Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0348321 (Haemophilus)
 15,372 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonencapsulated Haemophilus influenzae often causes chronic infections of the lower respiratory tract in both nonobstructive and obstructive chronic bronchitis. We assessed airway inflammation in clinically stable, chronically H. influenzae-infected patients with nonobstructive (CB-HI, n = 10) and in patients with obstructive chronic bronchitis (COPD-HI, n = 10) by analyses of the sol phase of spontaneously expectorated sputum (SSP). As compared with the CB-HI group, the COPD-HI group had significantly higher (p < 0.05) levels of myeloperoxidase (MPO) and tumor necrosis factor (TNF)-alpha in their SSP, whereas the degree of plasma protein leakage (SSP-to-serum ratio of plasma proteins) and the levels of interleukin (IL)-8, secretory IgA, and lactoferrin were similar in the two groups. These findings point to differences in pathophysiology in CB-HI and COPD-HI. The high level of TNF-alpha in the SSP of COPD-HI patients is in accord with the proposed role of TNF-alpha in the development of airway obstruction in COPD patients. In apparent contradiction, low levels of TNF-alpha were found in the SSP of noninfected but otherwise similar COPD patients (n = 9). This finding, however, does not exclude an exaggerated TNF-alpha response to infection or another stimulus in the airways of COPD patients. The SSP levels of MPO and IL-8, and the degree of plasma protein leakage in the COPD-HI group, were retrospectively compared with and found significantly higher than those of noninfected COPD patients, suggesting a more marked inflammatory response in COPD-HI. Whether this reflects a direct cause-and-effect relationship should be addressed in a future long-term prospective study involving repeated measurements in the same patients.
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PMID:Airway inflammation in nonobstructive and obstructive chronic bronchitis with chronic haemophilus influenzae airway infection. Comparison with noninfected patients with chronic obstructive pulmonary disease. 1098 11

Human lactoferrin proteolytically cleaves and inactivates two colonization factors of non-typable Haemophilus influenzae, the IgA protease precursor protein (Iga), and Hap, the non-pilus adhesin by which microoganisms adhere to host epithelial cells and form microcolonies. Iga and Hap are homologous proteins that are members of the autotransporter family of secreted proteins expressed by gram-negative bacteria. Studies of Iga cleaved by lactoferrin, reported here, show that proteolysis occurred within the helper region of Iga (Iga(beta)) domain which anchors the autotransporter within the Haemophilus outer membrane. The amino-terminus of the extracted Iga protein was not modified. The location of the proteolytic active site in human lactoferrin is under study. Lactoferrin proteolysis may attenuate pathogenicity of H. influenzae, an important cause of otitis media.
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PMID:Human lactoferrin proteolytic activity: analysis of the cleaved region in the IgA protease of Haemophilus influenzae. 1116 80

Numerous bacterial proteins are involved in microbial iron uptake and transport and considerable variation has been found in the uptake schemes used by different bacterial species. However, whether extracting iron from host proteins such as transferrin, lactoferrin or hemoglobin or importing low molecular weight iron-chelating compounds such as heme, citrate or siderophores, Gram-negative pathogenic bacteria typically employ a specific outer membrane receptor, a periplasmic binding protein and two inner membrane associated proteins: a transporter coupled with an ATP-hydrolyzing protein. Often, studies have shown that proteins with similar function but little amino acid sequence homology are structurally related. Elucidation of the structures of the Escherichia coli outer membrane siderophore transport proteins FepA and FhuA have provided the first insights into the conformational changes required for ligand transport through the bacterial outer membrane. The variations between the structures of the prototypical periplasmic ferric binding protein FbpA from Neisseria and Haemophilus influenzae and the unusual E coli periplasmic siderophore binding protein FhuD reveal that the different periplasmic ligand binding proteins exercise distinct mechanisms for ligand binding and release. The structure of the hemophore HasA from Serratia marcescens shows how heme may be extracted and utilized by the bacteria. Other biochemical evidence also shows that the proteins that provide energy for iron transport at the outer membrane, such as the TonB-ExbB-ExbD system, are structurally very similar across bacterial species. Likewise, the iron-sensitive gene regulatory protein Fur is found in most bacteria. To date, no structural information is available for Fur, but the structure for the related protein DxtR has been determined. Together, these three-dimensional structures complement our knowledge of iron transport systems from other pathogenic bacteria, including Pseudomonas aeruginosa, which has a number of homologous iron uptake proteins. More importantly, the current structures for iron transport proteins provide rational starting points for design of novel antimicrobial agents.
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PMID:Structural biology of bacterial iron uptake systems. 1189 94

Lactoferrin is a member of the lactotransferrin family of non-haem, iron-binding glycoproteins and is found at high concentrations in all human secretions, where it plays a major role in mucosal defence. In recent work, we observed that lactoferrin has proteolytic activity and attenuates the pathogenic potential of Haemophilus influenzae by cleaving and removing two putative colonization factors, namely the IgA1 protease protein and the Hap adhesin. Experiments with protease inhibitors further suggested that lactoferrin may belong to a serine protease family. In the present study we explored the mechanism of lactoferrin protease activity and discovered that mutation of either Ser259 or Lys73 results in a dramatic decrease in proteolysis. Examination of the crystal structure revealed that these two residues are located in the N-terminal lobe of the protein, adjacent to a 12-15 A cleft that separates the N-lobe and the C-lobe and that can readily accommodate large polypeptide substrates. In additional work, we found that lactoferrin cleaves IgA1 protease at an arginine-rich region defined by amino acids 1379-1386 (RRSRRSVR) and digests Hap at an arginine-rich sequence between amino acids 1016 and 1023 (VRSRRAAR). Based on our results, we conclude that lactoferrin is a serine protease capable of cleaving arginine-rich sequences. We speculate that Ser259 and Lys73 form a catalytic dyad, reminiscent of a number of bacterial serine proteases. In addition, we speculate that lactoferrin may cleave arginine-rich sequences in a variety of microbial virulence proteins, contributing to its long-recognized antimicrobial properties.
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PMID:Human milk lactoferrin is a serine protease that cleaves Haemophilus surface proteins at arginine-rich sites. 1253 64

The periodontal pathogen Actinobacillus actinomycetemcomitans possesses myriad virulence factors, among them the ability to adhere to and invade epithelial cells. Recent advances in the molecular manipulation of this pathogen and the sequencing of strain HK 1651 (http://www.genome.ou.edu/act.html) have facilitated examination of the genetics of its interaction with epithelial cells. The related gram-negative organism, Haemophilus influenzae, possesses autotransporter adhesins. A search of the sequence database of strain HK 1651 revealed a homologue with similarity in the pore-forming domain to that of the H. influenzae autotransporter, Hap. A. actinomycetemcomitans mutants deficient in the homologue, Aae, showed reduced binding to epithelial cells. A method for making A. actinomycetemcomitans SUNY 465 transiently resistant to spectinomycin was used with conjugation to generate an isogenic aae mutant. An allelic replacement mutant was created in the naturally transformable A. actinomycetemcomitans strain ATCC 29523. Lactoferrin, an important part of the innate host defense system, protects against bacterial infection by bactericidal and antiadhesion mechanisms. Lactoferrin in human milk removes or cleaves Hap and another autotransporter, an immunoglobulin A1 protease, from the surface of H. influenzae, thereby reducing their binding to epithelial cells. Human milk whey had similar effects on Aae from A. actinomycetemcomitans ATCC 29523 and its binding to epithelial cells; however, there was little effect on the binding of SUNY 465. A difference in the genetic structure of aae in the two strains, apparently due to the copy number of a 135-base repeated sequence, may be the cause of the differential action of lactoferrin. aae is the first A. actinomycetemcomitans gene involved in adhesion to epithelial cells to be identified.
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PMID:Aae, an autotransporter involved in adhesion of Actinobacillus actinomycetemcomitans to epithelial cells. 1270 8

One component of the anti-microbial function of lactoferrin (Lf) is its ability to sequester iron from potential pathogens. To overcome this iron limitation, a number of gram-negative bacterial pathogens have developed a mechanism for acquiring iron directly from this host glycoprotein. This mechanism involves surface receptors capable of specifically binding Lf from the host, removing iron and transporting it across the outer membrane. The iron is then bound by a periplasmic iron-binding protein, FbpA, and transported into the cell via an inner membrane complex comprised of FbpB and FbpC. The receptor has been shown to consist of two proteins, LbpA and LbpB. LbpB is bilobed lipoprotein anchored to the outer membrane via fatty acyl groups attached to the N-terminal cysteine. LbpA is a homologue of siderophore receptors, which consist of an N-terminal plug and a C-terminal beta-barrel region. We propose that the receptor proteins, LbpA and LbpB, induce conformational changes in human Lf (hLf) that lower its affinity for iron that binding by FbpA can drive the transport across the outer membrane, a mechanism shared with transferrin (Tf) receptors. The interaction between the receptor proteins and Lf is quite extensive and has been previously studied by using chimeric proteins comprised of Lf & Tf. In an attempt to evaluate the role of FbpA in the transport process, a series of site-directed mutants of FbpA were prepared and used to replace the wild-type protein in the iron acquisition pathway. The mutations were made in the iron-binding and anion-binding ligands of FbpA and were designed to result in altered binding properties. Protein crystallography of the iron-bound form of the Q58L mutant protein revealed that it was in the open conformation with iron coordinated by Y195 and Y196 from the C-terminal domain but not by the other iron-liganding amino acids from the N-terminal domain, H9 and E57. Replacement of the native FbpA in Neisseria meningitidis with wild-type or mutant Haemophilus influenzae FbpAs resulted in a defect in growth on Tf or Lf, suggesting that there may be a barrier to functional expression of H. influenzae FbpAs in Neisseria meningitidis. Thus mutants of the N. meningitidis FbpA are being prepared to replace wild-type protein in order to test their ability to mediate transport from hLf.
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PMID:Lactoferrin receptors in gram-negative bacteria: insights into the iron acquisition process. 1522 71

The role of bovine serum or plasma proteins in Haemophilus somnus virulence was investigated in a mouse model of septicemia. An increase in virulence was detected when the organism was pre-incubated for 5 min and inoculated with fetal calf serum. When purified bovine serum or plasma proteins were pre-incubated with H. somnus before inoculating into mice, transferrin was found to increase virulence. Bovine lactoferrin was also noted to increase virulence, but to a lesser extent and had a delayed time course when compared with transferrin. Using an ELISA assay, an increased amount of H. somnus whole cells and culture supernatant bound to bovine transferrin when the organism was grown in iron-restricted media. Lactoferrin also bound to H. somnus, but binding was not affected by growth in iron-restricted media and it was eliminated with 2M NaCl, which reversed charge mediated binding. Transferrin, but not lactoferrin, supported growth of H. somnus on iron-depleted agar based media using a disk assay. Therefore, lactoferrin increased virulence by an undetermined mechanism whereas transferrin increased virulence of H. somnus by binding to iron-regulated outer-membrane proteins (IROMPs) and providing iron to the pathogen.
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PMID:Bovine plasma proteins increase virulence of Haemophilus somnus in mice. 1712 64

Many host-adapted bacterial pathogens contain DNA methyltransferases (mod genes) that are subject to phase-variable expression (high-frequency reversible ON/OFF switching of gene expression). In Haemophilus influenzae, the random switching of the modA gene controls expression of a phase-variable regulon of genes (a "phasevarion"), via differential methylation of the genome in the modA ON and OFF states. Phase-variable mod genes are also present in Neisseria meningitidis and Neisseria gonorrhoeae, suggesting that phasevarions may occur in these important human pathogens. Phylogenetic studies on phase-variable mod genes associated with type III restriction modification (R-M) systems revealed that these organisms have two distinct mod genes--modA and modB. There are also distinct alleles of modA (abundant: modA11, 12, 13; minor: modA4, 15, 18) and modB (modB1, 2). These alleles differ only in their DNA recognition domain. ModA11 was only found in N. meningitidis and modA13 only in N. gonorrhoeae. The recognition site for the modA13 methyltransferase in N. gonorrhoeae strain FA1090 was identified as 5'-AGAAA-3'. Mutant strains lacking the modA11, 12 or 13 genes were made in N. meningitidis and N. gonorrhoeae and their phenotype analyzed in comparison to a corresponding mod ON wild-type strain. Microarray analysis revealed that in all three modA alleles multiple genes were either upregulated or downregulated, some of which were virulence-associated. For example, in N. meningitidis MC58 (modA11), differentially expressed genes included those encoding the candidate vaccine antigens lactoferrin binding proteins A and B. Functional studies using N. gonorrhoeae FA1090 and the clinical isolate O1G1370 confirmed that modA13 ON and OFF strains have distinct phenotypes in antimicrobial resistance, in a primary human cervical epithelial cell model of infection, and in biofilm formation. This study, in conjunction with our previous work in H. influenzae, indicates that phasevarions may be a common strategy used by host-adapted bacterial pathogens to randomly switch between "differentiated" cell types.
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PMID:Phasevarions mediate random switching of gene expression in pathogenic Neisseria. 1939 Jun 8

Lactoferrin (LF) is a glycoprotein widely distributed in mammalian organisms. It is synthesized by epithelial cells; hence it is present in secretions of mucous membranes. It is also contained in secondary granules of neutrophils and released to the circulation during trauma, infection or inflammation. LF belongs to the transferrin family--proteins binding iron ions with a high affinity. Upon isolation in 1961 LF was initially called a red, iron-binding protein. LF's ability to bind iron is associated with other functions which the protein fulfils in the body. As described in the part I. of the article, LF participates in acquisition of iron from food and its storage in the body, and to a certain degree also in iron transport to cells. In this part of the article the effect of LF in combating microorganisms by chelating iron is described. The iron-chelating property of LF renders iron inaccessible to the pathogens, thus restricting their growth. Iron, due to its participation in many metabolic processes, is an essential element for almost all microorganisms. Iron is not easily accessible for pathogens within the host. Since iron is crucial for normal function of both pathogens and the host, an ability to acquire iron during infection is regarded as an important virulence factor. Higher vertebrates have evolved a complicated protection system of iron storage and LF is an important element of this system. Low iron-saturated LF effectively combats bacteria and fungi, acting in a bacteriostatic and fungistatic way. The degree of iron saturation also influences antiviral activity of LF. Some pathogens (e.g. Helicobacter pylori, Neisseria sp, Haemophilus influenzae) have evolved a system of siderophores or cellular receptors which can acquire iron from LF and transferrin. The so-called lactoferrin theory of hypoferremia in inflammation assumes, in addition, a protective role of the protein in inflammation, sepsis and trauma. LF, by chelation and storage of plasma iron in the liver and spleen, temporarily restricts its accessibility for microorganisms and processes of formation of toxic, reactive oxygen species, which contributes to the amelioration of inflammatory states.
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PMID:[The role of lactoferrin in the iron metabolism. Part II. Antimicrobial and antiinflammatory effect of lactoferrin by chelation of iron]. 2116 95

Two conundrums puzzle COVID-19 investigators: 1) morbidity and mortality is rare among infants and young children and 2) rates of morbidity and mortality exhibit large variances across nations, locales, and even within cities. It is found that the higher the rate of pneumococcal vaccination in a nation (or city) the lower the COVID-19 morbidity and mortality. Vaccination rates with Bacillus Calmette-Guerin, poliovirus, and other vaccines do not correlate with COVID-19 risks, nor do COVID-19 case or death rates correlate with number of people in the population with diabetes, obesity, or adults over 65. Infant protection may be due to maternal antibodies and antiviral proteins in milk such as lactoferrin that are known to protect against coronavirus infections. Subsequent protection might then be conferred (and correlate with) rates of Haemophilus influenzae type B (Hib) (universal in infants) and pneumococcal vaccination, the latter varying widely by geography among infants, at-risk adults, and the elderly. Also see the video abstract here https://youtu.be/GODBYRbPL00.
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PMID:Age and Location in Severity of COVID-19 Pathology: Do Lactoferrin and Pneumococcal Vaccination Explain Low Infant Mortality and Regional Differences? 3290 69


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