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Infection and Immunity, June 2006, p. 3387-3395, Vol. 74, No. 6
0019-9567/06/$08.00+0     doi:10.1128/IAI.01985-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

High Levels of Interleukin-10 Impair Resistance to Pulmonary Coccidioidomycosis in Mice in Part through Control of Nitric Oxide Synthase 2 Expression

Maria del Pilar Jimenez,1,{dagger} Lorraine Walls,1 and Joshua Fierer1,2*

VA Healthcare System,1 Departments of Medicine and Pathology, University of California San Diego School of Medicine, San Diego, California2

Received 7 December 2005/ Returned for modification 26 January 2006/ Accepted 2 March 2006

We have shown previously that there is a direct correlation between IL-10 levels and susceptibility to Coccidioides immitis peritonitis in C57BL/6 (B6), DBA/2, and BXD recombinant inbred mice. We now show that B6 mice are also more susceptible to C. immitis pneumonia and that interleukin-10 (IL-10)-deficient (IL-10–/–) B6 mice are more resistant to C. immitis pneumonia. In addition, we established that high levels of IL-10 are sufficient to make genetically resistant mice susceptible to both C. immitis peritonitis and pneumonia by infecting h.IL-10 transgenic mice. Infected h.IL-10 transgenic mice express lower levels of gamma interferon, IL-12 p40, and inducible nitric oxide synthetase 2 (NOS2) mRNA in their lungs, implicating inducible NOS as a defense mechanism in this disease. We treated DBA/2 mice with aminoguanidine, and they became more susceptible to C. immitis peritonitis and pneumonia. We conclude that high levels of IL-10 are both necessary and sufficient to make mice susceptible to C. immitis, regardless of the genetic background of the mice, and that IL-10 impairs resistance to C. immitis in part by suppressing NO synthesis.

* Corresponding author. Mailing address: Infectious Diseases Section (111F), VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161. Phone: (858) 552-7446. Fax: (858) 552-4398. E-mail: jfierer{at}ucsd.edu.

Editor: A. Casadevall

{dagger} Present address: Grupo de Micología Médica y Experimental, Corporación para Investigaciones Biológicas, Medellín, Columbia.

Infection and Immunity, June 2006, p. 3387-3395, Vol. 74, No. 6
0019-9567/06/$08.00+0     doi:10.1128/IAI.01985-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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