Iron as a replacement for mucin in the establishment of meningococcal infection in mice

1976 ◽  
Vol 22 (6) ◽  
pp. 832-838 ◽  
Author(s):  
G. A. Calver ◽  
C. P. Kenny ◽  
G. Lavergne
Keyword(s):  
Neisseria Meningitidis ◽  
Experimental Infection ◽  
Ferrous Sulphate ◽  
Gastric Mucin ◽  
Meningococcal Infection ◽  
Iron Dextran ◽  
Iron Compounds ◽  
Fatal Infection ◽  
Lethal Doses

Experimental infection of mice with Neisseria meningitidis was established by the injection of the bacteria suspended in solutions of various iron compounds. The progressive and fatal infection caused by otherwise non-lethal doses of organisms was produced in these mice after prior injection with ferrous sulphate or concomitant injection with iron sorbitol citrate or iron dextran. Reduction in LD50 to levels at least comparable to those obtained in the mucin challenge system was achieved; in some serogroups of N. meningitidis the LD50 was decreased more than a million fold. The results suggest that iron, which is a component of hog gastric mucin, is a factor involved in the establishment of meningococcal infection in mice. Use of iron compounds as injection medium offers a more advantageous system than mucin, since controlled administration of chemically defined substances occurs.

scholarly journals Animal and Human Studies on Ferrous Fumarate, an Oral Hematinic

Blood ◽  
1960 ◽  
Vol 15 (4) ◽  
pp. 540-550 ◽  
Author(s):  
M. C. BERENBAUM ◽  
K. J. CHILD ◽  
B. DAVIS ◽  
HELEN M. SHARPE ◽  
E. G. TOMICH
Keyword(s):  
Ferrous Sulphate ◽  
Human Studies ◽  
The Other ◽  
Histologic Examination ◽  
Iron Dextran ◽  
Iron Compounds ◽  
Ferrous Fumarate ◽  
Iron Deficient

Abstract Ferrous fumarate, an oral hematinic, has been compared with the sulphate, succinate and gluconate for various aspects of toxicity. In mice, the relative acute oral toxicities were fumarate 1, succinate 1.1, gluconate 2.0 and sulphate 2.7. In cats, the relative emetic activities were fumarate 1, succinate and gluconate 3, and sulphate 4. Examination of the stomachs and livers of rabbits given massive doses of the four iron tablets showed that the sulphate and gluconate were much more toxic and irritant than the succinate or fumarate. Rats dosed for 12 weeks with ferrous fumarate (50 mg. Fe/Kg./day) grew normally, and histologic examination of the major organs revealed no abnormalities that could be attributed to the drug. Hematinic studies on iron-deficient rats, receiving the four iron compounds orally or iron-dextran intramuscularly, indicated that ferrous fumarate was as effective as the other compounds. Twenty-two hypochromic anemic patients were dosed with Fersamal (three tablets per day), and all except one showed hematologic improvement. The patient who proved refractory had previously undergone gastrectomy and had not improved on either ferrous sulphate or gluconate. The tablets were acceptable to all the patients.

scholarly journals MisR/MisS Two-Component Regulon in Neisseria meningitidis

2007 ◽  
Vol 76 (2) ◽  
pp. 704-716 ◽  
Author(s):  
Yih-Ling Tzeng ◽  
Charlene M. Kahler ◽  
Xinjian Zhang ◽  
David S. Stephens
Keyword(s):  
Neisseria Meningitidis ◽  
Target Genes ◽  
Inner Core ◽  
Consensus Sequence ◽  
Meningococcal Infection ◽  
Type I ◽  
Mobility Shift ◽  
Iron Assimilation ◽  
Wide Range ◽  
Two Component

ABSTRACT Two-component regulatory systems are involved in processes important for bacterial pathogenesis. Inactivation of the misR/misS system in Neisseria meningitidis results in the loss of phosphorylation of the lipooligosaccharide inner core and causes attenuation in a mouse model of meningococcal infection. One hundred seventeen (78 up-regulated and 39 down-regulated) potential regulatory targets of the MisR/MisS (MisR/S) system were identified by transcriptional profiling of the NMBmisR mutant and the parental wild-type meningococcal strain NMB. The regulatory effect was further confirmed in a subset of target genes by quantitative real-time PCR and β-galactosidase transcriptional fusion reporter assays. The MisR regulon includes genes encoding proteins necessary for protein folding in the bacterial cytoplasm and periplasm, transcriptional regulation, metabolism, iron assimilation, and type I protein transport. Mutation in the MisR/S system caused increased sensitivity to oxidative stress and also resulted in decreased susceptibility to complement-mediated killing by normal human serum. To identify the direct targets of MisR regulation, electrophoretic mobility shift assays were carried out using purified MisR-His6 protein. Among 22 genes examined, misR directly interacted with 14 promoter regions. Six promoters were further investigated by DNase I protection assays, and a MisR-binding consensus sequence was proposed. Thus, the direct regulatory targets of MisR and the minimal regulon of the meningococcal MisR/S two-component signal transduction system were characterized. These data indicate that the MisR/S system influences a wide range of biological functions in N. meningitidis either directly or via intermediate regulators.

Apparent Meningococcemia: Clinical Features of Disease Due to Haemophilus influenzae and Neisseria meningitidis

PEDIATRICS ◽  
1983 ◽  
Vol 72 (4) ◽  
pp. 469-472
Author(s):  
Richard F. Jacobs ◽  
Steven Hsi ◽  
Christopher B. Wilson ◽  
Denis Benjamin ◽  
Arnold L. Smith ◽  
...  
Keyword(s):  
Haemophilus Influenzae ◽  
Neisseria Meningitidis ◽  
Meningococcal Disease ◽  
Clinical Signs ◽  
Meningococcal Infection ◽  
Disseminated Intravascular Coagulopathy ◽  
Etiologic Agents ◽  
Intravascular Coagulopathy ◽  
Time Of Admission ◽  
Mean Time

To determine the etiology of apparent meningococcemia, all cases of sepsis with coagulopathy, purpura, and/or adrenal hemorrhage (Waterhouse-Friderichsen syndrome) with and without shock occurring over a 12-year period were reviewed. A total of 42 cases were identified; 30 cases were caused by Neisseria meningitidis and 12 cases were caused by Haemophilus influenzae. Compared with patients with disease caused by H influenzae, patients with meningococcal disease were older, more often male, more often contracted the disease in winter-spring, and had a longer duration of antecedent symptoms; however, none of these differences was statistically significant. All patients were febrile (>38°C) and appeared toxic. Similar proportions in each group had shock and disseminated intravascular coagulopathy at the time of admission. Ten of 12 patients with H influenzae infection compared with 15/30 (P < .05) with meningococcal infection were lethargic or comatose at the time of admission. Nine of 12 patients with H influenzae infection died compared with 5/30 with meningococcal disease (P < .005); the mean time from onset of symptoms to death with H influenzae infection (20.7 ± 11.4 [SE] hours) was significantly shorter (P < .05) than with meningococcal infection (120 ± 74.4 hours). Children with clinical signs of sepsis and with purpura, petechiae, or coagulopathy may have N meningitidis or H influenzae as etiologic agents. Initial antibiotic therapy should be directed against these pathogens.

Differences in virulence for mice between disease and carrier strains of Neisseria meningitidis

1981 ◽  
Vol 27 (7) ◽  
pp. 738-741 ◽  
Author(s):  
Bruce E. Holbein
Keyword(s):  
Neisseria Meningitidis ◽  
Model System ◽  
Iron Dextran ◽  
Good Assessment ◽  
High Virulence

The virulences of 11 prototype strains of Neisseria meningitidis, which had been used in the development of the serotyping scheme for serogroup B meningococci, were examined in mice treated with iron dextran. These strains, together with those previously examined, allowed for a good assessment of the virulence differences between carrier and disease strains. All of a total of 17 disease strains displayed virulence for mice (60% with high virulence), whereas only approximately 50% of 13 carrier strains possessed virulence (only 15% with high virulence).Because the ability to initiate infection in mice is independent of exogenous iron, this model system for infection appears particularly suited to studies of the physiological bases for virulence in N. meningitidis.

scholarly journals Immune Homeostatic Macrophages Programmed by the Bacterial Surface Protein NhhA Potentiate Nasopharyngeal Carriage ofNeisseria meningitidis

mBio ◽  
2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Xiao Wang ◽  
Mikael Sjölinder ◽  
Yumin Gao ◽  
Yi Wan ◽  
Hong Sjölinder
Keyword(s):  
Neisseria Meningitidis ◽  
Surface Protein ◽  
Meningococcal Infection ◽  
Necrosis Factor Alpha ◽  
Bacterial Surface ◽  
Proinflammatory Mediators ◽  
Anti Inflammatory ◽  
Nasopharyngeal Mucosa

ABSTRACTNeisseria meningitidiscolonizes the nasopharyngeal mucosa of healthy populations asymptomatically, although the bacterial surface is rich in motifs that activate the host innate immunity. What determines the tolerant host response to this bacterium in asymptomatic carriers is poorly understood. We demonstrated that the conserved meningococcal surface protein NhhA orchestrates monocyte (Mo) differentiation specifically into macrophage-like cells with a CD200Rhiphenotype (NhhA-Mφ). In response to meningococcal stimulation, NhhA-Mφ failed to produce proinflammatory mediators. Instead, they upregulated interleukin-10 (IL-10) and Th2/regulatory T cell (Treg)-attracting chemokines, such as CCL17, CCL18, and CCL22. Moreover, NhhA-Mφ were highly efficient in eliminating bacteria. Thein vivovalidity of these findings was corroborated using a murine model challenged withN. meningitidissystematically or intranasally. The NhhA-modulated immune response protected mice from septic shock; Mo/Mφ depletion abolished this protective effect. Intranasal administration of NhhA induced an anti-inflammatory response, which was associated withN. meningitidispersistence at the nasopharynx.In vitrostudies demonstrated that NhhA-triggered Mo differentiation occurred upon engaged Toll-like receptor 1 (TLR1)/TLR2 signaling and extracellular signal-regulated kinase (ERK) and Jun N-terminal protein kinase (JNK) activation and required endogenously produced IL-10 and tumor necrosis factor alpha (TNF-α). Our findings reveal a strategy that might be adopted byN. meningitidisto maintain asymptomatic nasopharyngeal colonization.IMPORTANCENeisseria meningitidisis an opportunistic human-specific pathogen that colonizes the nasopharyngeal mucosa asymptomatically in approximately 10% of individuals. Very little is known about how this bacterium evades immune activation during the carriage stage. Here, we observed thatN. meningitidis, via the conserved surface protein NhhA, skewed monocyte differentiation into macrophages with a CD200Rhiphenotype. Bothin vivoandin vitrodata demonstrated that these macrophages, upon meningococcal infection, played an important role in forming a homeostatic immune microenvironment through their capacity to eliminate invading bacteria and to generate anti-inflammatory mediators. This work provides novel insight into the mechanisms underlying the commensal persistence ofN. meningitidis.

L'IMMUNITÉ DANS LES INFECTIONS STAPHYLOCOCCIQUES : 1. ACTION DE L'ANTITOXINE CONTRE UNE INFECTION BACTÉRIENNE EXPÉRIMENTALE

1956 ◽  
Vol 2 (3) ◽  
pp. 271-280 ◽  
Author(s):  
A. Frappier ◽  
S. Sonea
Keyword(s):  
Experimental Infection ◽  
Marked Decrease ◽  
Appreciable Effect ◽  
Significant Protection ◽  
Infection Bactérienne ◽  
First Time ◽  
Lethal Doses ◽  
Living Bacteria ◽  
At Will

Using the intracerebral route in mice immunized with commercial antitoxin, complete or significant protection was obtained for the first time at will against lethal doses of living staphylococci. The protection was effective against the five staphylococcus strains used. The mechanism of this experimental infection was partially studied in normal and in immunized mice by counting at variable intervals the living bacteria at the inoculation point (brain) and in the blood. A moderate bacteraemia was present immediately after the inoculation, decreased later to few bacteria per drop of blood, and eventually disappeared. This bacteraemia was not influenced by the presence of the antitoxin. At the inoculation point, a marked decrease in the number of staphylococci was evident immediately after the injection of the bacteria, and one hour later. The antitoxin had no appreciable effect on this phenomenon. The local multiplication following the above mentioned decrease in the number of staphylococci was moderate and was not checked by the antitoxin. Mortality in unprotected animals seems to be caused by staphylococcal toxins liberated in greater quantity by the increased number of living staphylococci found about the fourth hour after inoculation.

Experimental meningococcal infection in neonatal mice: differences in virulence between strains isolated from human cases and carriers

1984 ◽  
Vol 30 (8) ◽  
pp. 1042-1045 ◽  
Author(s):  
Irving E. Salit ◽  
Lewis Tomalty
Keyword(s):  
Animal Model ◽  
Cerebrospinal Fluid ◽  
Mouse Model ◽  
Meningococcal Disease ◽  
Meningococcal Infection ◽  
Iron Dextran ◽  
Nasopharyngeal Colonization ◽  
Intranasal Inoculation ◽  
Suitable Animal Model ◽  
Colonization Rates

The lack of availability of a suitable animal model has limited understanding of the pathophysiology of meningococcal disease. We have utilized a neonatal mouse model in which atraumatic intranasal inoculation of meningococci results in nasopharyngeal colonization and ultimately bacteremia. Using this model, we compared the virulence of seven encapsulated meningococcal carrier strains with eight meningococcal strains which were isolated from cerebrospinal fluid or blood of patients (disease strains). Intraperitoneal (IP) iron dextran was given to some animals to enhance meningococcal virulence. After IP iron, carrier strains were still poorly invasive with rates of bacteremia ranging from 0 to 15% (mean = 3%), whereas disease-associated strains were significantly more invasive and caused bacteremia in 31–64% of animals (mean = 39%). Without iron injections, nasopharyngeal colonization rates were similar (36 versus 30%, P > 0.1) for case and carrier strains IP iron dextran significantly enhanced rates of colonization and bacteremia caused by the disease strains only. We have therefore, shown that the relative virulence of meningococcal strains for humans is maintained in this experimental model.

scholarly journals Immunization with the Recombinant PorB Outer Membrane Protein Induces a Bactericidal Immune Response against Neisseria meningitidis

2002 ◽  
Vol 70 (8) ◽  
pp. 4028-4034 ◽  
Author(s):  
J. Claire Wright ◽  
Jeannette N. Williams ◽  
Myron Christodoulides ◽  
John E. Heckels
Keyword(s):  
Recombinant Protein ◽  
Neisseria Meningitidis ◽  
Outer Membrane ◽  
Lipid A ◽  
Meningococcal Infection ◽  
Native Protein ◽  
Monophosphoryl Lipid A ◽  
Porin Protein ◽  
Life Threatening ◽  
Porin Proteins

ABSTRACT Infections with Neisseria meningitidis are characterized by life-threatening meningitis and septicemia. The meningococcal porin proteins from serogroup B meningococci have been identified as candidates for inclusion in vaccines to prevent such infections. In this study, we investigated the vaccine potential of the PorB porin protein free of other meningococcal components. The porB gene from a strain of Neisseria meningitidis expressing the class 3 outer membrane porin protein (PorB3) was cloned into the pRSETB vector, and the protein was expressed at high levels in a heterologous host Escherichia coli. The recombinant protein was purified to homogeneity by affinity chromatography and used for immunization after incorporation into liposomes and into micelles composed either of zwitterionic detergent or nondetergent sulfobetaine. The immunogenicity of these preparations was compared to recombinant PorB protein adsorbed to Al(OH)3 adjuvant as a control. Although sera raised against the protein adsorbed to Al(OH)3 reacted with the purified recombinant protein, sera raised against liposomes and micelles showed greater activity with native protein, as measured by enzyme immunoassay with outer membranes and by whole-cell immunofluorescence. Reactivity with native protein was considerably enhanced by incorporation of the adjuvant monophosphoryl lipid A into the liposome or micelle preparations. Recognition of the native protein was in a serotype-specific manner and was associated with the ability of the antisera to promote high levels of serotype-specific complement-mediated killing of meningococci. These results demonstrate that the PorB protein should be considered as a component of a vaccine designed to prevent serogroup B meningococcal infection.

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