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PubMed1995

Adhesion of nontypeable Haemophilus influenzae from blood and sputum to human tracheobronchial mucins and lactoferrin.

Nontypeable Haemophilus influenzae strains are the most common pathogens encountered in patients with chronic bronchitis. These organisms chronically colonize the airways of patients and occasionally cause bacteremia. Nontypeable H. influenzae strains have been demonstrated microscopically to bind to mucus, but quantitative studies of adhesion have not been published to date. We have therefore developed a reproducible microtiter plate assay to study mucin binding and have examined the adhesion of sputum and blood strains of nontypeable H. influenzae. The assay is similar to that described for Pseudomonas aeruginosa (S. Vishwanath and R. Ramphal, Infect. Immun. 45:197-202, 1984), but notably 2% Tween 20 is used to desorb bacteria from the wells to quantitate bacterial binding. Using a standard strain, we have established that 1 h of incubation is optimum with an inoculum of < or = 5 x 10(8) CFU/ml. The standard strain binds to bronchitic and cystic fibrosis mucins equally well but binds less to bronchiectasis mucins. It does not bind to bovine serum albumin or fetuin. We have also examined the levels of adhesion of freshly isolated sputum and bacteremia strains and find very significant differences in adhesion. Blood strains bound six to seven times less than sputum strains ([13.8 +/- 7] x 10(2) per well versus [102 +/- 43] x 10(2); P < 0.001). Studies with adhesion to lactoferrin, another glycosylated protein, revealed variable binding of respiratory strains but marked binding of blood strains compared with mucin. An isogenic pair of respiratory and blood isolates was examined by electron microscopy but did not show surface differences. We speculate that bacteremic strains studied may have masked, lost, or downregulated adhesin production to allow them to escape from mucins or upregulated adhesins for lactoferrin to invade the bloodstream.

Bacterial Adhesion↗
PubMed1998

Structure-function relationship of antibacterial synthetic peptides homologous to a helical surface region on human lactoferrin against Escherichia coli serotype O111.

Lactoferricin includes an 11-amino-acid amphipathic alpha-helical region which is exhibited on the outer surface of the amino-terminal lobe of lactoferrin. Synthetic peptides homologous to this region exhibited potent antibacterial activity against a selected range of both gram-negative and gram-positive bacteria. An analog synthesized with methionine substituted for proline at position 26, which is predicted to disrupt the helical region, abolished antibacterial activity against Escherichia coli and considerably reduced antibacterial activity against Staphylococcus aureus and an Acinetobacter strain. The mode of action of human lactoferrin peptide (HLP) 2 against E. coli serotype O111 (NCTC 8007) was established by using flow cytometry, surface plasmon resonance, and transmission electron microscopy. Flow cytometry was used to monitor membrane potential, membrane integrity, and metabolic processes by using the fluorescent probes bis-1,3-(dibutylbarbituric acid)-trimethine oxonol, propidium iodide, and carbonyl cyanide m-chlorophenylhydrazone, respectively. HLP 2 was found to act at the cell membrane, causing complete loss of membrane potential after 10 min and of membrane integrity within 30 min, with irreversible damage to the cell as shown by rapid loss of viability. The number of particles, measured by light scatter on the flow cytometer, dropped significantly, showing that bacterial lysis resulted. The peptide was shown to bind to E. coli O111 lipopolysaccharide by using surface plasmon resonance. Transmission electron microscopy revealed bacterial distortion, with the outer membrane becoming detached from the inner cytoplasmic membrane. We conclude that HLP 2 causes membrane disruption of the outer membrane, resulting in lysis, and that structural considerations are important for antibacterial activity.

Amino Acid Sequence↗
PubMed1999

Neutralization of endotoxin in vitro and in vivo by a human lactoferrin-derived peptide.

Endotoxin (lipopolysaccharide [LPS]) is the major pathogenic factor of gram-negative septic shock, and endotoxin-induced death is associated with the host overproduction of tumor necrosis factor alpha (TNF-alpha). In the search for new antiendotoxin molecules, we studied the endotoxin-neutralizing capacity of a human lactoferrin-derived 33-mer synthetic peptide (GRRRRSVQWCAVSQPEATKCFQWQRNMRKVRGP; designated LF-33) representing the minimal sequence for lactoferrin binding to glycosaminoglycans. LF-33 inhibited the coagulation of the Limulus amebocyte lysate and the secretion of TNF-alpha by RAW 264.7 cells induced by lipid A and four different endotoxins with a potency comparable to that of polymyxin B. The first six residues at the N terminus of LF-33 were critical for its antiendotoxin activity. The endotoxin-neutralizing capacity of LF-33 and polymyxin B was attenuated by human serum. Coinjection of Escherichia coli LPS (125 ng) with LF-33 (2.5 microg) dramatically reduced the lethality of LPS in the galactosamine-sensitized mouse model. Significant protection of the mice against the lethal LPS challenge was also observed when LF-33 (100 microg) was given intravenously after intraperitoneal injection of LPS. Protection was correlated with a reduction in TNF-alpha levels in the mouse serum. These results demonstrate the endotoxin-neutralizing capability of LF-33 in vitro and in vivo and its potential use for the treatment of endotoxin-induced septic shock.

Amino Acid Sequence↗
PubMed2001

Lactoferrin peptide increases the survival of Candida albicans-inoculated mice by upregulating neutrophil and macrophage functions, especially in combination with amphotericin B and granulocyte-macrophage colony-stimulating factor.

To develop a new strategy to control candidiasis, we examined in vivo the anticandidal effects of a synthetic lactoferrin peptide, FKCRRWQWRM (peptide 2) and the peptide that mimics it, FKARRWQWRM (peptide 2'). Although all mice that underwent intraperitoneal injection of 5 x 10(8) Candida cells with or without peptide 2' died within 8 or 7 days, respectively, the survival times of mice treated with 5 to 100 microg of intravenous peptide 2 per day for 5 days after the candidal inoculation were prolonged between 8.4 +/- 2.9 and 22.4 +/- 3.6 days, depending on the dose of peptide 2. The prolongation of survival by peptide 2 was also observed in mice that were infected with 1.0 x 10(9) Candida albicans cells (3.2 +/- 1.3 days in control mice versus 8.2 +/- 2.4 days in the mice injected with 10 microg of peptide 2 per day). In the high-dose inoculation, a combination of peptide 2 (10 microg/day) with amphotericin B (0.1 microg/day) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.1 microg/day) brought prolonged survival. With a combination of these agents, 60% of the mice were alive for more than 22 days. Correspondingly, peptide 2 activated phagocytes inducing inducible NO synthase and the expression of p47(phox) and p67(phox), and peptide 2 increased phagocyte Candida-killing activities up to 1.5-fold of the control levels upregulating the generation of superoxide, lactoferrin, and defensin from neutrophils and macrophages. These findings indicated that the anticandidal effects of peptide 2 depend not only on the direct Candida cell growth-inhibitory activity, but also on the phagocytes' upregulatory activity, and that combinations of peptide 2 with GM-CSF and antifungal drugs will help in the development of new strategies for control of candidiasis.

Amphotericin B↗
PubMed2004

A peptide domain of bovine milk lactoferrin inhibits the interaction between streptococcal surface protein antigen and a salivary agglutinin peptide domain.

The peptide domain of salivary agglutinin responsible for its interaction with cell surface protein antigen (PAc) of Streptococcus mutans or bovine lactoferrin was found in the same peptide, scavenger receptor cysteine-rich domain peptide 2 (SRCRP2). Inhibition studies suggest that PAc and lactoferrin, of which residues 480 to 492 seem important, competitively bind to the SRCRP2 domain of salivary agglutinin.

Agglutinins↗
PubMed1990

Bovine lactoferrin binding to six species of coagulase-negative staphylococci isolated from bovine intramammary infections.

Bovine lactoferrin (BLf), an acute-phase iron-binding secretory protein present in secretions of the bovine udder, was demonstrated to bind to the following staphylococcal species associated with bovine intramammary infections: S. epidermidis, S. warneri, S. hominis, S. xylosus, S. hyicus, and S. chromogenes. The degree of 125I-labeled BLf uptake significantly varied among the blood agar-grown cells of all six species of coagulase-negative staphylococci tested. Isolates identified as S. xylosus demonstrated the highest (mean, 35.1 x 10(6) +/- 13.3 x 10(6) nmol) and S. hyicus the lowest (mean, 10.7 x 10(6) +/- 5.9 x 10(6) nmol) binding to 125I-BLf. BLf binding was optimum at an acidic pH, with time-dependent binding saturation ranging from 70 min for S. warneri to 240 min for S. hominis. The BLf-binding mechanism was specific, with affinity constants (Ka values) ranging between 0.96 x 10(6) and 11.90 x 10(6) liters/mol. The numbers of BLf-binding sites per cell, as determined by using Scatchard analysis, were as follows: S. epidermidis, 3,600; S. warneri, 1,900; S. hominis, 4,100; S. xylosus, 4,400; S. hyicus, 6,100; and S. chromogenes, 4,700. 125I-BLf binding to all species was inhibited by unlabled BLf and unlabeled human lactoferrin, whereas none of the various plasma, connective tissue, or mucosal secretory proteins or carbohydrates tested caused significant interference. BLf-binding receptors of the six coagulase-negative staphylococcal species demonstrated marked differences in patterns of susceptibility to proteolytic or glycolytic enzyme digestion and to heat or periodate treatment. These data suggest that the BLf-binding components in S. epidermidis and S. warneri are proteins containing glycosidyl residues. In the remaining four species, the proteinaceous nature of the BLf-binding component was evident, but the involvement of glycosidyl residues was not clear. Results of this study establish the presence of specific binding components for BLf on coagulase-negative staphylococci isolated from bovine intramammary infections.

Animals↗
PubMed1995

Concurrence of Clostridium difficile toxin A enzyme-linked immunosorbent assay, fecal lactoferrin assay, and clinical criteria with C. difficile cytotoxin titer in two patient cohorts.

The accurate and sensitive diagnosis of Clostridium difficile-related diarrhea, normally treated with vancomycin, has become increasingly important in light of the emergence of dangerous new strains of vancomycin-resistant enterococci. In order to improve the threshold for C. difficile diagnosis and treatment, a number of commonly used assays for the diagnosis of C. difficile diarrhea were examined. These included an enzyme-linked immunosorbent assay for C. difficile toxin A (ToxA), a CHO cell culture assay for fecal C. difficile (cyto)toxin B, and a lactoferrin latex agglutination assay for fecal lactoferrin (LFLA). We studied 722 fecal specimens submitted by physicians for C. difficile toxin testing at the Salem, Va., Veterans' Affairs Hospital and at the University of Virginia Medical Center in Charlottesville. Charts were reviewed from 123 Veterans' Hospital patients and 114 University of Virginia patients for clinical criteria indicative of C. difficile diarrhea. An increasing titer of CHO cell cytotoxicity was correlated with an increasing likelihood of ToxA positivity (5 to 90%), LFLA positivity (39 to 77%), and clinical agreement (28 to 85%). However, some data indicate that the CHO cell cytotoxicity assay may be nonspecific when positive only at low titers. When the CHO assay result is positive at high titers, it remains the best diagnostic tool. Yet, when it is positive at a low titer, careful interpretation of the results in conjunction with other assays and the clinical setting is warranted, especially in light of new drug-resistant strains of microorganisms.

Animals↗
PubMed2005

Lactoferrin prevents dendritic cell-mediated human immunodeficiency virus type 1 transmission by blocking the DC-SIGN--gp120 interaction.

One of the cell types first encountered by human immunodeficiency virus type 1 (HIV-1) following sexual transmission are dendritic cells (DC). DC capture HIV-1 through C-type lectin receptors, of which the best studied example is DC-SIGN, which mediates HIV-1 internalization. DC can keep the virus infectious for several days and are able to transmit HIV-1 to CD4(+) T cells. We tested proteins from milk and serum for their ability to block DC-mediated HIV-1 transmission, of which bovine lactoferrin (bLF) is the most potent inhibitor. bLF binds strongly to DC-SIGN, thus preventing virus capture and subsequent transmission. Interestingly, bLF is a much more efficient inhibitor of transmission than human lactoferrin. Since bLF is nontoxic and easy to purify in large quantities, it is an interesting candidate microbicide against HIV-1. Another advantage of bLF is its ability to block HIV-1 replication in T cells. DC-mediated capture of a bLF-resistant HIV-1 variant that was selected during long-term culturing in T cells could still be blocked by bLF. This underscores the usefulness of bLF as a microbicide drug to prevent HIV-1 transmission.

Animals↗
PubMed1993

COUP-TF acts as a competitive repressor for estrogen receptor-mediated activation of the mouse lactoferrin gene.

We previously demonstrated that the estrogen response module (mERM) of the mouse lactoferrin gene, which contains an overlapping chicken ovalbumin upstream promoter transcription factor (COUP-TF)- and estrogen receptor-binding element, is responsible for estrogen induction. In this report we show that COUP-TF represses the mERM response to estrogen stimulation. Mutation and deletion of the COUP-TF-binding element or reduction of the endogenous COUP-TF increases mERM estrogen responsiveness. Likewise, overexpression of the COUP-TF expression vector blocked the estrogen-stimulated response of mERM in transfected cells. The molecular mechanism of this repression is due to the competition between COUP-TF and the estrogen receptor for binding at identical contact sites in the overlapping region of the mERM. Our results indicate that two members of the steroid-thyroid receptor superfamily work in concert to modulate lactoferrin gene expression.

Animals↗
PubMed1979

Trypsin and lactoferrin levels in pure pancreatic juice in patients with pancreatic disease.

Levels of immunoreactive trypsin were measured in pure pancreatic juice obtained endoscopically from 44 patients with suspected pancreatic disease. Patients with pancreatic cancer all had low trypsin concentrations (median 3.6 micrograms/ml, range 0.6--12.0), but those with chronic pancreatitis had very variable levels (median 14.2 micrograms/ml, range 3.2--76.8), showing a considerable overlap with patients without pancreatic disease (median 37.1 micrograms/ml, range 10.4--66.0). When levels of lactoferrin in pancreatic juice were measured, all patients with chronic pancreatitis were found to have much higher levels (all greater than 900 ng/ml) than control subjects or patients with pancreatic cancer (all less than 400 ng/ml). The combined measurement of trypsin and lactoferrin in pure pancreatic juice appeared to be more promising than any other currently available test for the separation of patients with pancreatic cancer from those with chronic pancreatitis.

Chronic Disease↗
PubMed1978

Distribution of transferrin, ferritin, and lactoferrin in human tissues.

An immunoperoxidase staining technique was used for detecting three major iron-binding proteins (transferrin, ferritin, and lactoferrin) in routine histological paraffin sections of human tissue. Transferrin was found mainly in hepatocytes, a variety of epithelial and myoepithelial cells, renal tubular cells, and histiocytes. Ferritin was most readily found in histiocytes and liver cells, with weaker reactions seen in epithelial cells. Lactoferrin was found in lactating breast tissue, bronchial glands, polymorphs, and gastric and duodenal epithelial cells. The technique is potentially valuable for investigating abnormal iron states.

Female↗
PubMed1989

Bactericidal effect of lactoferrin on Legionella pneumophila: effect of the physiological state of the organism.

Lactoferrin has been previously shown to be bactericidal for Legionella pneumophila. The current study showed that CaCl2, Mg(NO3)2, and MgCl2, but not NaCl, blocked killing. Activity was pH dependent with the greatest activity at 5.0. Sensitivity of the organism was dramatically affected by the growth conditions. Log phase 12 h, broth-grown cells were most sensitive, with older cultures becoming more resistant. Plate-grown cells were completely resistant. Lactoferrin binding, as detected by immunofluorescence microscopy, was temperature dependent (no binding at 4 degrees C), but was independent of killing.

Calcium Chloride↗
PubMed2002

Lactoferrin and transferrin: functional variations on a common structural framework.

Lactoferrin shares many structural and functional features with serum transferrin, including an ability to bind iron very tightly, but reversibly, a highly-conserved three-dimensional structure, and essentially identical iron-binding sites. Nevertheless, lactoferrin has some unique properties that differentiate it: an ability to retain iron to much lower pH, a positively charged surface, and other surface features that give it additional functions. Here, we review the structural basis for these similarities and differences, including the importance of dynamics and conformational change, and specific interactions that regulate iron binding and release.

Animals↗
PubMed2002

The physiology of lactoferrin.

This paper reviews our current knowledge of the structure and function of the iron-binding protein lactoferrin. In particular, it attempts to relate the various proposed physiological functions of lactoferrin to its most characteristic biochemical properties, i.e. its ability to bind iron and its highly basic nature. The extent to which various physiological functions can be considered as definitely established is critically reviewed, and suggestions for future research are proposed.

Animals↗
PubMed2006

Factors regulating lactoferrin gene expression.

Regulation of gene expression by nuclear receptors and transcription factors involves the concerted action of multiple proteins. The process of transcriptional activation involves chromatin modification, nuclear receptor or transcription factor binding to the response element of the promoter, and coregulator recruitment. Despite advances in knowledge pertaining to the molecular mechanisms of gene regulation overall, there is very limited information available on the molecular mechanism of lactoferrin gene regulation. This review will outline novel information relating to general gene regulation and will discuss the current understanding of the regulation of lactoferrin gene expression by nuclear receptors and transcription factors.

Animals↗
PubMed2006

Oral administration of lactoferrin increases hemoglobin and total serum iron in pregnant women.

Iron deficiency anemia (IDA) during pregnancy continues to be of world-wide concern. IDA is a risk factor for preterm delivery and subsequent low birth weight, and possibly for poor neonatal health. Iron supplementation in pregnancy is a widely recommended practice, yet intervention programs have met with many controversies. In our study, 300 women at different trimesters of pregnancy were enrolled in a trial of oral administration of ferrous sulfate (520 mg once a day) or 30% iron-saturated bovine lactoferrin (bLf) (100 mg twice a day). Pregnant women refusing treatment represented the control group. In this group hemoglobin and total serum iron values measured after 30 d without treatment decreased significantly, especially in women at 18-31 weeks of pregnancy. In contrast, after 30 d of oral administration of bLf, hemoglobin and total serum iron values increased and to a greater extent than those observed in women treated orally for 30 d with ferrous sulfate, independently of the trimester of pregnancy. Unlike ferrous sulfate, bLf did not result in any side effects. These findings lead us to hypothesize that lactoferrin could influence iron homeostasis directly or through other proteins involved in iron transport out of the intestinal cells into the blood.

Administration, Oral↗
PubMed2006

Microbicidal action of lactoferrin and lactoferricin and their synergistic effect with metronidazole in Entamoeba histolytica.

Lactoferrin (Lf), in its iron-free form, has been shown to inhibit the growth of pathogenic microorganisms. In the light of new agents to control amoebiasis, the microbicidal activity of human and bovine Lf and bovine lactoferricin (bLfcin, fragment 4-14), and of each combined with metronidazole, the main drug used in amoebiasis, was evaluated in trophozoites of Entamoeba histolytica. Both lactoferrins and bLfcin were able to kill amoebas in a concentration-dependent manner. This killing effect was modulated according to the culture age, pH, and temperature. Parasites obtained from the stationary phase were more susceptible to Lf than those from the early exponential phase. The effect of Lf and its derived peptide, bLfcin, was prevented by both Fe2+ and Fe3+. However, the divalent cations Mg2+ and Ca2+ prevented the killing effect of Lf but not of bLfcin. A synergistic amoebicidal effect was found between metronidazole and human Lf, bovine Lf, or bLfcin. These data suggest that Lf and bLfcin might be used in amoebiasis if they are administered with a low dose of metronidazole to diminish the toxicity of this drug. Thus, Lf and bLfcin are therapeutically potential candidates for use as antiamoebics in patients.

Animals↗
PubMed2001

Lactoferrin protects neonatal rats from gut-related systemic infection.

Lactoferrin is a milk protein that reportedly protects infants from gut-related, systemic infection. Proof for this concept is limited and was addressed during in vivo and in vitro studies. Neonatal rats pretreated orally with recombinant human lactoferrin (rh-LF) had less bacteremia and lower disease severity scores (P < 0.001) after intestinal infection with Escherichia coli. Control animals had 1,000-fold more colony-forming units of E. coli per milliliter of blood than treated animals (P < 0.001). Liver cultures from control animals had a twofold increase in bacterial counts compared with cultures from rh-LF-treated pups (P < 0.02). Oral therapy with rh-LF + FeSO(4) did not alter the protective effect. In vitro studies confirmed that rh-LF interacted with the infecting bacterium and rat macrophages. An in vitro assay showed that rh-LF did not kill E. coli, but a combination of rh-LF + lysozyme was microbicidal. In vitro studies showed that rat macrophages released escalating amounts of nitric oxide and tumor necrosis factor-alpha when stimulated with increasing concentrations of rh-LF. The in vitro studies suggest that rh-LF may act with other "natural peptide antibiotics" or may prime macrophages to kill E. coli in vivo.

Animals↗