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Journal of Bacteriology, February 2008, p. 1473-1483, Vol. 190, No. 4
0021-9193/08/$08.00+0     doi:10.1128/JB.01207-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Analysis of Genetic Relatedness of Haemophilus influenzae Isolates by Multilocus Sequence Typing ^,

Alice L. Erwin,^1*, Sara A. Sandstedt,^2, Paul J. Bonthuis,¹ Jennifer L. Geelhood,¹ Kevin L. Nelson,¹ William C. T. Unrath,¹ Mathew A. Diggle,³ Mary J. Theodore,⁴ Cynthia R. Pleatman,⁴ Elizabeth A. Mothershed,⁴ Claudio T. Sacchi,^4, Leonard W. Mayer,⁴ Janet R. Gilsdorf,^2,5 and Arnold L. Smith^1,6

Microbial Pathogens Program, Seattle Biomedical Research Institute, Seattle, Washington,¹ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan,² Stobhill Hospital, Scottish Meningococcus and Pneumococcus Reference Laboratory, Glasgow, United Kingdom,³ Meningitis and Special Pathogens Branch, Division of Bacterial and Mycotic Diseases, National Center for Infectious Diseases, CDC, Atlanta, Georgia,⁴ Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan,⁵ Department of Pathobiology, University of Washington School of Public Health, Seattle, Washington⁶

Received 27 July 2007/ Accepted 26 November 2007

The gram-negative bacterium Haemophilus influenzae is a human-restricted commensal of the nasopharynx that can also be associated with disease. The majority of H. influenzae respiratory isolates lack the genes for capsule production and are nontypeable (NTHI). Whereas encapsulated strains are known to belong to serotype-specific phylogenetic groups, the structure of the NTHI population has not been previously described. A total of 656 H. influenzae strains, including 322 NTHI strains, have been typed by multilocus sequence typing and found to have 359 sequence types (ST). We performed maximum-parsimony analysis of the 359 sequences and calculated the majority-rule consensus of 4,545 resulting equally most parsimonious trees. Eleven clades were identified, consisting of six or more ST on a branch that was present in 100% of trees. Two additional clades were defined by branches present in 91% and 82% of trees, respectively. Of these 13 clades, 8 consisted predominantly of NTHI strains, three were serotype specific, and 2 contained distinct NTHI-specific and serotype-specific clusters of strains. Sixty percent of NTHI strains have ST within one of the 13 clades, and eBURST analysis identified an additional phylogenetic group that contained 20% of NTHI strains. There was concordant clustering of certain metabolic reactions and putative virulence loci but not of disease source or geographic origin. We conclude that well-defined phylogenetic groups of NTHI strains exist and that these groups differ in genetic content. These observations will provide a framework for further study of the effect of genetic diversity on the interaction of NTHI with the host.

Published ahead of print on 7 December 2007.

Supplemental material for this article may be found at http://jb.asm.org/.

These authors contributed equally to this work.

Current address: Instituto Adolfo Lutz, Seção de Bacteriologia/Imunologia, São Paulo, Brasil.