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Infect Immun, March 1998, p. 899-906, Vol. 66, No. 3
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The Haemophilus influenzae HtrA Protein Is a Protective Antigen

Sheena M. Loosmore,* Yan-ping Yang, Ray Oomen, Jean M. Shortreed, Debbie C. Coleman, and Michel H. Klein

Pasteur Merieux Connaught Canada Research, North York, Ontario, Canada M2R 3T4

Received 29 September 1997/Returned for modification 4 November 1997/Accepted 30 December 1997

The htrA gene from two strains of nontypeable Haemophilus influenzae has been cloned and sequenced, and the encoded approximately 46-kDa HtrA proteins were found to be highly conserved. H. influenzae HtrA has approximately 55% identity with the Escherichia coli and Salmonella typhimurium HtrA stress response proteins, and expression of the H. influenzae htrA gene was inducible by high temperature. Recombinant HtrA (rHtrA) was expressed from E. coli, and the purified protein was found to have serine protease activity. rHtrA was found to be very immunogenic and partially protective in both the passive infant rat model of bacteremia and the active chinchilla model of otitis media. Immunoblot analysis indicated that HtrA is antigenically conserved in encapsulated and nontypeable H. influenzae species. Site-directed mutagenesis was performed on the htrA gene to ablate the endogenous serine protease activity of wild-type HtrA, and it was found that eight of nine recombinant mutant proteins had no measurable residual proteolytic activity. Two mutant proteins were tested in the animal protection models, and one, H91A, was found to be partially protective in both models. H91A HtrA may be a good candidate antigen for a vaccine against invasive H. influenzae type b disease and otitis media and is currently in phase I clinical trials.

* Corresponding author. Mailing address: Pasteur Merieux Connaught Canada Research, 1755 Steeles Ave. W., North York, Ontario, Canada M2R 3T4. Phone: (416) 667-2932. Fax: (416) 667-2740. E-mail:sloosmore{at}ca.pmc-vacc.com.




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