primers are 506 base pairs (bp) and 474 bp, respectively.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Human DCs may express various forms of CEACAM1
To examine whether human DCs express CEACAM1, GM-CSF/IL-4-treated monocytes, which differentiate into DCs, were collected daily. These cells were analyzed by flow cytometry and Western blot analysis using the anti-CD66 antibody YTH71.3, which reacts with CEACAM1, CEACAM3, and CEACAM6. The level of antigen expression in the monocytes correlated with the duration of GM-CSF treatment (Fig. 3A
and 3B
). However, instead of revealing a full-length form of CEACAM1 of 180 kDa, as per the HeLa-CEACAM1 control, Western blot analysis showed bands of 60 and 80 kDa (Fig. 3B)
. It is unlikely that either of these bands represents CEACAM3, which is expressed as a 30-kDa band in neutrophils [16
, 41
]. In our hands, CEACAM3 cannot be detected by Western blot analysis using YTH71.3 (unpublished data). Therefore, the bands most likely correspond to CEACAM6 or alternatively, represent other forms of CEACAM1. RT-PCR results demonstrated that only CEACAM1, but not CEACAM6, was expressed in human DCs (Fig. 3C)
. These results indicate that human DCs express other forms of CEACAM1. These data might explain why the Opa-CEACAM1 interaction does not play a major role in phagocytosis of OpaI GC by DCs.
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Figure 3. Human DCs may express different forms of CEACAM1. The expression of CEACAM1 on DCs was analyzed by flow cytometry, immunoblot, and RT-PCR. (A) The presence of CEACAM (CD66) antigens on DC (DC/Day 6) surface was detected by the anti-CD66 mAb YTH71.3, which recognizes CEACAM1, CEACAM6, and CEACAM3 with flow cytometry analysis (open histogram). Untreated DCs (monocytes or DC/Day 0, as described in this figure) served as a negative control in this experiment (filled histogram). (B) For Western blot analysis, cell lysates were obtained by harvesting from Day-1 to Day-6 cultures of monocytes differentiating to DCs. HeLa-CEACAM1 cells serve as controls. (C) CEACAM1, but not CEACAM6, is expressed by DCs, as assessed by RT-PCR analysis. mRNA was isolated from 2 x 106 human monocytes or DCs, and RT-PCR was performed using primers for CEACAM1 and CEACAM6 as well. The cDNAs of CEACAM1 and CEACAM6 served as positive controls for PCR.
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Figure 4. The phagocytosis of E. coli by DCs is reduced by anti-DC-SIGN antibody. Opa– and OpaI E. coli were incubated with DCs for 1.5 h in the presence or absence of anti-CD66 (5 µg/ml) and DC-SIGN (5 µg/ml). The concentration of each reagent used in this experiment was based on previously generated data as well as that published by other investigators [17
, 43
]. The phagocytosis rate of E. coli was evaluated by the recovery of bacteria from gentamicin protection. control = No antibodies added.
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Figure 5. HeLa-DC-SIGN cells adhere and phagocytose E. coli, which was blocked by anti-DC-SIGN antibody and mannan. (A) HeLa, HeLa-DC-SIGN, and HeLa-DC-SIGN-Y/A cells were incubated for 2.5 h with Opa– E. coli; bacterial adherence and phagocytosis were measured as described in Materials and Methods and were also shown by transmission EM. HeLa-DC-SIGN but not HeLa cells adhere and phagocytose Opa– E. coli, P < 0.001. Mutation of tyrosine residue slightly increases DC-SIGN ability to phagocytose E. coli, P> 0.05. It is not clear that the internalized E. coli were enclosed within vesicles in EM (B), as shown in HeLa-CEACAM3 (CD66d)-mediated phagocytosis of E. coli [16
]. (C) Pretreatment of cells with anti-DC-SIGN antibody (5 µg/ml) and mannan (0.5 mg/ml) blocked adherence of E. coli to HeLa-DC-SIGN. E. coli were incubated with HeLa-DC-SIGN for 2.5 h. Anti-CD66 antibody (5 µg/ml) had no effect when added to the same concentrations. The expression level of DC-SIGN and HeLa-DC-SIGN-Y/A in HeLa cells is shown (D).
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Figure 6. HeLa-DC-SIGN cells adherence and phagocytosis of lgtB mutant were inhibited by anti-DC-SIGN antibody and mannan. The procedures for examining the adherence (A), phagocytosis (B), and the antibody inhibition assay (C) of strain F62 and its isogenic LOS-mutated strains 3 (lgtD), I3 (lgtB), 2 (lgtA), and 4 (lgtE) with HeLa-DC-SIGN were the same as in Figure 5
. (D) Phagocytosis of E. coli and GC I3 by HeLa-DC-SIGN was also evaluated by flow cytometry analysis, which is to support the results from Figures 5
and 6
.
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HeLa-DC-SIGN cells bind to and phagocytose an lgtB mutant of GC
A recent report indicated that an lgtB LOS mutant of N. meningitidis interacts with DCs through DC-SIGN [44
]. In addition, we recently demonstrated that the core LPS of E. coli K12 probably serves as a ligand for DC-SIGN (CD209) [42
]. As shown in Figure 1
, lgtB-deficient LOS mutants of GC expose a terminal GlcNAc epitope within their core LPS region. This is the same situation with E. coli K12 [42
]. Therefore, we investigated whether a GC lgtB mutant bound to HeLa-DC-SIGN cells. GC WT strain F62 and four of its isogenic LOS derivatives, 3, I3, 2, and 4 (Fig. 1B)
, were examined regarding their ability to adhere and invade HeLa-DC-SIGN. Figure 6
, A and B, shows that I3 strain (lgtB) but not other F62 GC strains promoted a typical DC-SIGN-mediated binding and phagocytosis; i.e., HeLa-DC-SIGN but not HeLa cells phagocytosed the I3 strain, demonstrating that DC-SIGN is also a receptor for the lgtB mutant of GC. The interaction of I3 strain to HeLa-DC-SIGN was also inhibited by anti-DC-SIGN antibody or mannan (Fig. 6C)
. Furthermore, the phagocytosis rate of I3 by DCs is close to the rate of E. coli, judged by flow cytometry analysis (Fig. 6D)
. As indicated above, we used the flow cytometry method to measure the phagocytosis of GC, as most internalized GC were killed quickly in DCs.
Mutation of a tyrosine residue in the cytoplasmic domain of DC-SIGN does not significantly influence its phagocytic ability
The cytoplasmic domain of DC-SIGN contains a motif (YKSL) [32
], which has been implicated as a potential ITAM (YLYL) [23
]. ITAM-containing receptors, such as CEACAM3 (CD66d) [37
, 39
, 45
, 46
] and Fc receptors [47
], can promote phagocytosis of bacteria, and phosphorylation of the tyrosine residue plays an essential role in triggering the process. To test whether the tyrosine residue on the cytoplasmic domain of DC-SIGN was required for phagocytosis, we substituted it with alanine to construct DC-SIGN-Y/A, which was transfected into HeLa cells (HeLa-DC-SIGN-Y/A). A transfectant expressing a similar level of DC-SIGN-Y/A as HeLa cells expressing DC-SIGN (Fig. 5D)
was selected in the phagocytic assay. Figure 5A
shows that mutation of the tyrosine residue in the YKSL motif of DC-SIGN did not significantly decrease or increase its phagocytic ability, indicating that the ITAM-like motif on DC-SIGN is unlikely to participate in the phagocytosis of E. coli.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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That DC-SIGN acts as a bacterial receptor for GC LOS was demonstrated using LOS mutants. Of interest is that this interaction is specific for GC LOS, which exposes a terminal GlcNAc residue. This finding is similar to what we have reported previously for E. coli: Specific regions within the LPS core promoted DC-SIGN-mediated adherence. DC-SIGN-GC interactions were blocked by mannan, an antagonist of human mannose receptors, including DC-SIGN. These interactions were also inhibited specifically using an antibody specific for DC-SIGN. HeLa cells expressing DC-SIGN but not HeLa cells without DC-SIGN were able to bind and avidly internalize lgtB GC.
We further extended our knowledge of the interaction of DC-SIGN and E. coli as well as GC using transfected HeLa cells. The cytoplasmic domain of DC-SIGN contains a potential ITAM [23 , 32 ]. Activation of ITAM is essential to propagate cellular signaling and results in phagocytosis of microorganisms, as demonstrated for CEACAM3 (CD66d) with Opa-expressing bacteria [37 , 39 , 45 , 46 ]. It is unexpected that our results showed that mutation of the tyrosine residue of the potential ITAM on DC-SIGN slightly increased phagocytosis of E. coli (Fig. 5A) . Thus, the potential ITAM sequence in DC-SIGN does not take part in the phagocytosis of E. coli. It is possible that the tyrosine-containing sequence in the cytoplasmic domain of DC-SIGN might be an immunoreceptor tyrosine-based inhibition motif (ITIM). This is based on the observation that alteration of the tyrosine residue on ITIM of CEACAM1 increased the phagocytosis of OpaI E. coli in HeLa cells in comparison with WT of CEACAM1 [48 ].
DCs are professional phagocytic cells. However, the surface receptors that promote such phagocytosis have not been well-characterized. As shown here, DC-SIGN possesses a strong capacity to promote bacterial phagocytosis. Professional and nonprofessional phagocytosis requires the reorganization of the actin-based cytoskeleton, which is initiated by signals arising from the interaction of receptors on the cell surface with ligands on the microorganisms. Although human DCs express a limited amount of other forms of CEACAM1 (Fig. 3B) , the nature of the main interaction between human DCs and WT GC remains to be determined. It may occur through the interaction of GC LOS with asialoglycoprotein receptor on DCs [49 , 50 ]. This hypothesis was supported by our preliminary data showing that the ability of a deep, rough mutant of LOS (an lgtF derivative; Fig. 1B ) [10 , 51 ] to bind DCs was reduced in comparison with WT GC (data not shown). However, this reduced interaction could be an indirect effect, as such mutations in LOS can influence several other aspects of the Neisseria-host cell interaction [51 52 53 54 ].
The focus of this manuscript is the interaction of a laboratory-adapted, rough (no capacity for O-antigen synthesis) bacterium, E. coli and lgtBGC. The environment within the human body, which these two pathogens colonize, is also fundamentally different (intestinal tract vs. genitourinary tract). We show that although there are basic biological and ecological differences between E. coli and GC, the core chain of the LPS/LOS interacts with DC-SIGN. GC LOS is capable of phase variation, whereas E. coli LPS is not. It is interesting to speculate that perhaps phase variation of the GC LOS arose to prevent interaction of GC to professional phagocytic cells. E. coli has developed an alternative strategy that achieves the same result by attaching a bulky O-polysaccharide to the LPS core.
This may be the first time that a pathogen is proposed to have evolved to avoid recognition by phagocytic receptors such as DC-SIGN. It is generally believed that ancestral bacteria possessed only LOS and that bacterial O-antigens, like adaptive immunity, were acquired as a consequence of pathogen-host coevolution. Therefore, the interaction of bacterial core LOS/LPS and the innate immune receptor, DC-SIGN, may represent a primitive interaction between microbial pathogens and the professional phagocytic host cells.
Received April 10, 2005; revised September 20, 2005; accepted October 19, 2005.
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