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Infection and Immunity, January 2006, p. 504-515, Vol. 74, No. 1
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.1.504-515.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Urease Produced by Coccidioides posadasii Contributes to the Virulence of This Respiratory Pathogen

Fariba Mirbod-Donovan, Ruth Schaller, Chiung-Yu Hung, Jianmin Xue, Utz Reichard, and Garry T. Cole*

Department of Medical Microbiology and Immunology, Medical College of Ohio, Toledo, Ohio 43614

Received 19 May 2005/ Returned for modification 17 June 2005/ Accepted 12 October 2005

Urease activity during in vitro growth in the saprobic and parasitic phases of Coccidioides spp. is partly responsible for production of intracellular ammonia released into the culture media and contributes to alkalinity of the external microenvironment. Although the amino acid sequence of the urease of Coccidioides posadasii lacks a predicted signal peptide, the protein is transported from the cytosol into vesicles and the central vacuole of parasitic cells (spherules). Enzymatically active urease is released from the contents of mature spherules during the parasitic cycle endosporulation stage. The endospores, together with the urease and additional material which escape from the ruptured parasitic cells, elicit an intense host inflammatory response. Ammonia production by the spherules of C. posadasii is markedly increased by the availability of exogenous urea found in relatively high concentrations at sites of coccidioidal infection in the lungs of mice. Direct measurement of the pH at these infection sites revealed an alkaline microenvironment. Disruption of the urease gene of C. posadasii resulted in a marked reduction in the amount of ammonia secreted in vitro by the fungal cells. BALB/c mice challenged intranasally with the mutant strain showed increased survival, a well-organized granulomatous response to infection, and better clearance of the pathogen than animals challenged with either the parental or the reconstituted (revertant) strain. We conclude that ammonia and enzymatically active urease released from spherules during the parasitic cycle of C. posadasii contribute to host tissue damage, which exacerbates the severity of coccidioidal infection and enhances the virulence of this human respiratory pathogen.

* Corresponding author. Present address: Department of Biology, Margaret Batts Tobin Building, Room 1.308E, University of Texas at San Antonio, 6900 North Loop 1604 West, San Antonio, TX 78249. Phone: (210) 458-7017. Fax: (210) 458-5658. E-mail: garry.cole{at}utsa.edu.

Editor: T. R. Kozel

Infection and Immunity, January 2006, p. 504-515, Vol. 74, No. 1
0019-9567/06/$08.00+0     doi:10.1128/IAI.74.1.504-515.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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