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The Journal of Immunology, 2007, 178, 6316-6319
Copyright © 2007 by The American Association of Immunologists, Inc.
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Characterization of the IgD Binding Site of Encapsulated Haemophilus influenzae Serotype b1

Martin Samuelsson, Teresia Hallström, Arne Forsgren and Kristian Riesbeck2

Medical Microbiology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Encapsulated Haemophilus influenzae is a causative agent of invasive disease, such as meningitis and septicemia. Several interactions exist between H. influenzae and the human host. H. influenzae has been reported to bind IgD in a nonimmune manner, but the responsible protein has not yet been identified. To define the binding site on IgD for H. influenzae, full-length IgD and four chimeric IgDs with interspersed IgG sequences and Ag specificity for dansyl chloride were expressed in stably transfected Chinese hamster ovary cells. The binding of recombinant IgD to a panel of encapsulated H. influenzae serotype b (Hib) and nontypeable strains were investigated using a whole cell ELISA and flow cytometry. IgD binding was detected in 50% of the encapsulated Hib strains examined, whereas nontypeable H. influenzae did not interact with IgD. Finally, mapping experiments using the chimeric IgD/IgG indicated that IgD CH1 aa 198–224 were involved in the interaction between IgD and H. influenzae. Thus, by using recombinant IgD and chimeras with defined Ag specificity, we have confirmed that Hib specifically binds IgD, and that this binding involves the IgD CH1 region.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Disclosures
 References
 
Strains of Haemophilus influenzae are classified as typeable encapsulated or nontypeable H. influenzae (NTHi).3 The typeable H. influenzae are further divided into six serotypes (a through f), depending on the serological specificities of the polysaccharide capsule (1). H. influenzae serotype b (Hib) is mostly associated with invasive disease in humans, causing life-threatening conditions such as bacteremia and meningitis (2). The use of vaccines against Hib has, however, greatly reduced the incidence of disease (3, 4). Because vaccine introduction is a costly proposition for many developing countries, Hib infection still poses a significant medical challenge in those areas (5). The remaining serotypes have generally been considered nonvirulent, but recent data indicate that a pathogenic role for serotypes other than b may be emerging in a Hib-vaccinated population (6, 7). In contrast to Hib, NTHi is a common cause of upper and lower respiratory tract infections such as acute otitis media and sinusitis in infants, children (8, 9), or in adults with chronic obstructive pulmonary disease. The infectious capacity of H. influenzae is augmented by predisposing conditions such as concurrent viral infection or impaired mucociliary clearance caused by underlying lung disease.

Nonimmune binding of Igs to Gram-positive bacteria is relatively common, but rare among Gram-negative bacteria. The most thoroughly characterized Ig binding proteins to date are protein A and protein G from Staphylococcus aureus and Streptococcus pyogenes (group C and group G streptococcus), respectively. Protein A has a strong affinity for IgG and binds in the elbow region between CH2 and CH3 (10). Protein A also has a weaker affinity for Abs other than IgG through interaction with the VH3 region (11). In parallel to protein A, protein G also has affinity for both Fab and Fc regions (12).

Nearly three decades ago the nonimmune binding of IgD by H. influenzae and Moraxella catarrhalis was reported (13). M. catarrhalis binds IgD via the 200-kDa outer membrane Moraxella IgD binding protein MID and the IgD binding site is located at MID962–1200 in the central part of the molecule (14, 15). Recently, we reported that the IgD binding site of MID is within the CH1 region of IgD (16). MID also functions as an adhesin, and the sequence responsible for the adhesive properties is just adjacent to the IgD binding site (17). This part of the molecule (MID764–913) has been shown to be protective in a mouse pulmonary clearance model (18).

In the present study, we characterize the binding site on IgD for H. influenzae. A series of full-length recombinant IgD and IgD/IgG chimeras with defined Ag binding specificity were expressed in Chinese hamster ovary (CHO) cells. Thereafter, a panel of Hib and NTHi were tested for IgD binding. IgD binding was found to be a property displayed by 50% of the Hib strains, whereas NTHi did not bind. By substituting defined regions of IgD with IgG, we were able to show that the IgD CH1 region aa 198–224 were required for IgD binding by Hib. Furthermore, our results indicated that the IgD CH1 aa 198–206 were particularly important for the IgD interaction to occur.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Disclosures
 References
 
Bacterial strains and culture conditions

Clinical H. influenzae isolates used in this study were from our collection (Malmö University Hospital, Malmö, Sweden). H. influenzae were grown on chocolate agar plates at 37°C in a humid atmosphere with 5% CO2.

Construction of recombinant IgD and IgD/IgG chimeras

All recombinant Igs used in this study were full-length Ig molecules and have been manufactured in our laboratory (16). The IgD H chain sequences used were derived from the vector pAZ6812, encoding human IgD H chain with murine VH containing dansyl chloride (DNS) specificity (19). The nucleotide sequences used for IgD and IgG have GenBank files (accession numbers 2168527 and 6110571, respectively). All IgD variants were expressed in the CHO Flp-In cell line (Invitrogen Life Technologies) that had been stably transfected with the linearized vector pAH3266 encoding {kappa} L chain (KLC) (20). The {kappa} L chain encoded by pAH3266 has murine VL sequence specificity for DNS. The stable pAH3266 CHO Flp-In transfectant was designated CHO-KLC, and was the recipient for all of the DNA constructs in this study. Stable transfectants expressing IgD variants were manufactured with the Flp-In technology (Invitrogen Life Technologies) and Ig secretion was verified in the supernatant of all transfectants used.

The IgD-expressing CHO cell line was made by amplification of the complete IgD sequence from pAZ6812 using the primers 5'-gagcungctagccagtgtgatggatatccaccatgtacttgggac-3' and 5'-gtcggatcctcaatagctgacttctaggctccggctggcgttgag-3' (NheI, respectively, BamHI underlined). The resulting PCR product was cloned into pcDNA5/FRT for subsequent transfection into CHO-KLC. The IgD 157–224 IgG chimera was made by splicing the IgG1 CH1 loop region into the IgD sequences. The IgG subclass 1 H chain CH1 region was amplified by PCR using the primers 5'-gccctggcatgcctggtcaaggactacttc-3' and 5'-cacaagattagatctcaactttcttgtc-3' (containing recognition sequences for SphI and BglII); cDNA from human PBL was used as a template. The IgD H chain was excised from pAZ6812 and inserted into pBluescript II KS+ (Stratagene) using the restriction enzymes NotI and EcoRI. The sequences corresponding to the IgD 157–224 were excised using SphI and BglII, and the IgG CH1 PCR product was ligated in its place. The chimeric H chain was subcloned back into pAZ6812 using NotI and EcoRI. The new chimeric H chain was amplified by PCR using the primers 5'-gagcgctagccagtgtgatggatatccaccatgtacttgggac-3' (NheI site underlined) and 5'-gtcggatccatagctgacttctaggctccggctggcgttgag-3' (BamHI site underlined), and cloned into pcDNA5/FRT. The IgD 157–197 IgG, IgD 185–224 IgG, and IgD 167–206 IgG chimeras were made using double overlap extension PCR with IgD and IgG DNA as templates. The overlap extension PCR products were ligated into pCDNA5/FRT using NheI and BamHI and transfected into CHO-KLC.

Culture conditions and preparation of recombinant IgD

The transfected cell lines were maintained in Ham’s F12 medium (Invitrogen Life Technologies) with 10% FCS (PAA Laboratories) and gentamicin (Schering-Plough). Hygromycin (Invitrogen Life Technologies) was added to 200 µg/ml for selection. Growth medium was collected after 5–7 days of culture and centrifuged to remove cells. The resulting cell-free supernatant was concentrated at 4°C using 100-kDa cutoff spin filters (Viva Science). The concentrated IgD containing supernatant was aliquoted and immediately transferred to –20°C. Normalization was conducted before the concentrated Igs were used in subsequent experiments.

DNS binding normalization ELISA

To ensure that the same amount of each Ig was added in all experiments, IgD and chimeric IgD/IgG were normalized using the binding to their Ag DNS. This was done by coating microtiter plates (C8 Starwell MAXI; Nunc) with DNS conjugated to BSA (16) and subsequent incubation at room temperature for 2 h. The plates were blocked using PBS Tween 0.05% with 1.5% OVA for 1 h. After washing, the Igs were added in serial dilutions and incubated at room temperature for 1 h. A round of washings was followed by incubation with HRP-conjugated anti-human IgD polyclonal Abs (Bethyl Laboratories) for 1 h. The plates were developed and read at 450 nm.

Bacterial whole cell ELISA

Bacteria grown on chocolate agar plates overnight were resuspended in PBS from overnight cultures to OD600 of 0.6. This suspension (100 µl) was applied to MAXISorp plates (Nunc) and incubated for 2 h at room temperature. The plates were washed twice with PBS supplemented with 0.05% Tween 20. After washing, the plates were blocked in PBS Tween 0.05% with 1.5% OVA for 30 min. A new round of washings was followed by the addition of Ig and incubation for 1 h at room temperature. The plates were washed as described before incubation with HRP-conjugated anti-human IgD polyclonal Abs (Bethyl Laboratories) for 30 min. After incubation, the plates were washed, developed and read at 450 nm.

Flow cytometry analysis

H. influenzae were grown overnight on chocolate agar plates and resuspended in PBS to an OD600 of 0.6. Resuspended bacteria (200 µl) were washed in PBS by centrifugation at 4°C. The recombinant Igs were added and the bacteria were incubated on ice. After 1 h, the bacteria were washed and FITC-conjugated anti-human IgD polyclonal Abs (DakoCytomation) were added, followed by incubation on ice for 1 h. After washing twice as above, the bacteria were resuspended in PBS for analysis on a FACSCalibur flow cytometer (BD Biosciences).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Disclosures
 References
 
Encapsulated Hib binds IgD

It has previously been reported that H. influenzae bind IgD (13, 21). In those studies IgD myeloma sera were used that consequently may recognize bacterial epitopes. To circumvent the fact that myeloma IgD specifically might be directed against bacterial outer membrane proteins, recombinant IgD was manufactured to analyze the binding of IgD by H. influenzae. When the Hib strains (n = 14) were screened, we found seven IgD binding strains (Fig. 1). Five were classified as moderate and two were classified as high IgD binders. Our panel also included a number of NTHi strains (n = 9), but none of these bound IgD.


Figure 1
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  		FIGURE 1. Hib binds IgD, unlike nontypeable H. influenzae. A whole cell ELISA was used for the determination of IgD binding. Bacteria shown were coated to microtiter plates followed by addition of recombinant IgD. After several washings, IgD binding was detected using an HRP-conjugated anti-IgD polyclonal Ab. Mean values from triplicate readings at OD450 are shown.

 
Hib binds IgD through an interaction with the IgD CH1 region

To identify the region of IgD that is bound by Hib, four IgD/IgG chimeras (Fig. 2) were tested for interaction with two IgD binding Hib strains that were identified in the initial screening. One high IgD binding strain (Hib 570) and one moderate IgD binding strain (Hib B4-23) were chosen. Data obtained from these experiments showed that replacement of IgD CH1 aa 157–224 with IgG rendered bacteria unable to bind IgD (Fig. 3). To narrow down the binding region, the overlapping chimeric IgD/IgG variants (Fig. 2) were used in our analysis. Replacement of IgD aa 157–197 with IgG did not disrupt the interaction between Hib and IgD. However, when IgD aa 167–206 or IgD aa 185–224 sequences were replaced by corresponding IgG sequences, the binding by Hib was abolished. No difference was found between the Hib strains, i.e., although a low IgD binding capacity by Hib B4-23 was observed (Fig. 3B), this strain bound to the same apparent site on the IgD CH1 region as compared with the high IgD binding strain Hib 570 (Fig. 3A).


Figure 2
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  		FIGURE 2. Schematic outline of the IgD/IgG CH1 chimeric recombinant proteins. The IgD/IgG chimera contains parts of CH1 replaced by IgG sequences located at IgD CH1 aa IgD 157–224 IgG, IgD 157–197 IgG, IgD 185–224 IgG, and IgD 167–206 IgG are shown.

 

Figure 3
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  		FIGURE 3. Hib binds IgD in the CH1 region within IgD aa 198–224. A, The high IgD binding Hib 570. B, The moderate IgD binding Hib B4-23. Binding of IgD, IgD 157–224 IgG, IgD 157–197 IgG, IgD 185–224 IgG, and IgD 167–206 IgG to the two different Hib strains was analyzed using a whole cell ELISA. An HRP-conjugated anti-IgD polyclonal Ab was used as a detection system. Data are mean values of triplicate determinations and are representative of three experiments performed. Error bars denote SD.

 
When IgD aa 157–197 were replaced with corresponding IgG sequences, no effect was seen on the IgD binding (Fig. 3); hence these amino acids were not involved in the interaction between IgD and Hib. This observation indicated that the Hib protein responsible for the interaction bound IgD in the regions altered in chimeric IgD 167–206 IgG and chimeric IgD 185–224 IgG. Furthermore, because Hib bound IgD 157–197 IgG, this sequence could be excluded and the binding region narrowed down to IgD CH1 aa 198–224. The overlap between chimeras IgD 157–197 IgG and IgD 167–206 IgG indicated that IgD aa 198–206 likely played a critical role.

We also wanted to confirm the results obtained by the whole cell ELISA and therefore established a flow cytometry assay. Bacteria in solution were incubated with the IgD variants, and binding was monitored using FITC-conjugated anti-human IgD polyclonal Abs. When the IgD binding Hib strains were investigated using flow cytometry, the binding patterns observed in the whole cell ELISA were confirmed (Fig. 4). The two selected Hib strains bound both IgD and the IgD 157–197 IgG chimera, but not the IgD 185–224 IgG and IgD 167–206 IgG chimeras. Thus, based upon these experiments we have shown that the IgD binding site for Hib involves IgD CH1 aa 198–224, and furthermore we suggest that aa 198–206 are crucial for the interaction.


Figure 4
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  		FIGURE 4. Flow cytometry analyses of IgD binding Hib prove that Hib binds IgD in the CH1 aa 198–224 region. Hib 570 (A) and Hib B4-23 (B) were incubated with IgD and the chimeric proteins IgD 157–197 IgG, IgD 185–224 IgG, and IgD 167–206 IgG. After washing, bound Ig was detected using a FITC-conjugated anti-IgD polyclonal Ab.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Disclosures
 References
 
In the present study we show that IgD CH1 aa 198–224 are involved in the interaction between IgD and Hib. Interestingly, the identified binding region of Hib to IgD bears remarkable similarity to the binding site of M. catarrhalis protein MID (16). It could therefore be possible that the presently unknown Hib IgD binding protein could be similar in structure to MID. In 1991, it was reported that H. influenzae protein D was responsible for the IgD binding (22). In that study, the authors used a myeloma IgD to search for the IgD binding protein. However, protein D was later shown to be recognized by the IgD myeloma serum, and thus was not a universal IgD binding protein (21). Moreover, Sasaki and Munson (21) showed that Hib strains but not nontypeable H. influenzae bind IgD, a finding that is supported by our results (Fig. 1).

The Ig-fold is a conserved structure despite considerable sequence variation between the different Ig classes. The Ig-fold of the CH1 region of IgD and IgG is composed of seven antiparallel beta sheets, interconnected by flexible loops. The loops are solvent exposed, and are thus available for potential interactions. An alignment between IgD and IgG aa 196 through 224 of the CH1 regions is shown in Fig. 5. Loop 5 of the CH1 region spans aa 202 through 210 (23). Interestingly, loop 5 is partially covered by the proposed crucial Hib binding sequence, namely aa 198–206, which were altered in the nonbinding chimeras. It is therefore tempting to speculate that all or part of this solvent-exposed loop may be the target for the IgD binding protein of Hib.


Figure 5
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  		FIGURE 5. Comparative alignment of the IgD and IgG aa 196 through 224 CH1 region. Identities (•) and the sequence corresponding to Ig loop 5 (aa 202 through 210) (brace) are indicated.

 
The role of IgD binding in regards to the virulence of respiratory pathogens is poorly understood, but IgD binding is likely beneficial for the bacteria. Soluble IgD is present at very low concentrations in normal human sera, but a significant local production can be found in the middle ear (24). In fact, this has been proposed as a possible link between the IgD-binding phenotype of M. catarrhalis and its prominent role in acute otitis media (14). This explanation presents, however, an interesting paradox in the case of H. influenzae. The IgD binding Hib strains are not typically associated with otitis media but rather with invasive disease. This is in contrast to the non-IgD binding NTHi strains, which are commonly associated with otitis media but do not bind IgD. Hib-dependent IgD binding may, however, be important in the initial colonization of the host. In addition, H. influenzae has the capacity to reside in tonsils (25), where the IgD binding phenotype could allow for interaction with the human BCR. In fact, a mitogenic effect of Hib on human B cells has been reported (26). This effect might parallel the one M. catarrhalis has on human PBLs (27, 28) and possibly serve to increase the virulence of Hib. It is nonetheless intriguing to note that H. influenzae and M. catarrhalis are the only two bacterial species presently known to bind IgD. This observation likely points to a multifaceted role for the bacterial IgD binding.

Taken together, our findings show that the IgD CH1 region is involved in the interaction with Hib and that aa 198–206 of IgD CH1 likely play a key role in this interaction. Because bacteria have a profound capacity to rapidly dispose of gene sequences not required for their survival in a particular environment, the IgD binding phenotypes displayed by Hib and M. catarrhalis most likely play a part in the pathogenicity of these two respiratory pathogens. Further studies are, however, required to define the exact role of these interactions. A deeper understanding of bacterial outer membrane proteins with the capacity to interact with our immune system may also lead to future treatment options or novel biomedical applications.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by grants from the Alfred Österlund, the Anna and Edwin Berger, the Crawfoord, and the Greta and Johan Kock foundations, the Swedish Medical Research Council, the Swedish Society of Medicine, and the Cancer Foundation at the University Hospital in Malmö. Back

2 Address correspondence and reprint requests to Dr. Kristian Riesbeck, Medical Microbiology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden. E-mail address: kristian.riesbeck{at}med.lu.se Back

3 Abbreviations used in this paper: NTHi, nontypeable Haemophilus influenzae; Hib, Haemophilus influenzae serotype b; CHO, Chinese hamster ovary; DNS, dansyl chloride. Back

Received for publication September 29, 2006. Accepted for publication March 7, 2007.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Disclosures
 References
 

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