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PubMed2006

Complex role of hemoglobin and hemoglobin-haptoglobin binding proteins in Haemophilus influenzae virulence in the infant rat model of invasive infection.

Haemophilus influenzae requires an exogenous heme source for aerobic growth in vitro. Hemoglobin or hemoglobin-haptoglobin satisfies this requirement. Heme acquisition from hemoglobin-haptoglobin is mediated by proteins encoded by hgp genes. Both Hgps and additional proteins, including those encoded by the hxu operon, provide independent pathways for hemoglobin utilization. Recently we showed that deletion of the set of three hgp genes from a nontypeable strain (86-028NP) of H. influenzae attenuated virulence in the chinchilla otitis media model of noninvasive disease. The present study was undertaken to investigate the role of the hgp genes in virulence of the wild-type serotype b clinical isolate HI689 in the infant rat model of hematogenous meningitis, an established model of invasive disease requiring aerobic growth. Bacteremia of high titer and long duration (>14 days) and histopathologically confirmed meningitis occurred in >95% of infant rats challenged at 5 days of age with strain HI689. While mutations disrupting either the Hgp- or Hxu-mediated pathway of heme acquisition had no effect on virulence in infant rats, an isogenic mutant deficient for both pathways was unable to sustain bacteremia or produce meningitis. In contrast, mutations disrupting either pathway decreased the limited ability of H. influenzae to initiate and sustain bacteremia in weanling rats. Biochemical and growth studies also indicated that infant rat plasma contains multiple heme sources that change with age. Taken together, these data indicate that both the hgp genes and the hxuC gene are virulence determinants in the rat model of human invasive disease.

Animals↗
PubMed2000

Detection of phase variation in expression of proteins involved in hemoglobin and hemoglobin-haptoglobin binding by nontypeable Haemophilus influenzae.

Haemophilus influenzae can utilize different protein-bound forms of heme for growth in vitro. A previous study (I. Maciver, J. L. Latimer, H. H. Liem, U. Muller-Eberhard, Z. Hrkal, and E. J. Hansen. Infect. Immun. 64:3703-3712, 1996) indicated that nontypeable H. influenzae (NTHI) strain TN106 expressed a protein that bound hemoglobin-haptoglobin and was encoded by an open reading frame (ORF) that contained a CCAA nucleotide repeat. Southern blot analysis revealed that several NTHI strains contained between three and five chromosomal DNA fragments that bound an oligonucleotide probe for CCAA repeats. Three ORFs containing CCAA repeats were identified in NTHI strain N182; two of these ORFs were arranged in tandem. The use of translational fusions involving these three ORFs and the beta-lactamase gene from pBR322 revealed that these three ORFs, designated hgbA, hgbB, and hgbC, encoded proteins that could bind hemoglobin, hemoglobin-haptoglobin, or both compounds. Monoclonal antibodies (MAbs) specific for the HgbA, HgbB, and HgbC proteins were produced by immunizing mice with synthetic peptides unique to each protein. Both HgbA and HgbB were readily detected by Western blot analysis in N182 cells grown in the presence of hemoglobin as the sole source of heme, whereas expression of HgbC was found to be much less abundant than that of HgbA and HgbB. The use of these MAbs in a colony blot radioimmunoassay analysis revealed that expression of both HgbA and HgbB was subject to phase variation. PCR and nucleotide sequence analysis were used in conjunction with Western blot analyses to demonstrate that this phase variation involved the CCAA repeats in the hgbA and hgbB ORFs.

Amino Acid Sequence↗
PubMed2006

High-affinity binding of the staphylococcal HarA protein to haptoglobin and hemoglobin involves a domain with an antiparallel eight-stranded beta-barrel fold.

Iron scavenging from the host is essential for the growth of pathogenic bacteria. In this study, we further characterized two staphylococcal cell wall proteins previously shown to bind hemoproteins. HarA and IsdB harbor homologous ligand binding domains, the so called NEAT domain (for "near transporter") present in several surface proteins of gram-positive pathogens. Surface plasmon resonance measurements using glutathione S-transferase (GST)-tagged HarAD1, one of the ligand binding domains of HarA, and GST-tagged full-length IsdB proteins confirmed high-affinity binding to hemoglobin and haptoglobin-hemoglobin complexes with equilibrium dissociation constants (K(D)) of 5 to 50 nM. Haptoglobin binding could be detected only with HarA and was in the low micromolar range. In order to determine the fold of this evolutionarily conserved ligand binding domain, the untagged HarAD1 protein was subjected to nuclear magnetic resonance spectroscopy, which revealed an eight-stranded, purely antiparallel beta-barrel with the strand order (-beta1 -beta2 -beta3 -beta6 -beta5 -beta4 -beta7 -beta8), forming two Greek key motifs. Based on structural-homology searches, the topology of the HarAD1 domain resembles that of the immunoglobulin (Ig) fold family, whose members are involved in protein-protein interactions, but with distinct structural features. Therefore, we consider that the HarAD1/NEAT domain fold is a novel variant of the Ig fold that has not yet been observed in other proteins.

Amino Acid Sequence↗
PubMed1999

Role of CCAA nucleotide repeats in regulation of hemoglobin and hemoglobin-haptoglobin binding protein genes of Haemophilus influenzae.

Haemophilus influenzae utilizes hemoglobin and hemoglobin-haptoglobin as heme sources. The H. influenzae hemoglobin- and hemoglobin-haptoglobin binding protein genes, hgpA, hgpB, and hgpC, contain lengths of tetrameric CCAA repeats. Using an hgpA-lacZ translational gene fusion, we demonstrate phase-variable expression of lacZ associated with alteration in the length of the CCAA repeat region.

Bacterial Outer Membrane Proteins↗
PubMed1988

Binding of haptoglobin, inter-alpha-trypsin inhibitor, and alpha 1 proteinase inhibitor to synovial fluid hyaluronate and the influence of these proteins on its degradation by oxygen derived free radicals.

Synovial fluid from 201 normal and pathological knee joints was subjected to gel filtration by Sepharose CL-2B chromatography to separate hyaluronic acid (HA) from unbound proteins, which were retarded on this column. HA from all normal fluids was excluded from the gel and contained 1% or less bound protein. Synovial fluids taken from joints of patients with rheumatoid arthritis (RA) contained considerably more protein bound to HA. In 46% of RA samples the level of protein was greater than 4%, whereas only one fluid examined from osteoarthritic joints contained this amount. The proteins bound to HA from RA joints were identified by sodium dodecyl sulphate/polyacrylamide gel electrophoresis (SDS-PAGE) and immunodiffusion techniques as the acute phase proteins alpha 1 proteinase inhibitor, inter-alpha-trypsin inhibitor, and haptoglobin. The average relative percentages of these proteins bound to HA were 17.6%, 32.6%, and 29.2% respectively. These HA-protein complexes could be generated in vitro by mixing normal (low protein) HA with any one of the three acute phase proteins. The HA-protein complexes formed in vitro with inter-alpha-trypsin inhibitor or haptoglobin, and those isolated from RA synovial fluids, were more resistant to degradation by oxygen derived free radicals (ODFR) than HA from normal fluids. From these findings we conclude that certain acute phase proteins diffusing into synovial fluid during inflammatory episodes may play an important part in protecting HA from depolymerisation by activated phagocytes.

Alpha-Globulins↗
PubMed1991

Differences in HLA-B27 positive and negative patients with ankylosing spondylitis: study of clinical disease activity and concentrations of serum IgA, C reactive protein, and haptoglobin.

To find out whether disease activity and B27 status were associated with serum concentrations of IgA, C reactive protein (CRP), and haptoglobin in ankylosing spondylitis (AS) multivariate analysis of variance was used to study 101 patients with AS whose disease was clinically classified as active or inactive, and who were HLA-B27 typed. It was found that B27 and disease activity do interact significantly to affect the serum concentrations of IgA, CRP, and haptoglobin. When the 77 B27+ patients were examined, however, it was found that disease activity was significantly associated with serum concentrations IgA. In contrast, in the 24 B27- patients concentrations of serum IgA were significantly associated with disease activity, but not. These results emphasise the known difference between B27+ and B27- AS and suggest different pathogenic mechanisms in the two forms of AS.

C-Reactive Protein↗
PubMed1989

Distribution of haptoglobin phenotypes in oesophageal and gastric cancer.

Haptoglobin (Hp) phenotypes were studied in 72 oesophageal and 104 gastric cancer patients and compared with 100 healthy controls to see if there is any association between oesophageal and gastric cancer and haptoglobin type. There was a significantly increased frequency of Hp 2-1 (59.7%) and Hp 2-2 (91.3%) in oesophageal and gastric cancer patients. Our results suggest that genetic factors play a role in the aetiology and pathogenesis of gastrointestinal tract malignancy.

Esophageal Neoplasms↗
PubMed1976

The purification of porcine haptoglobin by affinity chromatography with concanavalin A-Sepharose.

Methods designed for the isolation of human haptoglobin (Hp) were found insufficient when applied to pig plasma due to the formation of a material tentatively identified as albumin dimer. Small scale separation is possible by preparative polyacrylamide gel electrophoresis. Larger scale purification from nonglycoprotein contaminants such as albumin dimer is achieved by affinity chromatography using immobilized concanavalin A. Porcine haptoglobin is microheterogeneous. More than 14 components, partially resolveable by gel filtration, were detected.

Animals↗
PubMed1976

The reaction between hemoglobin alpha-subunit and haptoglobin.

The interaction between human hemoglobin alpha-subunit and porcine haptoglobin was investigated by polyacrylamide gel electrophoresis, gel filtration chromatography, sedimentation through excess alpha-subunit and gel filtration in an alpha-subunit-containing medium. No interaction was detected by the first two methods indicating dissociation of the complex during the application of these separation techniques. The latter two methods, in which the complex is studied in a medium of excess subunits, showed that haptoglobin became saturated with the binding of two alpha-subunits.

Animals↗
PubMed1980

Modification of hemoglobin upon covalent coupling to dextran: enhanced stability against acid denaturation and reduced affinity for haptoglobin.

Alkylation of human hemoglobin by bromoacetylaminoethylamino-substituted dextran gave rise to a covalent dextran-hemoglobin complex with enhanced stability against acid denaturation, and reduced affinity for binding to haptoglobin, compared with free hemoglobin. These effects increased with increasing size of the dextran moiety and were not elicited by either free dextran or alkylation of hemoglobin by iodoacetamide. These observations are consistent with an inhibition by covalently attached dextran of the binding of beta-subunit of hemoglobin to haptoglobin.

Alkylation↗
PubMed1986

Localization of the human haptoglobin genes distal to the fragile site at 16q22 using in situ hybridization.

The distamycin A-sensitive fragile site fra(16)(q22) is a precisely localized chromosomal marker. When expressed at metaphase, it visibly separates the chromosome material on either side of the fragile site. Using a cDNA probe encoding both the alpha and beta haptoglobin chains, the haptoglobin loci were found by in situ hybridization to be distal to fra(16)(q22).

Chromosome Fragile Sites↗
PubMed1980

Survey on haemoglobin variants, beta-thalassaemia, glucose-6-phosphate dehydrogenase deficiency and haptoglobin types in Turkish people living in Manavgat, Serik and Boztepe (Antalya).

135 Turks living in the vicinity of Antalya, a Turkish city on the Mediterranean coast, were studied for haemoglobin variants, beta-thalassaemia G-6-PD deficiency and haptoglobin types. The incidence of Hb-S was 2.3%. 8 beta-thalassaemic individuals with increased Hb-A2 and patient with 1 sickle cell-beta2-thalassaemia disease were found. The incidence of beta-thalassaemia with increased Hb-A2 was 6.7% and that of G-6-PD deficiency was 5.4%. The distribution of haptoglobin types in these people was very similar to that found in Turkish people in general; the only exception was the presence of Hp O in 2 individuals without haemolytic disorder. Gene frequencies of Hp1 and Hp2 were 0.26 and 0.7p4, respectively.

Adult↗
PubMed1987

Haptoglobin groups and serum cholesterol levels.

The serum levels of cholesterol and cholesterol esters were studied in relation to haptoglobin groups in a series of 277 healthy blood donors from northern Sweden. Previous reports of associations between Hp 2-2 and high serum cholesterol levels were not confirmed, though a nonsignificant deviation in the same direction was observed. Possible mechanisms behind an association between haptoglobin groups and serum cholesterol were discussed.

Cholesterol↗
PubMed1987

Haptoglobin patterns in essential hypertension and associated conditions--increased risk for Hp 2-2.

Blood samples from 257 hypertensive patients and 180 normotensive controls were analysed for their association with haptoglobin levels and phenotypes. Compared to controls, patients with Hp 2-2 phenotype showed a significantly increased risk for essential hypertension (p less than 0.001) and hypertension associated with ischaemic heart disease (p less than 0.05). There was a significant decrease in the mean levels of serum haptoglobins in hypertension as compared to controls, suggesting the possibility for intravascular haemolysis due to vascular damage leading to further complications.

Diabetes Complications↗
PubMed1988

Haptoglobin groups and transferrin subtypes in multiple myeloma.

Haptoglobin and transferrin types were determined for 27 multiple myeloma patients and a series of case controls. No association was found between haptoglobin and the disease, which confirms the findings of an earlier investigation. However, we found a significantly increased relative risk of 2.6 for TFC1C1 individuals. It is suggested that the role of transferrin in erythropoiesis and cell proliferation of both malignant and normal cells, may, at least in part, explain the association. Of additional relevance may be the suggestion that TFC1C1 individuals have higher blood iron levels than other subtypes.

Adult↗
PubMed1980

Haemolytic uraemic syndrome and accumulation of haemoglobin-haptoglobin complexes in plasma in serum sickness caused by penicillin drugs.

2 patients treated with penicillin and ampicillin, respectively, suffered from haemorrhagic diathesis, haemolysis, cerebral symptoms and renal insufficiency, resembling a haemolytic-uraemic syndrome. Their plasma was red due to the presence during several days of haemoglobin-haptoglobin complexes, the P-haemoglobin being 2.8 and 1.6 g/l, respectively. Coagulation tests showed an unusual pattern with prolonged activated partial thromboplastin times, an extremely long thrombin time and very high levels of fibrinogen degradation products. Repeated transfusion had no effect. The patients were considered to have developed a drug-induced serum sickness associated with insufficient function of the reticuloendothelial system, and secondary to this an accumulation of haemoglobin-haptoglobin complexes in plasma. When the penicillin drugs were discontinued, all measured variables rapidly normalised and the patients recovered completely. Thus, the haemolyticuraemic syndrome seemed to be caused by the serum sickness, possibly via circulating or cell-associated immune complexes. The possibility of a type III allergic reaction should be considered in patients with haemolytic-uraemic-like syndromes.

Adult↗
PubMedDate not supplied

Abdominal aortic aneurysm: association between haptoglobin phenotypes, elastase activity, and neutrophil count in the peripheral blood.

To investigate the role of genetic factors on susceptibility to atherosclerotic arterial disease, the influence of haptoglobin phenotypes (Hp) on serum elastase activity, neutrophil count, and elastin concentration in the aorta was measured in patients with abdominal aortic aneurysm (AAA; n=52) and aortoiliac atherosclerotic occlusive disease (AOD; n=37). Findings (serum elastase activity, peripheral blood neutrophil count) were compared to a control group (CG) of 37 subjects without atherosclerosis. Hp phenotyping performed by starch-gel electrophoresis produced a haptoglobin-hemoglobin complex of three phenotypes: Hp1-1, Hp2-2, and Hp2-1. Distribution of Hp phenotypes was similar in the three study groups (AAA, AOD, CG). Significant increases in serum elastase activity and neutrophil count was measured in Hp2-1 phenotype of AAA patients. Although the aorta wall of aneurysm patients contained less (p<0.001) elastin than that of AOD patients, no significant difference of aorta elastin concentration between the three Hp phenotypes, including Hp2-1, was measured. The postulated association of AAA susceptibility with Hp2-1 phenotype was supported by the study data that demonstrated an increase in serum elastase activity in patients undergoing AAA repair.

Aged↗
PubMed2001

Development of a fecal occult blood test using a monoclonal antibody to haptoglobin.

Monoclonal antibodies (mAbs) were produced to human haptoglobin by immunising with fecal extracts from patients with colon cancer. An enzyme-linked immunosorbent assay was developed with one of the mAbs (FE14.1), and its ability to diagnose colorectal carcinoma evaluated. Patients with colorectal cancer were positive (43/46 = 93.5%) compared to normal individuals (4/211 = 1.9%). The assay has a specificity 93.5% and sensitivity 98.1% and has several advantages over current fecal occult blood tests. The test is potentially useful for bowel cancer diagnosis and to quantitate the level of haptoglobin in other body fluids such as urine and in effusions.

Adult↗