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Infect. Immun. doi:10.1128/IAI.00395-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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

Department of Genetics, University of Leicester, Leicester, United Kingdom, LE1 7RH; Molecular Infectious Diseases Group, Institute for Molecular Medicine, University of Oxford, Oxford, United Kingdom, OX3 9DU

^* To whom correspondence should be addressed. Email: cdb12{at}le.ac.uk.

	Abstract

Bacteria adapt to environmental changes through high frequency switches in expression of specific phenotypes. Localised 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 polyC tract located in the reading frame produce switches in expression of lgtG and determine whether a glucose or a phosphoethanolamine (PEtn) is added to a specific position within the inner core lipopolysaccharide (LPS). Monoclonal antibody (mAb) B5 is bactericidal for N. meningitidis strain 8047 when PEtn is present on the inner core LPS and lgtG is switched ‘off'. Escape of 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 out-competed in this assay by 8047mutS due to the elevated PV rate of this mismatch repair mutant and hence to a greater proportion of pre-existing phase variants of lgtG in the inoculum. This mutS mutant was also more virulent than strain 8047 during escape of passive protection by mAb B5 in an in vivo infant rat model of bacteraemia. 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 occurring during persistence within and transmission between hosts.