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Antimicrobial Agents and Chemotherapy, December 2004, p. 4513-4519, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4513-4519.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Intranasal Interleukin-12 Treatment Promotes Antimicrobial Clearance and Survival in Pulmonary Francisella tularensis subsp. novicida Infection

Michael A. Pammit,1 Varija N. Budhavarapu,1 Erin K. Raulie,1 Karl E. Klose,1 Judy M. Teale,2 and Bernard P. Arulanandam1*

Department of Biology, University of Texas at San Antonio,1 Department of Microbiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas2

Received 26 March 2004/ Returned for modification 7 June 2004/ Accepted 31 August 2004

Francisella tularensis is a highly virulent facultative intracellular bacterium and is considered a potential biological warfare agent. Inhalation tularemia can lead to the development of bronchopneumonia, which is frequently fatal without medical intervention. Treatment strategies that directly target the respiratory mucosa may extend the efficacy of therapy, particularly for the medical management of acute aerosol exposure. To this end, we describe an intranasal (i.n.) strategy for the treatment of pulmonary Francisella infection in mice that uses a combinatorial approach with the conventional antibiotic gentamicin and interleukin 12 (IL-12). The i.n. administration of IL-12 alone promoted bacterial clearance and extended the time to death but did not prevent mortality against lethal pulmonary challenge with Francisella tularensis subsp. novicida. However, i.n. treatment with gentamicin and IL-12 therapeutically at 8 and 24 h after challenge markedly enhanced the rate of survival (70 to 100%) against pulmonary infection compared to the rates of survival for animals treated with antibiotic alone (17%) or IL-12 alone (0%). A delay in combinatorial therapy over a span of 4 days progressively decreased the efficacy of this treatment regimen. This combinatorial treatment was shown to be highly dependent upon the induction of endogenous gamma interferon and may also involve the activation of natural killer cells. Together, these findings suggest that IL-12 may be a potent adjunct for chemotherapy to enhance drug effectiveness against pulmonary Francisella infection.

* Corresponding author. Mailing address: Department of Biology, University of Texas at San Antonio, 6900 North Loop 1604 West, San Antonio, TX 78249. Phone: (210) 458-5492. Fax: (210) 458-5523. E-mail: barulanandam{at}utsa.edu.

Antimicrobial Agents and Chemotherapy, December 2004, p. 4513-4519, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4513-4519.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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