Dataset Information

Serum resistance of Neisseria meningitidis strains of the ST-41/44 clonal complex is influenced by a homopolymeric adenosine tract in the promotor region of the nspA gene

ABSTRACT: Although usually a harmless colonizer of the human nasopharynx, Neisseria meningitidis (meningococcus) can spread to the blood stream and cause invasive disease. For survival in blood, N. meningitidis evades the complement system by expression of a polysaccharide capsule and surface proteins sequestering the complement regulator fH. Meningococcal strains are highly diverse and are categorized by their serogroup and multilocus sequence typing. The sequence type 41/44 clonal complex makes up a major proportion of serogroup B meningococcal disease worldwide, but it is also common in asymptomatic carriers. Proteome analysis of a serum resistant isolate from invasive meningococcal disease and two less resistant isolates from healthy carriers identified NspA as the sole protein consistently expressed more abundantly in the invasive isolate. Knock-out of nspA reduced serum resistance, accompanied by stronger deposition of membrane attack complex (C5b9). High or low expression of NspA was associated with sequence variation within a homopolymeric tract located in the -10/-35 region of the nspA promotor: A tract with 5 adenosines dictated low NspA expression, whereas a 6-adenosine motif led to high NspA expression. High levels of NspA correlated with high factor H sequestration onto the bacteria. We could not link the homopolymeric tract length to phase variation, unlike described for other N. meningitidis surface proteins with similar sequence motifs. Epidemiological evidence from carriage and disease isolates indicates that NspA contributes to serum resistance, but is not a prerequisite for invasive disease. Thus, the lineage ST-41/44 meningococcal strains are heterogenous in their NspA expression.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Neisseria Meningitidis

SUBMITTER: Andreas Otto

LAB HEAD: Prof. Dr. Becher

PROVIDER: PXD010505 | Pride | 2019-02-28

REPOSITORIES: Pride

ACCESS DATA

Publications

A homopolymeric adenosine tract in the promoter region of nspA influences factor H-mediated serum resistance in Neisseria meningitidis.

Claus Heike H Hubert Kerstin K Becher Dörte D Otto Andreas A Pawlik Marie-Christin MC Lappann Ines I Strobel Lea L Vogel Ulrich U Johswich Kay K

Scientific reports 20190225 1

Although usually asymptomatically colonizing the human nasopharynx, the Gram-negative bacterium Neisseria meningitidis (meningococcus) can spread to the blood stream and cause invasive disease. For survival in blood, N. meningitidis evades the complement system by expression of a polysaccharide capsule and surface proteins sequestering the complement regulator factor H (fH). Meningococcal strains belonging to the sequence type (ST-) 41/44 clonal complex (cc41/44) cause a major proportion of sero ...[more]

PMID: 30804422

Similar Datasets

Project description:Vaccines to prevent capsular group B meningococcal disease have been based on proteins, as the polysaccharide capsule was deemed unsuitable due to its similarity to human tissues. Outer membrane vesicle (OMV) vaccines have been targeted at specific capsular group B epidemics in Cuba, Norway, and New Zealand, with the major immunogen determined as porin A (PorA). Subcapsular protein vaccines aim to increase breadth of coverage of meningococcal strains, by the inclusion of protein variants from many different clonal complexes (ccs). Using scalable and portable genomic techniques, it is possible to study the diversity of OMV and subcapsular proteins in relevant meningococcal populations. Shotgun proteomics identified 461 proteins in the OMVs derived from NZ98/254, a component of the Bexsero® vaccine, with a complex proteome comprised of outer membrane proteins and proteins from other cellular compartments. Amino acid sequences for 24 selected proteins were catalogued within the PubMLST Neisseria database as part of the OMV peptide Typing (OMVT) scheme. Of the 24 proteins included, there was variation in the extent of diversity and association with ccs from the most conserved peptides FbpA (NEISp0578) and putative periplasmic proteins (NEISp1063) to the most diverse TbpA (NEISp1690). There were 1752 OMVTs identified amongst 2492/3506 isolates. OMVTs were further grouped into clusters (identical at ≥18 peptide sequences), 45.3% of isolates were assigned to one of 27 OMVT clusters. Both OMVTs and clusters were strongly associated with cc, genogroup and recombinant Bexsero® antigens. The OMVT scheme represents an open-access, web-based tool for the systematic analysis of the multiple components of OMV vaccines, demonstrating that combinations of OMV proteins exist in discrete, non-overlapping combinations associated with both genogroup and Bexsero® Antigen Sequence type (BAST). This highly structured population of disease-causing meningococci is consistent with proposed effects of host immune selection and competition between allelic variants on meningococcal population structure. This has implications for future vaccine assessment, and development, especially the choice of antigen combinations. The methodology is portable and will facilitate region-specific WGS interrogation, allowing informed choices about vaccine development or implementation.

Project description:Background: Biological interpretation of gene expression data may differ depending on underlying assumptions and statistical tests used by the chosen bioinformatic tool. We used Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) to analyze previously generated gene expression profiles induced in human monocytes by N. meningitidis and IL-10 (“the model system”), and by meningococcal sepsis plasma before and after immunodepletion of IL-10 (“the patient plasma system”). The objectives were to compare whether these two methods resulted in similar biological interpretation of the datasets; and identify whether GSEA provided additional insight about the human monocyte host response to meningococcal activation. Results: In both experimental models, GSEA and IPA associated genes induced in monocytes by N. meningitidis with pro-inflammatory innate immune activation, including TNF-signaling, Toll-like receptor signaling, JAK-STAT-signaling, type I and type II interferon. GSEA associated genes regulated by the presence of IL-10 with similar gene sets in both the model system and the patient plasma system. In the model system, GSEA and IPA identified 170 genes associated with oxidative phosphorylation/mitochondrial function to be down-regulated in monocytes stimulated with meningococci. In the patient plasma system, GSEA and IPA combined identified 122 genes associated with oxidative phosphorylation/mitochondrial dysfunction to be down-regulated by meningococcal sepsis plasma depleted for IL-10. Combining analyses from GSEA and IPA identified that some genes associated with oxidative phosphorylation/mitochondrial function that were inhibited by N. meningitidis were partially up-regulated by IL-10. Conclusions: Biological processes associated with the gene expression changes in the model system of meningococcal sepsis was comparable to the results found in the patient plasma system. By combining GSEA with IPA, we have discovered an inhibitory effect exerted by N. meningitidis on genes associated with oxidative phosphorylation, and that IL-10 possibly partially dampen this strong inhibitory effect, thereby identifying, to our knowledge, yet another area where IL-10 regulates the effect of LPS. We suggest that relying on a single bioinformatic tool together with arbitrarily chosen filtering criteria for data analysis may result in overlooking relevant biological processes and signaling pathways associated with genes differentially expressed between compared experimental conditions.

Dataset Information

Serum resistance of Neisseria meningitidis strains of the ST-41/44 clonal complex is influenced by a homopolymeric adenosine tract in the promotor region of the nspA gene

Publications

A homopolymeric adenosine tract in the promoter region of nspA influences factor H-mediated serum resistance in Neisseria meningitidis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure