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Infection and Immunity, December 2001, p. 7832-7838, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7832-7838.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Comparison of Genetic Divergence and Fitness between Two Subclones of Helicobacter pylori

Britta Björkholm,1,2,3 Annelie Lundin,1,4 Anna Sillén,1 Karen Guillemin,5 Nina Salama,5 Carlos Rubio,6 Jeffrey I. Gordon,3 Per Falk,2,3,7 and Lars Engstrand1,*

Swedish Institute for Infectious Disease Control, 171 82 Solna,1 Department of Medicine,2 Microbiology and Tumor Biology Center,4 and Department of Pathology,6 Karolinska Institute, 171 77 Stockholm, and Department of Molecular Biology, AstraZeneca R&D, 431 83 Mölndal,7 Sweden; Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 631103; and Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 943055

Received 4 June 2001/Returned for modification 25 July 2001/Accepted 31 August 2001

Helicobacter pylori has a very plastic genome, reflecting its high rate of recombination and point mutation. This plasticity promotes divergence of the population by the development of subclones and presumably enhances adaptation to host niches. We have investigated the genotypic and phenotypic characteristics of two such subclones isolated from one patient as well as the genetic evolution of these isolates during experimental infection. Whole-genome genotyping of the isolates using DNA microarrays revealed that they were more similar to each other than to a panel of other genotyped strains recovered from different hosts. Nonetheless, they still showed significant differences. For example, one isolate (67:21) contained the entire Cag pathogenicity island (PAI), whereas the other (67:20) had excised the PAI. Phenotypic studies disclosed that both isolates expressed adhesins that recognized human histo-blood group Lewisb glycan receptors produced by gastric pit and surface mucus cells. In addition, both isolates were able to colonize, to equivalent density and with similar efficiency, germ-free transgenic mice genetically engineered to synthesize Lewisb glycans in their pit cells (12 to 14 mice/isolate). Remarkably, the Cag PAI-negative isolate was unable to colonize conventionally raised Lewisb transgenic mice harboring a normal gastric microflora, whereas the Cag PAI-positive isolate colonized 74% of the animals (39 to 40 mice/isolate). The genomic evolution of both isolates during the infection of conventionally raised and germ-free mice was monitored over the course of 3 months. The Cag PAI-positive isolate was also surveyed after a 10 month colonization of conventionally raised transgenic animals (n = 9 mice). Microarray analysis of the Cag PAI and sequence analysis of the cagA, recA, and 16S rRNA genes disclosed no changes in recovered isolates. Together, these results reveal that the H. pylori population infecting one individual can undergo significant divergence, creating stable subclones with substantial genotypic and phenotypic differences.

* Corresponding author. Mailing address: Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden. Phone: 46-8-457 24 15. Fax: 46-8-30 17 97. E-mail: lars.engstrand{at}smi.ki.se.

Infection and Immunity, December 2001, p. 7832-7838, Vol. 69, No. 12
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.12.7832-7838.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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