Abstract
Neisseria meningitidis is a human nasopharyngeal commensal capable of causing life-threatening septicemia and meningitis. Many meningococcal surface structures, including the autotransporter proteins NalP and MspA, are subject to phase variation (PV) due to the presence of homopolymeric tracts within their coding sequences. The functions of MspA are unknown. NalP proteolytically cleaves several surface-located virulence factors including the 4CMenB antigen NhbA. Therefore, NalP is a phase-variable regulator of the meningococcal outer membrane and secretome whose expression may reduce isolate susceptibility to 4CMenB-induced immune responses. To improve our understanding of the contributions of MspA and NalP to meningococcal-host interactions, their distribution and phase-variable expression status was studied in epidemiologically relevant samples, including 127 carriage and 514 invasive isolates representative of multiple clonal complexes and serogroups. Prevalence estimates of >98% and >88% were obtained for mspA and nalP, respectively, with no significant differences in their frequencies in disease versus carriage isolates. 16% of serogroup B (MenB) invasive isolates, predominately from clonal complexes ST-269 and ST-461, lacked nalP. Deletion of nalP often resulted from recombination events between flanking repetitive elements. PolyC tract lengths ranged from 6–15 bp in nalP and 6–14 bp in mspA. In an examination of PV status, 58.8% of carriage, and 40.1% of invasive nalP-positive MenB isolates were nalP phase ON. The frequency of this phenotype was not significantly different in serogroup Y (MenY) carriage strains, but was significantly higher in invasive MenY strains (86.3%; p<0.0001). Approximately 90% of MenB carriage and invasive isolates were mspA phase ON; significantly more than MenY carriage (32.7%) or invasive (13.7%) isolates. This differential expression resulted from different mode mspA tract lengths between the serogroups. Our data indicates a differential requirement for NalP and MspA expression in MenB and MenY strains and is a step towards understanding the contributions of phase-variable loci to meningococcal biology.
Highlights
The encapsulated diplococcus, Neisseria meningitidis, persists in the upper respiratory tract of 10–30% of individuals without causing clinical symptoms [1,2]
This has been licensed for use in European countries and contains four antigenic components: factor H binding protein, Neisserial adhesin A (NadA), Neisseria heparin binding antigen (NhbA) and outer membrane vesicles from a New Zealand epidemic strain [4]
To exclude the possibility that the apparent lack of mspA or nalP in some genome sequences was due to a lack of coverage, BLAST analysis was undertaken using the sequences of genes flanking mspA and nalP
Summary
The encapsulated diplococcus, Neisseria meningitidis, persists in the upper respiratory tract of 10–30% of individuals without causing clinical symptoms [1,2]. One vaccine developed for this purpose is 4CMenB (Bexsero). This has been licensed for use in European countries and contains four antigenic components: factor H binding protein (fHbp), Neisserial adhesin A (NadA), Neisseria heparin binding antigen (NhbA) and outer membrane vesicles from a New Zealand epidemic strain [4]. This vaccine is predicted to provide protection against ,78% of European invasive MenB strains suggesting a requirement for additional vaccine components [5]
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