Abstract
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 serogroup B meningococcal disease worldwide, but they are also common in asymptomatic carriers. Proteome analysis comparing cc41/44 isolates from invasive disease versus carriage revealed differential expression levels of the outer membrane protein NspA, which binds fH. Deletion of nspA reduced serum resistance and NspA expression correlated with fH sequestration. Expression levels of NspA depended on the length of a homopolymeric tract in the nspA promoter: A 5-adenosine tract dictated low NspA expression, whereas a 6-adenosine motif guided high NspA expression. Screening German cc41/44 strain collections revealed the 6-adenosine motif in 39% of disease isolates, but only in 3.4% of carriage isolates. Thus, high NspA expression is associated with disease, but not strictly required. The 6-adenosine nspA promoter is most common to the cc41/44, but is also found in other hypervirulent clonal complexes.
Highlights
Neisseria meningitidis causes invasive meningococcal diseases (IMD) such as meningitis or septicaemia predominantly in infants and toddlers, and in adolescents
The outer membrane proteins fHbp and NHBA are components of the multi-component serogroup B vaccine (Bexsero)14. fHbp directly sequesters the complement regulator of the alternative pathway, factor H, thereby reducing deposition of C3b to the meningococcal surface and intercepting the amplification feedback loop of complement activation[9,15]
Triple mutants were generated which lacked capsule, LOS sialylation and fHbp, thereby excluding factors of established serum resistance mechanisms, in order to focus on novel or less well perceived factors
Summary
Neisseria meningitidis causes invasive meningococcal diseases (IMD) such as meningitis or septicaemia predominantly in infants and toddlers, and in adolescents. In addition to the capsule, several other surface components have been demonstrated to enhance serum resistance These factors comprise sialylation of the meningococcal lipooligosaccharide (LOS)[7,8], the factor H binding protein (fHbp, formerly called GNA1870)[9,10], the Neisseria heparin binding antigen (NHBA, formerly called GNA2132)[11] and the Neisserial surface protein A (NspA, NMB0663)[12,13]. NspA can directly recruit fH to the bacterial surface to limit C3b deposition and thereby intercepts the positive feedback loop of the alternative pathway, leading to increased serum resistance of N. meningitidis[12,13]. Presentation of the antigen in outer membrane vesicle-derived vaccine (strains H44/76 and NZ98/254) did not elicit measurable anti-NspA antibodies in humans[29]. The length of a poly(A) tract of the nspA promoter correlated with expression levels of NspA, and N. meningitidis with high NspA expression displayed reduction of membrane attack complex insertion and increased serum resistance
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