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IL-18, but not IL-12, Regulates NK Cell Activity following Intranasal Herpes Simplex Virus Type 1 Infection¹

Department of Microbiology and Immunology, The University of Melbourne, Parkville, Victoria, Australia

Infection of the respiratory tract with HSV type 1 (HSV-1) can have severe clinical complications, yet little is known of the immune mechanisms that control the replication and spread of HSV-1 in this site. The present study investigated the protective role of IL-12 and IL-18 in host defense against intranasal HSV-1 infection. Both IL-12 and IL-18 were detected in lung fluids following intranasal infection of C57BL/6 (B6) mice. IL-18-deficient (B6.IL-18^–/–) mice were more susceptible to HSV-1 infection than wild-type B6 mice as evidenced by exacerbated weight loss and enhanced virus growth in the lung. IL-12-deficient (B6.IL-12^–/–) mice behaved similarly to B6 controls. Enhanced susceptibility of B6.IL-18^–/– mice to HSV-1 infection correlated with a profound impairment in the ability of NK cells recovered from the lungs to produce IFN- or to mediate cytotoxic activity ex vivo. The weak cytotoxic capacity of NK cells from the lungs of B6.IL-18^–/– mice correlated with reduced expression of the cytolytic effector molecule granzyme B. Moreover, depletion of NK cells from B6 or B6.IL-12^–/– mice led to enhanced viral growth in lungs by day 3 postinfection; however, this treatment had no effect on viral titers in lungs of B6.IL-18^–/– mice. Together these studies demonstrate that IL-18, but not IL-12, plays a key role in the rapid activation of NK cells and therefore in control of early HSV-1 replication in the lung.

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 supported by a Program Grant from The National Health and Medical Research Council of Australia. P.C.R. is a National Health and Medical Research Council R. D. Wright Fellow.

² Address correspondence and reprint requests to Dr. Patrick C. Reading, Department of Microbiology and Immunology, University of Melbourne, Melbourne, 3010 Victoria, Australia. E-mail address: preading{at}unimelb.edu.au

³ Abbreviations used in this paper: HSV-1, HSV type 1; AAGM, anti-asialo-GM1; TG, trigeminal ganglion; BALF, bronchoalveolar lavage fluid; p.i., postinfection; gB, glycoprotein B.

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