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NOD2-Deficient Mice Have Impaired Resistance to Mycobacterium tuberculosis Infection through Defective Innate and Adaptive Immunity¹

Maziar Divangahi^*, Serge Mostowy^*, François Coulombe^*, Robert Kozak^*, Loïc Guillot^*, Frédéric Veyrier^*, Koichi S. Kobayashi, Richard A. Flavell, Philippe Gros and Marcel A. Behr^2,*

^* Department of Medicine, McGill University Health Centre, Montreal, Canada; Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115; Howard Hughes Medical Institute and Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06510; and Department of Biochemistry, McGill University, Montreal, Canada

NOD2/CARD15 mediates innate immune responses to mycobacterial infection. However, its role in the regulation of adaptive immunity has remained unknown. In this study, we examined host defense, T cell responses, and tissue pathology in two models of pulmonary mycobacterial infection, using wild-type and Nod2-deficient mice. During the early phase of aerosol infection with Mycobacterium tuberculosis, Nod2^–/– mice had similar bacterial counts but reduced inflammatory response on histopathology at 4 and 8 wk postchallenge compared with wild-type animals. These findings were confirmed upon intratracheal infection of mice with attenuated Mycobacterium bovis bacillus Calmette-Guérin. Analysis of the lungs 4 wk after bacillus Calmette-Guérin infection demonstrated that Nod2^–/– mice had decreased production of type 1 cytokines and reduced recruitment of CD8⁺ and CD4⁺ T cells. Ag-specific T cell responses in both the spleens and thoracic lymph nodes were diminished in Nod2^–/– mice, indicating impaired adaptive antimycobacterial immunity. The immune regulatory role of NOD2 was not restricted to the lung since Nod2 disruption also led to reduced type 1 T cell activation following i.m. bacillus Calmette-Guérin infection. To determine the importance of diminished innate and adaptive immunity, we measured bacterial burden 6 mo after aerosol infection with M. tuberculosis and followed a second infected group for assessment of survival. Nod2^–/– mice had a higher bacterial burden in the lungs 6 mo after infection and succumbed sooner than did wild-type controls. Taken together, these data indicate that NOD2 mediates resistance to mycobacterial infection via both innate and adaptive immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by a group grant from the Canadian Genetic Diseases Network to P.G. and M.B. and an operating grant (MOP-86536) from the Canadian Institutes for Health Research to M.B. F.C. was supported by a studentship award of the Fonds de la Recherche en Santé du Québec (FRSQ). R.A.F. is an investigator of the Howard Hughes Medical Institute. P.G. is a James McGill Professor of McGill University. M.B. is a William Dawson Scholar of McGill University and a Chercheur-Boursier Senior of the FRSQ.

² Address correspondence and reprint requests to Dr. Marcel Behr, Department of Medicine, McGill University Health Centre, A5.156, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada. E-mail address: marcel.behr{at}mcgill.ca

³ Abbreviations used in this paper: PRM, pattern recognition molecule; BAL, bronchoalveolar lavage; BCG, bacillus Calmette-Guérin; CD, Crohn’s disease; MDP, muramyl dipeptide; M.tb-CF, M. tuberculosis culture filtrate; WT, wild type.

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