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Infection and Immunity, November 2006, p. 6213-6225, Vol. 74, No. 11
0019-9567/06/$08.00+0     doi:10.1128/IAI.00744-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Complex Role of Hemoglobin and Hemoglobin-Haptoglobin Binding Proteins in Haemophilus influenzae Virulence in the Infant Rat Model of Invasive Infection{triangledown}

Thomas W. Seale,1 Daniel J. Morton,1 Paul W. Whitby,1 Roman Wolf,2 Stanley D. Kosanke,2 Timothy M. VanWagoner,1 and Terrence L. Stull1,3*

Departments of Pediatrics,1 Pathology,2 Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 731903

Received 9 May 2006/ Returned for modification 23 June 2006/ Accepted 29 August 2006

Haemophilus influenzae requires an exogenous heme source for aerobic growth in vitro. Hemoglobin or hemoglobin-haptoglobin satisfies this requirement. Heme acquisition from hemoglobin-haptoglobin is mediated by proteins encoded by hgp genes. Both Hgps and additional proteins, including those encoded by the hxu operon, provide independent pathways for hemoglobin utilization. Recently we showed that deletion of the set of three hgp genes from a nontypeable strain (86-028NP) of H. influenzae attenuated virulence in the chinchilla otitis media model of noninvasive disease. The present study was undertaken to investigate the role of the hgp genes in virulence of the wild-type serotype b clinical isolate HI689 in the infant rat model of hematogenous meningitis, an established model of invasive disease requiring aerobic growth. Bacteremia of high titer and long duration (>14 days) and histopathologically confirmed meningitis occurred in >95% of infant rats challenged at 5 days of age with strain HI689. While mutations disrupting either the Hgp- or Hxu-mediated pathway of heme acquisition had no effect on virulence in infant rats, an isogenic mutant deficient for both pathways was unable to sustain bacteremia or produce meningitis. In contrast, mutations disrupting either pathway decreased the limited ability of H. influenzae to initiate and sustain bacteremia in weanling rats. Biochemical and growth studies also indicated that infant rat plasma contains multiple heme sources that change with age. Taken together, these data indicate that both the hgp genes and the hxuC gene are virulence determinants in the rat model of human invasive disease.

* Corresponding author. Mailing address: Department of Pediatrics, CHO 2308, University of Oklahoma Health Sciences Center, 940 NE 13th Street, Oklahoma City, OK 73104. Phone: (405) 271-4401. Fax: (405) 271-8710. E-mail: terrence-stull{at}ouhsc.edu.

{triangledown} Published ahead of print on 11 September 2006.

Editor: F. C. Fang

Infection and Immunity, November 2006, p. 6213-6225, Vol. 74, No. 11
0019-9567/06/$08.00+0     doi:10.1128/IAI.00744-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Rosadini, C. V., Wong, S. M. S., Akerley, B. J. (2008). The Periplasmic Disulfide Oxidoreductase DsbA Contributes to Haemophilus influenzae Pathogenesis. Infect. Immun. 76: 1498-1508 [Abstract] [Full Text]  
  • Paulley, J. T., Anderson, E. S., Roop, R. M. II (2007). Brucella abortus Requires the Heme Transporter BhuA for Maintenance of Chronic Infection in BALB/c Mice. Infect. Immun. 75: 5248-5254 [Abstract] [Full Text]  
  • Mocny, J. C., Olson, J. S., Connell, T. D. (2007). Passively Released Heme from Hemoglobin and Myoglobin Is a Potential Source of Nutrient Iron for Bordetella bronchiseptica. Infect. Immun. 75: 4857-4866 [Abstract] [Full Text]  
  • Morton, D. J., Seale, T. W., Madore, L. L., VanWagoner, T. M., Whitby, P. W., Stull, T. L. (2007). The haem-haemopexin utilization gene cluster (hxuCBA) as a virulence factor of Haemophilus influenzae. Microbiology 153: 215-224 [Abstract] [Full Text]  


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