Enhancement of Neisseria meningitidis infection in mice by addition of iron bound to transferrin

Abstract

Small quantities of iron bound specifically to human transferrin were found to stimulate infection with Neisseria meningitidis strain M1011 in mice. An intraperitoneal injection of 17.5 mg of transferrin carrying 22.7 ytg of Fe resulted in 100% mortality from infection, as compared with no mortality for the controls which had received saline. Five milligrams of ferri-transferrin (FeTf), carrying 6.5 yg of Fe, stimulated and prolonged bacteremia in the mice. Thus, FeTf maintained infection, whereas infection was controlled due to iron limitation in control mice. Comparative studies with apotransferrin (iron-free) revealed that the enhancement of infection was due to the supply of iron. FeTf was also found to relieve an iron limitation of growth achieved by ethylenediaminedihydroxyphenylacetic acid (EDDA) in vitro. FeTf abolished the lag phase for growth of N. meningitidis in a defined medium. The results of this study suggest that human FeTf is an immediate source of iron to N. meningitidis both in vitro and in vivo. These findings support the hypothesis that the levels of iron in the circulating transferrin pool of mice determine the course of experimental N. meningitidis infection.

Mechanisms of iron acquisition and bacterial virulence

“…The receptor for transferrin is iron regulated, and seems to be highly specific for human transferrin [1471. Furthermore, it has been described that injection of human transferrin has a very important impact in the development of experimental infections by meningococci in mice [141]. These data may explain the host specificity of this pathogen as Neisseria meningitidis is normally apathogenie for mice.…”

“…it has been shown that the availability of iron influences the virulent properties of Neisseria meningitidis [139][140][141]. Although Neisseria seems not to produce siderophores |142-144], Neisseria meningttidJs might acquire iron from transferrin [143][144][145] and iactofcrrin [146] through specific membrane receptors [147,148].…”

Purification of the Neisseria meningitidis transferrin binding protein-2 (TBP2) to homogeneity using column chromatography

“…Human apotransferrin was purchased from Sigma Chemical Co. Human diferric transferrin (Fe-Tf) was prepared essentially as described by Holbein [21]. Briefly, 0.025/xmol of FeC13 complexed with 0.25/~mol of sodium citrate and 1 mg of Tf were diluted in 40 mM Tris (hydroxymethylaminomethane)-chloride buffer (Tris.…”

The Neisseria meningitidis haemoglobin receptor: its role in iron utilization and virulence

“…These pathogens can directly bind the host's ironbinding proteins such as lactoferrin, transferrin, and haem-containing compounds, and use them as sole sources of iron, Neisseriae meningitidis is one of the leading causes of bacterial meningitis in children and heaithy adults in the worid. The severity of the disease is epitomised by the ability of meningococci to cause the death of previously healthy individuals in less than 24 h. The importance of iron in the virulence of N. meningitidis was dsmonstrated by in vivo studies using mice as the animal model system (Oalver etat., 1976;Holbein, 1981). Specific ironregulated outer membrane receptors have been shown to be involved in the binding and the utilization of lactoferrin-and transferrin-lron in neisseriae (Schtyvers and Morris, 1988a.b;Legrain el al., 1993;Pettersson et at., 1993;.…”