Neisseria meningitidis Escape from the Bactericidal Activity of a Monoclonal Antibody Is Mediated by Phase Variation of lgtG and Enhanced by a Mutator Phenotype

Abstract

Bacteria adapt to environmental changes through high-frequency switches in expression of specific phenotypes. Localized hypermutation mediated by simple sequence repeats is an important mechanism of such phase variation (PV) in Neisseria meningitidis. Loss or gain of nucleotides in a poly(C) tract located in the reading frame results in switches in expression of lgtG and determines whether a glucose or a phosphoethanolamine (PEtn) is added at a specific position in the inner core lipopolysaccharide (LPS). Monoclonal antibody (MAb) B5 is bactericidal for N. meningitidis strain 8047 when PEtn is present in the inner core LPS and lgtG is switched "off." Escape from the bactericidal activity of this antibody was examined by subjecting strain 8047 to multiple cycles of growth in the presence of MAb B5 and human serum. Escape variants with alterations in the lgtG repeat tract rapidly accumulated in bacterial populations during selection with this antibody. Strain 8047 was outcompeted in this assay by the 8047 ⌬mutS strain due to the elevated PV rate of this mismatch repair mutant and hence the greater proportion of preexisting phase variants of lgtG in the inoculum. This mutS mutant was also more virulent than strain 8047 during escape from passive protection by MAb B5 in an in vivo infant rat model of bacteremia. These results provide an example of how PV rates can modulate the occurrence and severity of infection and have important implications for understanding the evolution of bacterial fitness in species subject to environmental variations that occur during persistence within and transmission between hosts.

Persistence, Replacement, and Rapid Clonal Expansion of Meningococcal Carriage Isolates in a 2008 University Student Cohort

“…The PorA antigen is a major surface protein and target of adaptive immune responses. The low level of antigenic variation in this protein during long-term persistence (i.e., in only 1 of 15 individuals who exhibited 5 to 6 months of carriage) is surprising and suggests that other mechanisms such as phase-variable changes in the level of expression may contribute to immune evasion (2,28). An alternative explanation is that meningococcal strains might escape detection by the host immune system or prevent activation of host immune responses (22).…”

Low-dose recombinant properdin provides substantial protection againstStreptococcus pneumoniaeandNeisseria meningitidisinfection

“…Samples were obtained at 0, 30, 60, and 120 min. To measure viable bacteria, samples were serially diluted in HBSS and plated onto brain heart infusion (BHI) agar supplemented with Levinthal's broth (10%, vol/vol), followed by overnight incubation at 37°C in 5% (vol/vol) CO 2 (47).…”

Investigation on the Effect of Immune Selection on Resistance to Bactericidal Antibodies to Group B Meningococci In Vitro

“…Because of the extensive diversity observed in MenB strains for antigens such as the porins and pili (1,2,16), it is possible that resistance to bactericidal antibodies might occur via selective pressure from vaccination. While it is difficult to model in vitro the cumulative effects of the general use of a vaccine in a large human population over a sustained period, these studies show that within the expected range of appearance of phase variants, a loss of susceptibility to bactericidal antibodies raised by these MenB vaccine combinations was not observed.…”