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Infection and Immunity, January 2008, p. 308-316, Vol. 76, No. 1
0019-9567/08/$08.00+0     doi:10.1128/IAI.00599-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

c-Jun NH2-Terminal Kinase 2 Inhibits Gamma Interferon Production during Anaplasma phagocytophilum Infection{triangledown}

Joao H. F. Pedra,1,{dagger} Jochen Mattner,2,{dagger} Jian Tao,1,{ddagger} Steven M. Kerfoot,3 Roger J. Davis,4 Richard A. Flavell,5 Philip W. Askenase,3 Zhinan Yin,1 and Erol Fikrig1*

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520,1 Committee on Immunology, Department of Pathology, University of Chicago, Chicago, Illinois 60637,2 Section of Allergy and Clinical Immunology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520,3 Howard Hughes Medical Institute, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605,4 Howard Hughes Medical Institute, Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 065205

Received 26 April 2007/ Returned for modification 15 June 2007/ Accepted 29 October 2007

Gamma interferon (IFN-{gamma}) plays a critical role in the early eradication of Anaplasma phagocytophilum. However, the mechanisms that regulate IFN-{gamma} production upon infection remain poorly understood. Here we show that c-Jun NH2-terminal kinase 2 (JNK2) inhibits IFN-{gamma} production during A. phagocytophilum infection. jnk2-null mice were more refractory to infection with A. phagocytophilum and produced increased levels of IFN-{gamma} after challenge with the pathogen. The resistance of jnk2-null mice to A. phagocytophilum infection was due to elevated levels of IFN-{gamma} secreted by conventional and natural killer (NK) T cells. The administration of {alpha}-galactosylceramide, a strong NK T-cell agonist, increased IFN-{gamma} release and protected mice from A. phagocytophilum, further demonstrating the inhibitory effect of JNK2 on IFN-{gamma} production. Collectively, these findings provide strong evidence that JNK2 is an important regulatory protein for IFN-{gamma} secretion upon challenge with A. phagocytophilum.

* Corresponding author. Mailing address: Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520. Phone: (203) 785-2453. Fax: (203) 785-7053. E-mail: erol.fikrig{at}yale.edu

{triangledown} Published ahead of print on 12 November 2007.

Editor: J. L. Flynn

{dagger} These authors contributed equally to this work.

{ddagger} Present address: Department of Microbiology, Columbia University, New York, NY 11032.

Infection and Immunity, January 2008, p. 308-316, Vol. 76, No. 1
0019-9567/08/$08.00+0     doi:10.1128/IAI.00599-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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