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

doi:10.1128/IAI.69.12.7832-7838.2001

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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 plasticitypromotes divergence of the population by the development of subclonesand presumably enhances adaptation to host niches. We have investigatedthe genotypic and phenotypic characteristics of two such subclonesisolated from one patient as well as the genetic evolution ofthese isolates during experimental infection. Whole-genome genotypingof the isolates using DNA microarrays revealed that they weremore similar to each other than to a panel of other genotypedstrains recovered from different hosts. Nonetheless, they stillshowed significant differences. For example, one isolate (67:21)contained the entire Cag pathogenicity island (PAI), whereas theother (67:20) had excised the PAI. Phenotypic studies disclosedthat both isolates expressed adhesins that recognized human histo-bloodgroup Lewis^b glycan receptors produced by gastric pit and surface mucus cells.In addition, both isolates were able to colonize, to equivalentdensity and with similar efficiency, germ-free transgenic micegenetically engineered to synthesize Lewis^b glycans in their pit cells (12 to 14 mice/isolate). Remarkably,the Cag PAI-negative isolate was unable to colonize conventionallyraised Lewis^b transgenic mice harboring a normal gastric microflora, whereasthe Cag PAI-positive isolate colonized 74% of the animals (39to 40 mice/isolate). The genomic evolution of both isolates duringthe infection of conventionally raised and germ-free mice wasmonitored over the course of 3 months. The Cag PAI-positive isolatewas also surveyed after a 10 month colonization of conventionallyraised transgenic animals (n = 9 mice). Microarray analysis ofthe Cag PAI and sequence analysis of the cagA, recA, and 16S rRNAgenes disclosed no changes in recovered isolates. Together, theseresults reveal that the H. pylori population infecting one individualcan undergo significant divergence, creating stable subcloneswith substantial genotypic and phenotypicdifferences.

^* Corresponding author. Mailing address: Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden. Phone: 46-8-45724 15. Fax: 46-8-30 17 97. E-mail: lars.engstrand{at}smi.ki.se.

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