Ulrich Vogel
Research interests
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InterestsMicrobial Pathogenesis, Population Biology, Medical Microbiology, Molecular Epidemiology
Publications
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0.45Impact points
[Infections with Pneumococci, Menigococci, H. influenzae and Diphtheria in Germany: the RKI Reference Network for Invasive Bacterial Infections (IBI) at the 5th Würzburg Workshop on Epidemiology, Prevention and Therapy for Invasive Meningococcal Diseases 2010 (Meeting Report).]
Gesundheitswesen (Bundesverband der Arzte des Offentlichen Gesundheitsdienstes (Germany)). 12/2011;
The surveillance and prevention of invasive bacterial infections requires flexible strategic coordination of all involved health-care professionals. For this purpose, the German National Reference Centres for Meningococci, Streptococci and the Consultant Laboratories for Haemophilus influenzae and d... [more] The surveillance and prevention of invasive bacterial infections requires flexible strategic coordination of all involved health-care professionals. For this purpose, the German National Reference Centres for Meningococci, Streptococci and the Consultant Laboratories for Haemophilus influenzae and diphtheria have formed the Reference Network for Invasive bacterial infections (IBI). The 5th Würzburg Workshop on Meningococcal Diseases 2010 provided the network with a forum for the interdisciplinary exchange between scientists, public health professionals, medical microbiologists and clinicians. The topics covered the analysis of surveillance data for meningococcal disease in the last decade, as well as methods to control for antibody response following vaccination, including a serum bactericidal antibody (SBA) assay, and the development of new vaccines that also include the most common serogroup B. The presentation on diphtheria showed that this rare disease in Germany has become a diagnostic challenge, and that apart from the classical pathogen also toxigenic C. ulcerans strains must be considered. Due to the successful vaccination against Hib, H. influenzae disease has changed from a classical childhood disease to an infection of elderly people mainly caused by unencapsulated strains. Following the introduction of vaccines, changes in the serotype distribution and antibiotic resistance profiles have become apparent for S. pneumoniae infections. The epidemiological data were complemented by clinical aspects concerning the vaccination of immunocompromised children.
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3.62Impact points
Capsule null locus meningococci: typing of antigens used in an investigational multicomponent meningococcus serogroup B vaccine.
Vaccine. 11/2011; 30(2):155-60.
The investigational multicomponent meningococcus serogroup B vaccine (4CMenB) targets the antigenetically variable population of serogroup B meningococci. Forty-one strains of capsule null locus (cnl) meningococci, which are frequent among healthy carriers, were selected from nine sequence types (ST... [more] The investigational multicomponent meningococcus serogroup B vaccine (4CMenB) targets the antigenetically variable population of serogroup B meningococci. Forty-one strains of capsule null locus (cnl) meningococci, which are frequent among healthy carriers, were selected from nine sequence types (ST), which belong to four clonal complexes (cc), and three countries. They were antigen sequence typed and analyzed for antigen expression to predict whether these strains harbor the genes and express the four vaccine antigens of 4CMenB as measured by the meningococcal antigen typing system (MATS). The PorA variant used in the vaccine was not found. The nadA gene was absent in all but one strain, which did not express the antigen in vitro. Only strains of clonal complex ST-198 harbored a factor H binding protein (FHBP) allele of the cross-reactive variant 1 family which is included in the vaccine. All these strains expressed the antigen. Five variants of the Neisserial heparin binding antigen (NHBA) gene were identified. Expression of NHBA was observed in all strains with highest levels in ST-198 cc and ST-845. The data suggest a potential impact of 4CMenB immunization at least on cnl meningococci of the ST-198 cc and ST-845.
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1.57Impact points
Immunogenicity of meningococcus C vaccination in a patient with atypical hemolytic uremic syndrome (aHUS) on eculizumab therapy.
Pediatric transplantation. 10/2011;
Zlamy M, Hofer J, Elias J, Vogel U, Frosch M, Jungraithmayr T, Zimmerhackl LB, Prelog M. Immunogenicity of meningococcus C vaccination in a patient with atypical hemolytic uremic syndrome (aHUS) on eculizumab therapy. Pediatr Transplantation 2011. © 2011 John Wiley & Sons A/S. Abstract: We repo... [more] Zlamy M, Hofer J, Elias J, Vogel U, Frosch M, Jungraithmayr T, Zimmerhackl LB, Prelog M. Immunogenicity of meningococcus C vaccination in a patient with atypical hemolytic uremic syndrome (aHUS) on eculizumab therapy. Pediatr Transplantation 2011. © 2011 John Wiley & Sons A/S. Abstract: We report successful kidney transplantation in a 10-yr-old boy with aHUS and heterozygous factor H mutation using the terminal complement inhibitor eculizumab to avoid recurrence of aHUS in the renal graft. Vaccination against meningococcus C (Men C) is essential in patients with dysfunction of the complement system, as induced by eculizumab. In our patient, we report waning SBA titers but maintenance of protective SBA titers (≥1:8) after kidney transplantation under immunosuppressive therapy with mycophenolate mofetil, tacrolimus, steroids, and eculizumab over a 27-month observational period. Our case illustrates that a humoral immune response to conjugate Men C vaccination may be mounted and maintained despite chronic renal disease, kidney transplantation, immunosuppressive drugs, and immunomodulatory therapy with eculizumab. However, it remains unclear whether serologically defined protective SBA titers mediate true protection from invasive meningococcal disease in an immunocompromised patient, particularly under treatment with a complement inhibitor. Thus, close monitoring of SBA titers seems mandatory in this patient.
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3.62Impact points
Immunogenicity of conjugate meningococcus C vaccine in pediatric solid organ transplant recipients.
Vaccine. 06/2011; 29(37):6163-6.
The present study was aimed to evaluate the immunogenicity of a single dose of conjugate Meningococcus C (Men C) vaccine by analyzing the serum bactericidal antibody (SBA) titers in 10 pediatric solid organ transplant (SOT) patients. Four patients showed a delayed immune response after 1 month, but ... [more] The present study was aimed to evaluate the immunogenicity of a single dose of conjugate Meningococcus C (Men C) vaccine by analyzing the serum bactericidal antibody (SBA) titers in 10 pediatric solid organ transplant (SOT) patients. Four patients showed a delayed immune response after 1 month, but all patients demonstrated an increase of SBA titers after vaccination. A significant decrease of SBA titers was seen after 6 months. However, all patients maintained protective SBA titers (≥1:8) despite rapidly waning titers. For patients with significantly decreasing titers, a booster dose may be discussed with close monitoring of SBA titers over time.
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2.15Impact points
Sequence analysis of serotype-specific synthesis regions II of Haemophilus influenzae serotypes c and d: evidence for common ancestry of capsule synthesis in Pasteurellaceae and Neisseria meningitidis.
Research in microbiology. 06/2011; 162(5):483-7.
Sequencing of yet unknown Haemophilus influenzae serotype c (Hic) and d (Hid) capsule synthesis regions II revealed four (ccs1-4) and five (dcs1-5) open reading frames, respectively. The inferred gene functions were in line with capsular polysaccharide structures. One or more proteins encoded by the... [more] Sequencing of yet unknown Haemophilus influenzae serotype c (Hic) and d (Hid) capsule synthesis regions II revealed four (ccs1-4) and five (dcs1-5) open reading frames, respectively. The inferred gene functions were in line with capsular polysaccharide structures. One or more proteins encoded by the Hic capsule synthesis region II showed similarity to Actinobacillus pleuropneumoniae serotype 1 and Actinobacillus suis K1 enzymes. Orthologues to the complete operon were observed in Actinobacillus minor strain 202, where even the gene order was conserved. Furthermore, Ccs4 was related to the capsule O-acetyltransferase of Neisseria meningitidis serogroup W-135. For the Hid locus, similarities to Hie, Mannheimia haemolytica A1 and N. meningitidis serogroup A were identified and the succession of genes was similar in the different species. The resemblance of genes and gene organization found for Hic and Hid with other species suggested horizontal gene transfer during capsule evolution across the bacterial classes.
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4.41Impact points
Virulence evolution of the human pathogen Neisseria meningitidis by recombination in the core and accessory genome.
PloS one. 01/2011; 6(4):e18441.
Neisseria meningitidis is a naturally transformable, facultative pathogen colonizing the human nasopharynx. Here, we analyze on a genome-wide level the impact of recombination on gene-complement diversity and virulence evolution in N. meningitidis. We combined comparative genome hybridization using ... [more] Neisseria meningitidis is a naturally transformable, facultative pathogen colonizing the human nasopharynx. Here, we analyze on a genome-wide level the impact of recombination on gene-complement diversity and virulence evolution in N. meningitidis. We combined comparative genome hybridization using microarrays (mCGH) and multilocus sequence typing (MLST) of 29 meningococcal isolates with computational comparison of a subset of seven meningococcal genome sequences. We found that lateral gene transfer of minimal mobile elements as well as prophages are major forces shaping meningococcal population structure. Extensive gene content comparison revealed novel associations of virulence with genetic elements besides the recently discovered meningococcal disease associated (MDA) island. In particular, we identified an association of virulence with a recently described canonical genomic island termed IHT-E and a differential distribution of genes encoding RTX toxin- and two-partner secretion systems among hyperinvasive and non-hyperinvasive lineages. By computationally screening also the core genome for signs of recombination, we provided evidence that about 40% of the meningococcal core genes are affected by recombination primarily within metabolic genes as well as genes involved in DNA replication and repair. By comparison with the results of previous mCGH studies, our data indicated that genetic structuring as revealed by mCGH is stable over time and highly similar for isolates from different geographic origins. Recombination comprising lateral transfer of entire genes as well as homologous intragenic recombination has a profound impact on meningococcal population structure and genome composition. Our data support the hypothesis that meningococcal virulence is polygenic in nature and that differences in metabolism might contribute to virulence.
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4.43Impact points
Comparative proteomic analysis of biofilm and planktonic cells of Neisseria meningitidis.
Proteomics. 12/2010; 10(24):4512-21.
Neisseria meningitidis is a commensal of the human nasopharynx occasionally causing invasive disease. In vitro biofilms have been employed to model meningococcal carriage. A proteomic analysis of meningococcal biofilms was conducted and metabolic changes related to oxygen and nutrient limitation and... [more] Neisseria meningitidis is a commensal of the human nasopharynx occasionally causing invasive disease. In vitro biofilms have been employed to model meningococcal carriage. A proteomic analysis of meningococcal biofilms was conducted and metabolic changes related to oxygen and nutrient limitation and upregulation of proteins involved in ROS defense were observed. The upregulated MntC which protects against ROS was shown to be required for meningococcal biofilm formation, but not for planktonic growth. ROS-induced proteomic changes might train the biofilm to cope with immune effectors.
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New diagnostic PCR for Haemophilus influenzae serotype e based on the cap locus of strain ATCC 8142
Int.J.Med.Microbiol. 10/2010;
A new PCR protocol for molecular typing of Haemophilus influenzae serotype e (Hie) was developed. To this end, the sequence of the cap region II of Hie strain ATCC8142 was identified, which was >99% identical to the recently published sequence of Hie isolate 274. The PCR using primer pair TTL63/T... [more] A new PCR protocol for molecular typing of Haemophilus influenzae serotype e (Hie) was developed. To this end, the sequence of the cap region II of Hie strain ATCC8142 was identified, which was >99% identical to the recently published sequence of Hie isolate 274. The PCR using primer pair TTL63/TTL64 amplifies an internal 592-bp fragment of ecs4, an e-specific capsule synthesis gene, in 40 of 40 Hie strains. Of all non-Hie strains, there were no false positives. False-negative results of the PCR proposed by Falla et al. (1994) are explained by single nucleotide insertions in the primer sequences
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Panton-Valentine leukocidin-positive Staphylococcus aureus infections in returning travelers
Am.J.Trop.Med.Hyg. 10/2010; 83.
Skin and soft tissue infections caused by Panton-Valentine leukocidin-producing strains of Staphylococcus aureus are emerging among travelers returning from the tropics. Here, we here present data on 15 affected individuals. Intrafamiliar spread was documented in one case, and occupational transmiss... [more] Skin and soft tissue infections caused by Panton-Valentine leukocidin-producing strains of Staphylococcus aureus are emerging among travelers returning from the tropics. Here, we here present data on 15 affected individuals. Intrafamiliar spread was documented in one case, and occupational transmission was assumed in another. Spa typing of the strains revealed a broad spectrum of variants, but some were clonally related. Methicillin-resistant Staphylococcus aureus (MRSA) was found in three cases
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2.80Impact points
Panton-Valentine leukocidin-positive Staphylococcus aureus infections in returning travelers.
The American journal of tropical medicine and hygiene. 10/2010; 83(4):748-50.
Skin and soft tissue infections caused by Panton-Valentine leukocidin-producing strains of Staphylococcus aureus are emerging among travelers returning from the tropics. Here, we here present data on 15 affected individuals. Intrafamiliar spread was documented in one case, and occupational transmiss... [more] Skin and soft tissue infections caused by Panton-Valentine leukocidin-producing strains of Staphylococcus aureus are emerging among travelers returning from the tropics. Here, we here present data on 15 affected individuals. Intrafamiliar spread was documented in one case, and occupational transmission was assumed in another. Spa typing of the strains revealed a broad spectrum of variants, but some were clonally related. Methicillin-resistant Staphylococcus aureus (MRSA) was found in three cases.
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2.80Impact points
New diagnostic PCR for Haemophilus influenzae serotype e based on the cap locus of strain ATCC 8142.
International journal of medical microbiology : IJMM. 10/2010; 301(2):176-9.
A new PCR protocol for molecular typing of Haemophilus influenzae serotype e (Hie) was developed. To this end, the sequence of the cap region II of Hie strain ATCC8142 was identified, which was >99% identical to the recently published sequence of Hie isolate 274. The PCR using primer pair TTL63/T... [more] A new PCR protocol for molecular typing of Haemophilus influenzae serotype e (Hie) was developed. To this end, the sequence of the cap region II of Hie strain ATCC8142 was identified, which was >99% identical to the recently published sequence of Hie isolate 274. The PCR using primer pair TTL63/TTL64 amplifies an internal 592-bp fragment of ecs4, an e-specific capsule synthesis gene, in 40 of 40 Hie strains. Of all non-Hie strains, there were no false positives. False-negative results of the PCR proposed by Falla et al. (1994) are explained by single nucleotide insertions in the primer sequences.
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4.01Impact points
Nosocomial outbreak of VIM-2 metallo-β-lactamase-producing Pseudomonas aeruginosa associated with retrograde urography.
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 09/2010; 16(9):1494-500.
Pseudomonas aeruginosa is well adapted to the hospital setting and can cause a wide array of nosocomial infections that occasionally culminate in recalcitrant outbreaks. In the present study, we describe the first nosocomial outbreak of infection caused by bla(VIM-2)-positive P. aeruginosa in German... [more] Pseudomonas aeruginosa is well adapted to the hospital setting and can cause a wide array of nosocomial infections that occasionally culminate in recalcitrant outbreaks. In the present study, we describe the first nosocomial outbreak of infection caused by bla(VIM-2)-positive P. aeruginosa in Germany. In November and December 2007, highly resistant P. aeruginosa isolates were recovered from the urine of 11 patients in the Department of Urology of a University Hospital. Bacterial isolates were typed by multilocus sequence typing and screened for known metallo-β-lactamase (MBL) genes by PCR. Environmental sources of transmission were tested for bacterial contamination using surveillance cultures. Furthermore, a matched case-control study was performed in search of medical procedures significantly associated with case status. Typing of recovered isolates confirmed VIM-2 MBL-producing P. aeruginosa of sequence type 175 in all cases. Surveillance cultures did not lead to the identification of an environmental source of the outbreak strain. Case-control analysis revealed retrograde urography as the only exposure significantly associated with case status. The analyses suggest the transmission of a single clone of VIM-2 MBL-producing P. aeruginosa leading to the infection of 11 patients within 47 days. Events in temporal proximity to retrograde urographies appear to have facilitated infection in the majority of cases. Department-specific infection control measures, including reinforced hygiene procedures during retrograde urography, quickly terminated the outbreak.
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4.16Impact points
Molecular discrimination between Neisseria meningitidis serogroups W-135 and Y based on the nucleotide recognition domain sequence of the capsule polymerases.
Journal of clinical microbiology. 09/2010; 48(9):3459-60.
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4.80Impact points
Multicenter study for defining the breakpoint for rifampin resistance in Neisseria meningitidis by rpoB sequencing.
Antimicrobial agents and chemotherapy. 09/2010; 54(9):3651-8.
Identification of clinical isolates of Neisseria meningitidis that are resistant to rifampin is important to avoid prophylaxis failure in contacts of patients, but it is hindered by the absence of a breakpoint for resistance, despite many efforts toward standardization. We examined a large number (n... [more] Identification of clinical isolates of Neisseria meningitidis that are resistant to rifampin is important to avoid prophylaxis failure in contacts of patients, but it is hindered by the absence of a breakpoint for resistance, despite many efforts toward standardization. We examined a large number (n = 392) of clinical meningococcal isolates, spanning 25 years (1984 to 2009), that were collected in 11 European countries, Argentina, and the Central African Republic. The collection comprises all clinical isolates with MICs of > or = 0.25 mg/liter (n = 161) received by the national reference laboratories for meningococci in the participating countries. Representative isolates displaying rifampin MICs of < 0.25 mg/liter were also examined (n = 231). Typing of isolates was performed, and a 660-bp DNA fragment of the rpoB gene was sequenced. Sequences differing by at least one nucleotide were defined as unique rpoB alleles. The geometric mean of the MICs was calculated for isolates displaying the same allele. The clinical isolates displaying rifampin MICs of > 1 mg/liter possessed rpoB alleles with nonsynonymous mutations at four critical amino acid residues, D542, H552, S548, and S557, that were absent in the alleles found in all isolates with MICs of < or = 1 mg/liter. Rifampin-susceptible isolates could be defined as those with MICs of < or = 1 mg/liter. The rpoB allele sequence and isolate data have been incorporated into the PubMLST Neisseria database (http://pubmlst.org/neisseria/). The rifampin-resistant isolates belonged to diverse genetic lineages and were associated with lower levels of bacteremia and inflammatory cytokines in mice. This biological cost may explain the lack of clonal expansion of these isolates.
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Vaccine development against Neisseria meningitidis.
Microbial biotechnology. 05/2010; 4(1):20-31.
Meningococcal disease is communicable by close contact or droplet aerosols. Striking features are high case fatality rates and peak incidences of invasive disease in infants, toddlers and adolescents. Vaccine development is hampered by bacterial immune evasion strategies including molecular mimicry.... [more] Meningococcal disease is communicable by close contact or droplet aerosols. Striking features are high case fatality rates and peak incidences of invasive disease in infants, toddlers and adolescents. Vaccine development is hampered by bacterial immune evasion strategies including molecular mimicry.As for Haemophilus influenzae and Streptococcus pneumoniae, no vaccine has therefore been developed that targets all serogroups of Neisseria meningitidis. Polysaccharide vaccines available both in protein conjugated and non-conjugated form, have been introduced against capsular serogroups A, C,W-135 and Y, but are ineffective against serogroup B meningococci, which cause a significant burden of disease in many parts of the world. Detoxified outer membrane vesicles are used since decades to elicit protection against epidemic serogroup B disease. Genome mining and biochemical approaches have provided astounding progress recently in the identification of immunogenic, yet reasonably conserved outer membrane proteins. As subcapsular proteins nevertheless are unlikely to immunize against all serogroup B variants, thorough investigation by surrogate assays and molecular epidemiology approaches are needed prior to introduction and post-licensure of protein vaccines. Research currently addresses the analysis of life vaccines, meningococcus B polysaccharide modifications and mimotopes, as well as the use of N. lactamica outer membrane vesicles.
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3.77Impact points
Biofilm formation by the human pathogen Neisseria meningitidis.
Medical microbiology and immunology. 04/2010; 199(3):173-83.
The past decade has seen an increasing interest in biofilm formation by Neisseria meningitidis, a human facultative pathogen causing life-threatening childhood disease commencing from asymptomatic nasopharyngeal colonization. Studying the biology of in vitro biofilm formation improves the understand... [more] The past decade has seen an increasing interest in biofilm formation by Neisseria meningitidis, a human facultative pathogen causing life-threatening childhood disease commencing from asymptomatic nasopharyngeal colonization. Studying the biology of in vitro biofilm formation improves the understanding of inter-bacterial processes in asymptomatic carriage, of bacterial aggregate formation on host cells, and of meningococcal population biology. This paper reviews publications referring to meningococcal biofilm formation with an emphasis on the role of motility and of extracellular DNA. The theory of sub-dividing the meningococcal population in settler and spreader lineages is discussed, which provides a mechanistic framework for the assumed balance of colonization efficacy and transmission frequency.
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6.79Impact points
Vaccine preventability of meningococcal clone, Greater Aachen Region, Germany.
Emerging infectious diseases. 03/2010; 16(3):465-72.
Emergence of serogroup B meningococci of clonal complex sequence type (ST) 41/44 can cause high levels of disease, as exemplified by a recent epidemic in New Zealand. Multiplication of annual incidence rates (3.1 cases/100,000 population) of meningococcal disease in a defined German region, the city... [more] Emergence of serogroup B meningococci of clonal complex sequence type (ST) 41/44 can cause high levels of disease, as exemplified by a recent epidemic in New Zealand. Multiplication of annual incidence rates (3.1 cases/100,000 population) of meningococcal disease in a defined German region, the city of Aachen and 3 neighboring countries (Greater Aachen) prompted us to investigate and determine the source and nature of this outbreak. Using molecular typing and geographic mapping, we analyzed 1,143 strains belonging to ST41/44 complex, isolated from persons with invasive meningococcal disease over 6 years (2001-2006) from 2 German federal states (total population 26 million) and the Netherlands. A spatially slowly moving clone with multiple-locus variable-number tandem repeat analysis type 19, ST42, and antigenic profile B:P1.7-2,4:F1-5 was responsible for the outbreak. Bactericidal activity in serum samples from the New Zealand MeNZB vaccination campaign confirmed vaccine preventability. Because this globally distributed epidemic strain spreads slowly, vaccination efforts could possibly eliminate meningococcal disease in this area.
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5.36Impact points
A dual role of extracellular DNA during biofilm formation of Neisseria meningitidis.
Molecular microbiology. 02/2010; 75(6):1355-71.
Major pathogenic clonal complexes (cc) of Neisseria meningitidis differ substantially in their point prevalence among healthy carriers. We show that frequently carried pathogenic cc (e.g. sequence type ST-41/44 cc and ST-32 cc) depend on extracellular DNA (eDNA) to initiate in vitro biofilm formatio... [more] Major pathogenic clonal complexes (cc) of Neisseria meningitidis differ substantially in their point prevalence among healthy carriers. We show that frequently carried pathogenic cc (e.g. sequence type ST-41/44 cc and ST-32 cc) depend on extracellular DNA (eDNA) to initiate in vitro biofilm formation, whereas biofilm formation of cc with low point prevalence (ST-8 cc and ST-11 cc) was eDNA-independent. For initial biofilm formation, a ST-32 cc type strain, but not a ST-11 type strain, utilized eDNA. The release of eDNA was mediated by lytic transglycosylase and cytoplasmic N-acetylmuramyl-L-alanine amidase genes. In late biofilms, outer membrane phospholipase A-dependent autolysis, which was observed in most cc, but not in ST-8 and ST-11 strains, was required for shear force resistance of microcolonies. Taken together, N. meningitidis evolved two different biofilm formation strategies, an eDNA-dependent one yielding shear force resistant microcolonies, and an eDNA-independent one. Based on the experimental findings and previous epidemiological observations, we hypothesize that most meningococcal cc display a settler phenotype, which is eDNA-dependent and results in a stable interaction with the host. On the contrary, spreaders (ST-11 and ST-8 cc) are unable to use eDNA for biofilm formation and might compensate for poor colonization properties by high transmission rates.
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Molecular epidemiology of meningococci: Application of DNA sequence typing
Int.J.Med.Microbiol. 01/2010; epub ahead of print.
Neisseria meningitidis is an invasive pathogen contributing significantly to childhood mortality worldwide. The organism is adapted to the human host and transmitted by close contact or droplet aerosols. In comparison to healthy carriage, invasive disease is a rare event. Nevertheless, due to a high... [more] Neisseria meningitidis is an invasive pathogen contributing significantly to childhood mortality worldwide. The organism is adapted to the human host and transmitted by close contact or droplet aerosols. In comparison to healthy carriage, invasive disease is a rare event. Nevertheless, due to a high case-fatality rate and the fact that meningococcal infection is a communicable disease, molecular typing of meningococci has been driven forward considerably in the past decades. Multilocus and antigen sequence typing data are assembled in large databases accessible via the internet. For epidemiological purposes, representative case ascertainment strategies are necessary if data are to be exploited for trend analysis, geographic visualization, detection of abnormalities such as outbreaks, and prediction of vaccine coverage. In Europe, a consensus for molecular typing has been achieved
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8.98Impact points
The meningococcal vaccine candidate neisserial surface protein A (NspA) binds to factor H and enhances meningococcal resistance to complement.
PLoS pathogens. 01/2010; 6(7):e1001027.
Complement forms an important arm of innate immunity against invasive meningococcal infections. Binding of the alternative complement pathway inhibitor factor H (fH) to fH-binding protein (fHbp) is one mechanism meningococci employ to limit complement activation on the bacterial surface. fHbp is a l... [more] Complement forms an important arm of innate immunity against invasive meningococcal infections. Binding of the alternative complement pathway inhibitor factor H (fH) to fH-binding protein (fHbp) is one mechanism meningococci employ to limit complement activation on the bacterial surface. fHbp is a leading vaccine candidate against group B Neisseria meningitidis. Novel mechanisms that meningococci employ to bind fH could undermine the efficacy of fHbp-based vaccines. We observed that fHbp deletion mutants of some meningococcal strains showed residual fH binding suggesting the presence of a second receptor for fH. Ligand overlay immunoblotting using membrane fractions from one such strain showed that fH bound to a approximately 17 kD protein, identified by MALDI-TOF analysis as Neisserial surface protein A (NspA), a meningococcal vaccine candidate whose function has not been defined. Deleting nspA, in the background of fHbp deletion mutants, abrogated fH binding and mAbs against NspA blocked fH binding, confirming NspA as a fH binding molecule on intact bacteria. NspA expression levels vary among strains and expression correlated with the level of fH binding; over-expressing NspA enhanced fH binding to bacteria. Progressive truncation of the heptose (Hep) I chain of lipooligosaccharide (LOS), or sialylation of lacto-N-neotetraose LOS both increased fH binding to NspA-expressing meningococci, while expression of capsule reduced fH binding to the strains tested. Similar to fHbp, binding of NspA to fH was human-specific and occurred through fH domains 6-7. Consistent with its ability to bind fH, deleting NspA increased C3 deposition and resulted in increased complement-dependent killing. Collectively, these data identify a key complement evasion mechanism with important implications for ongoing efforts to develop meningococcal vaccines that employ fHbp as one of its components.
Following (33)
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Johannes Schnitzer
Institute for molecular infection biology -
Marie-Christin Pawlik
Julius-Maximilians-Universität Würzburg -
Uwe Völker
Ernst-Moritz-Arndt-Universität Greifswald -
Nicole von Maltzahn
Institute for Med. Microbiology, Hannover Medical School -
Sven Hammerschmidt
Interfaculty Institute for Genetics and Functional Genomics
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