lactoferrin and Gonorrhea

Transition metals are essential for metalloprotein function among all domains of life. Humans utilize nutritional immunity to limit bacterial infections, employing metalloproteins such as hemoglobin, transferrin, and lactoferrin across a variety of physiological niches to sequester iron from invading bacteria. Consequently, some bacteria have evolved mechanisms to pirate the sequestered metals and thrive in these metal-restricted environments.

Topics: Gonorrhea; Hemoglobins; Humans; Iron; Lactoferrin; Metalloproteins; Neisseria gonorrhoeae

Topics: Anti-Bacterial Agents; Antibodies, Bacterial; Bacterial Outer Membrane Proteins; Bacterial Vaccines; Carrier State; Complement System Proteins; Drug Resistance, Microbial; Fallopian Tubes; Female; Fimbriae, Bacterial; Gonorrhea; Humans; Intrauterine Devices; Lactoferrin; Lipopolysaccharides; Male; Menstruation; Models, Biological; Mucus; Neisseria gonorrhoeae; Neutrophils; Salpingitis; Urethra; Urethritis; Vaccination; Vagina

Typing of the porB variable region (VR) is an epidemiological tool that classifies gonococcal strains based on sequence differences in regions of the porB gene that encode surface-exposed loops. The frequent isolation of certain porB VR types suggests that some porin sequences confer a selective advantage during infection and/or transmission. Alternatively, certain porin types may be markers of strains that are successful due to factors unrelated to porin. In support of the first hypothesis, here we show urogenital tract isolates representing the most common PIA VR types identified in an urban clinic in Baltimore, MD, over a 10-year period belonged to several different clonal types, as determined by pulsed-field gel electrophoresis (PFGE). Serum resistance, which was confirmed by factor H and C4b-binding protein binding studies, was more often associated with gonococcal the most common VR types. In contrast, three porin-independent phenotypes, namely, lactoferrin utilization, beta-lactamase production, and multiple transferable resistance (Mtr), were segregated with the PFGE cluster and not with the VR type. Data combined with another PIA strain collection showed a strong correlation between serum resistance and the most common VR types. A comparison of VR typing hybridization patterns and nucleotide sequences of 12 porB1a genes suggests that certain porin loop 1, 3, 6, and/or 7 sequences may play a role in the serum resistance phenotype. We conclude that some PorB PIA sequences confer a survival or transmission advantage in the urogenital tract, perhaps via increased resistance to complement-mediated killing. The capacity of some porin types to evade a porin-specific adaptive immune response must also be considered.

Topics: Bacterial Typing Techniques; Baltimore; beta-Lactamases; Blood Bactericidal Activity; Cluster Analysis; Complement C4b-Binding Protein; Complement Factor H; DNA Fingerprinting; DNA, Bacterial; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Female Urogenital Diseases; Genotype; Gonorrhea; Humans; Lactoferrin; Male; Male Urogenital Diseases; Molecular Motor Proteins; Neisseria gonorrhoeae; Polymorphism, Genetic; Porins; Protein Binding; Urban Population

All isolates of Neisseria gonorrhoeae express receptors that bind human transferrin (Tf). Although lactoferrin (Lf) is abundant on mucosa and in purulent exudates, many gonococci do not express an Lf receptor. The naturally occurring Lf receptor deletion mutant FA1090 (LbpB-LbpA-) is infectious, but a Tf receptor mutant of FA1090 is unable to infect male volunteers [Cornelissen, C.N., Kelley, M., Hobbs, M.M., Anderson, J.E., Cannon, J.G., Cohen, M.S., and Sparling, P.F. (1998) Mol Microbiol 27: 611-616]. Here, we report that expression of an Lf receptor in the absence of the Tf receptor was sufficient for infection, and that expression of both Lf and Tf receptors resulted in a competitive advantage over a strain that made only the Tf receptor in mixed infection of male volunteers. We confirmed that nearly 50% of clinical isolates do not make an Lf receptor. Surprisingly, about half of geographically diverse Lf - isolates representing many different auxotypes and porin serovars carried an identical lbpB lbpA deletion. Among Lf+ strains, all produced the integral outer membrane protein LbpA, but 70% did not express the lipoprotein LbpB. Thus, there are apparently selective pressures for expression of the Lf receptor in the male urethra that are balanced by others against expression of the Lf receptor in niches other than the male urethra.

Topics: Bacterial Outer Membrane Proteins; Bacterial Proteins; Carrier Proteins; Culture Media; Gene Expression Regulation, Bacterial; Gonorrhea; Humans; Lactoferrin; Male; Neisseria gonorrhoeae; Receptors, Cell Surface; Transferrin; Urethra

Neisseria gonorrhoeae expresses receptors for both lactoferrin (LF) and transferrin (TF). To determine whether qualitative or quantitative changes in these receptors, or both, correlate with the pattern of disease due to N. gonorrhoeae, a dot binding assay with whole cells was used to measure the absolute receptor levels expressed during iron-limited growth of strains isolated from asymptomatic patients and patients with urethritis, cervicitis, pelvic inflammatory disease and disseminated infection. Lactoferrin and transferrin receptor complexes were purified by affinity chromatography and their protein profiles were compared. The molecular weights of the LF and TF receptor complexes from a representative sample of gonococci were homogeneous. We conclude that there is no relationship between the LF and TF receptor levels and disease manifestation, auxotype or serotype.

Topics: Carrier State; Cell Membrane; Chromatography, Affinity; Electrophoresis, Polyacrylamide Gel; Female; Gonorrhea; Humans; Lactoferrin; Male; Neisseria gonorrhoeae; Pelvic Inflammatory Disease; Receptors, Cell Surface; Receptors, Transferrin; Urethritis; Uterine Cervicitis

The concentration of the iron-binding protein lactoferrin was measured in vaginal mucus of women throughout the menstrual cycle. Lactoferrin is proposed to limit growth of mucosal pathogens such as Neisseria gonorrhoeae. Lactoferrin concentration in mucus was highest just after menses (62.9 to 218 micrograms/mg of protein) and lowest (3.8 to 11.4 micrograms/mg of protein) just before menses. Overall concentration of mucus protein showed no variation with menstrual cycle, and little lactoferrin was detectable in cell debris. Plasma lactoferrin did not show the variation seen in vaginal mucus. Because of the suggestion of hormonal influence on vaginal lactoferrin, its concentration was determined in women receiving oral contraceptive therapy. Mean lactoferrin concentration in women taking oral contraceptives was significantly lower than in the control group (never exceeding 19.8 micrograms/mg of protein) and showed no monthly variation. Vaginal lactoferrin appears to be under hormonal control. Variation in vaginal lactoferrin concentration may result in alterations in susceptibility to bacterial pathogens such as Neisseriae gonorrhoeae.

Topics: Cervix Mucus; Contraceptives, Oral, Hormonal; Enzyme-Linked Immunosorbent Assay; Female; Gonorrhea; Humans; Lactoferrin; Lactoglobulins; Menstrual Cycle; Neisseria gonorrhoeae; Vagina; Vaginal Smears

Mouse transferrin was used to specifically label the plasma transferrin iron pool for studies of iron kinetics in normal mice and infected mice during the hypoferremic phase of experimental meningococcal infection. The plasma transferrin iron pool of normal mice was found to be very dynamic, with a half-life of iron in the pool of 0.7 h. Iron left the plasma pool, entered the bone marrow, and was released into the blood in erythrocytes. Iron from the transferrin pool also entered the liver and spleen and was presumably in the reticuloendothelial system components of these organs. Most of the iron that had been supplied as transferrin iron was found in erythrocytes by 48 h after injection. Studies with mice infected with Neisseria meningitidis strain M1011 revealed similar kinetics for transferrin iron. There was no redistribution of iron within the various iron pools as a result of infection. Iron turnover in the plasma transferrin pool during the hypoferremic phase was similar to control rates, and iron leaving the pool entered its normal erythroid compartments. The lack of accelerated turnover of plasma iron and the finding that plasma iron was not rerouted to storage compartments during the hypoferremic phase provided good evidence that lactoferrin and leukocytic endogenous mediator were not directly involved in redirecting transferrin iron. Our evidence has implicated an impaired return of reticuloendothelial system-processed iron to the transferrin pool during the hypoferremic response. This appears to be a logical point in the erythroid iron cycle for host-mediated iron sequestration, as the reticuloendothelial system is involved in iron storage and may regulate iron levels in the plasma transferrin pool under normal conditions.

Topics: Animals; Gonorrhea; Interleukin-1; Iron; Kinetics; Lactoferrin; Male; Mice; Mice, Inbred C57BL; Mononuclear Phagocyte System; Proteins; Transferrin