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Infection and Immunity, November 2008, p. 5038-5048, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00395-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Christopher D. Bayliss,1* J. Claire Hoe,2 Katherine Makepeace,2 Patricia Martin,2,{dagger} Derek W. Hood,2 and E. Richard Moxon2

Department of Genetics, University of Leicester, Leicester, United Kingdom LE1 7RH,1 Molecular Infectious Diseases Group, Institute for Molecular Medicine, University of Oxford, Oxford, United Kingdom OX3 9DU2

Received 28 March 2008/ Returned for modification 6 June 2008/ Accepted 1 August 2008

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 {Delta}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.

* Corresponding author. Mailing address: Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, United Kingdom. Phone: 44 116 2523465. Fax: 44 116 2523378. E-mail: cdb12{at}le.ac.uk

{triangledown} Published ahead of print on 11 August 2008.

Editor: J. N. Weiser

{dagger} Present address: Institut National de la Santé et de la Recherche Médicale, Unité 570, Hopital Necker Enfants Malades, 156 Rue de Vaugirard, F-75015 Paris, France.

Infection and Immunity, November 2008, p. 5038-5048, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00395-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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