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Chapter 18 : Haemophilus

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Haemophilus, Page 1 of 2

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Abstract:

The genus consists of several species of small pleomorphic gram-negative organisms, isolated as pathogens or commensals of a single host species. Studies of iron acquisition in the haemophili have been performed primarily with ; therefore, this chapter focuses on , with reference to other species as appropriate. The majority of studies regarding the heme dependence of under anaerobic growth conditions have been performed with complex media, raising the possibility that residual heme is sufficient to support growth. Lipoprotein (P4) was identified as complementing the mutant for growth on heme. (P4) was later shown to be required for the utilization of NAD and NADP, and the growth deficiencies of mutants were attributed to failure to utilize NAD rather than failure to use heme. The protein is antigenically conserved among heme-dependent species (excluding ) but not heme-independent species. HxuC is essential for utilization of hemoglobin by in a background where the entire complement of a strain is mutated. The authors recently confirmed this observation by using complete deletion backgrounds in three additional strains (HI689, E1a, and HI1388). The availability of the genomic sequences and the consequent ability to identify specific genes of interest potentially allows a systematic investigation of the relevant phenotypes.

Citation: Morton D, Stull T. 2004. Haemophilus, p 273-292. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch18

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Outer Membrane Proteins
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Figures

Image of FIGURE 1
FIGURE 1

Alignment of the hemoglobin/hemoglobin-haptoglobin binding proteins (Hgp) of . (A) Similarity plot derived from a comparison of all available full-length Hgp sequences. Sequences used were from strains Rd KW20 (HgpB, HgpC, HgpE, and HgpD), HI689 (HgpA, HgpB, and HgpC), N182 (HgpA, HgpB, and HgpC), Ela (HgpB), and TN106 (HgpA) (see the Table 1 footnotes for appropriate GenBank accession numbers). The similarity plot was generated using the sequence alignment application, AlignX, of the Vector NTI suite v.7 (Informax, Bethesda, Md). (B) Alignment of the region directly downstream of the QPTN amino acid repeats encoded by the CCAA nucleotide repeats (approximately amino acids 100 to 400) for all available sequences. In addition to the complete Hgp sequences, partial Hgp sequences were available from the following strains: HI3224A, one unspecified Hgp and HgpC (http://www.micro-gen.ouhsc.edu); HI1388, one unspecified Hgp, HgpB, and HgpC; and 86–028NP, HgpC (http://www.microbial-pathogenesis.org). The similarity plot was generated using the sequence alignment application, AlignX, of the Vector NTI suite v.7.

Citation: Morton D, Stull T. 2004. Haemophilus, p 273-292. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch18
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Image of FIGURE 2
FIGURE 2

Nucleotide sequence of the portion of the gene from type b strain E1a encoding the N-terminal region of the protein. The nucleotide sequence as shown contains 15 CCAA repeats; one CCAA repeat has been added to the sequence as it was originally cloned to bring the gene into frame. The translation shown in frame 1 continues to produce a full-length protein of ∼113 kDa. The introduction of stop codons following the removal of one or two CCAA repeats is shown. The underlined CCAA repeats are those that have been removed.

Citation: Morton D, Stull T. 2004. Haemophilus, p 273-292. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch18
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Image of FIGURE 3
FIGURE 3

Schematic of proposed pathways for the acquisition of heme from the heme-albumin complex (A) and the acquisition of free heme (B) by . Heme derived from hemoglobin or heme-containing enzymes is bound by albumin at two binding domains (in this schematic, a single heme molecule is shown bound to albumin). In the acquisition of heme from heme-albumin (pathway A), the heme-albumin complex is bound by a proposed heme-albumin binding outer membrane protein (Apb). Abp is proposed to interact with HxuC in the TonB-dependent transport of heme across the outer membrane to the periplasmic transport system. Free heme is bound by either HxuC or TdhA, which are responsible for the TonB-dependent transport of heme across the outer membrane (pathway B). HxuC and TdhA may act independently or together. HxuC is essential for the acquisition of low levels of heme in vitro. The role of TdhA is proposed based on homology, but no heme-related phenotype has been demonstrated in a TdhA-lacking mutant. Internalization of heme involves a putative periplasmic system. In this model, heme binds to a pleriplasmic binding protein (possibly HbpA) that interacts with a permease to transport heme into the cytoplasm through a process requiring an ATPase. OM, outer membrane; PS, periplasmic space; IM, inner membrane; C, cytoplasm.

Citation: Morton D, Stull T. 2004. Haemophilus, p 273-292. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch18
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Image of FIGURE 5
FIGURE 5

Schematic of proposed pathways for the acquisition of heme from hemoglobin (Hb) and the hemoglobin-haptoglobin complex (Hb-Hp) by . In pathway A, hemoglobin released by the lysis of red blood cells (RBC) is bound by the serum protein haptoglobin (Hp) in a 1:1 molar ratio. In localized areas of RBC lysis, sufficient hemoglobin may be present to saturate available haptoglobin; under such circumstances, uncomplexed hemoglobin may represent a significant heme source. The hemoglobin-haptoglobin complex is bound by one of the hemoglobin-haptoglobin-binding proteins (Hgp), this is followed by the TonB-dependent transport of heme across the outer membrane to the periplasmic transport system. In pathway B, hemoglobin may be bound by one of the Hgp proteins or Hup followed by the TonB-dependent transport of heme across the outer membrane to the periplasmic transport system. Since a mutant strain lacking expression of its Hgp proteins and Hup retains the ability to utilize hemoglobin, additional pathways for utilization of heme from hemoglobin exist. Internalization of heme involves a putative periplasmic system. In this model, heme binds to a pleriplasmic binding protein (possibly HbpA) that interacts with a permease to transport heme into the cytoplasm through a process requiring an ATPase. OM, outer membrane; PS, periplasmic space; IM, inner membrane; C, cytoplasm.

Citation: Morton D, Stull T. 2004. Haemophilus, p 273-292. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch18
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Image of FIGURE 4
FIGURE 4

Schematic of proposed pathways for the acquisition of heme from the heme-hemopexin (Heme-Hx) complex by . Heme derived from hemoglobin or heme-containing enzymes is complexed by hemopexin (Hx) in a 1:1 molar ratio. The heme-hemopexin complex-binding protein, HxuA, is secreted from the bacterial cell by using the secretor protein, HxuB. Two alternative pathways of heme-hemopexin binding to the bacterial outer membrane are shown. In the first pathway (pathway A), secreted HxuA binds to the heme-hemopexin complex and the resulting HxuA-heme-hemopexin complex binds to an outer membrane binding protein. This model proposes the existence of an outer membrane HxuA binding protein (Hxp) interacting with HxuC to deliver heme to the periplasmic transport system in a TonB-dependent manner. Alternatively, HxuC may provide both HxuA binding and heme transport functions. In the second pathway (pathway B), the heme-hemopexin complex binds to membrane-anchored HxuA; this is followed by TonB-dependent delivery of heme to the periplasmic transport system through HxuC. Internalization of heme involves a putative periplasmic system. In this model, heme binds to a pleriplasmic binding protein (possibly HbpA) that interacts with a permease to transport heme into the cytoplasm through a process requiring an ATPase. OM, outer membrane; PS, periplasmic space; IM, inner membrane; C, cytoplasm.

Citation: Morton D, Stull T. 2004. Haemophilus, p 273-292. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch18
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References

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1. Al-Tawfiq, J. A.,, K. R. Fortney,, B. P. Katz,, A. F. Hood,, C. Elkins,, and S. M. Spinola. 2000. An isogenic hemoglobin receptor-deficient mutant of Haemophilus ducreyi is attenuated in the human model of experimental infection. J. Infect. Dis. 181: 10491054.
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12. Kirby, S. D.,, S. D. Gray-Owen,, and A. B. Schryvers. 1997. Characterization of a ferric-binding protein mutant in Haemophilus influenzae. Mol. Microbiol 25:979987.
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15. Morton, D. J.,, P. W. Whitby,, H. Jin,, Z. Ren,, and T. L. Stull. 1999. Effect of multiple mutations in the hemoglobin- and hemoglobin-haptoglobin-binding proteins, HgpA, HgpB, and HgpC of Haemophilus influenzae type b. Infect. Immun. 67: 27292739.
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Tables

Generic image for table
TABLE 1

Heme and iron acquisition related proteins of

Citation: Morton D, Stull T. 2004. Haemophilus, p 273-292. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch18
Generic image for table
TABLE 2

Roles of heme and iron acquisition proteins in vivo

Citation: Morton D, Stull T. 2004. Haemophilus, p 273-292. In Crosa J, Mey A, Payne S, Iron Transport in Bacteria. ASM Press, Washington, DC. doi: 10.1128/9781555816544.ch18

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