While infection of the respiratory tract with herpes simplex virus type 1 (HSV-1) can have severe clinical complications, little is known of the immune mechanisms that control both the replication and spread of HSV-1 in this site. To better understand the contribution of innate immunity and in particular natural killer (NK) cells to the control of infection at this site, we have utilized a mouse model of intranasal HSV-1 infection. NK cell numbers increased in the lung following intranasal infection and they produced IFN-c and acquired an enhanced cytotoxic capacity. While depletion of NK cells resulted in increased HSV-1 titres in the lung, the time taken to clear the virus was unaffected. Interestingly, HSV-1 was also effectively cleared from the lungs of RAG-1 -/-mice that lack both B and T cells. However, RAG-1 -/-mice could not control the spread of virus to the central nervous system and its subsequent replication in the brain. Together, these data demonstrate that NK cells are recruited, activated and contribute to early protection of the lung during acute HSV-1 infection of the respiratory tract, but in the absence of adaptive immunity are unable to control the replication and spread of virus in the nervous system.

Natural killer (NK) cells play a crucial role in the initial response to viral infections but the mechanisms controlling their activation are unclear. We show a rapid and transient activation of NK cells that results in the production of IFN-γ immediately following infection with herpes simplex virus type 1 (HSV-1). Activation of NK cells leading to synthesis of IFN-γ was not mediated by a direct interaction with virus but required the presence of additional cell types and was largely dependent on the cytokine IL-18, but not IL-12. HSV-1-induced IFN-γ expression by NK cells in vitro was impaired in spleen cultures depleted of CD11c+ cells. Conversely, coculture of NK cells with virus-exposed conventional DC or plasmacytoid (p)DC restored the production of IFN-γ, indicating that multiple DC subsets could mediate NK cell activation. While conventional DC populations stimulated NK cells independently of IL-18, they were less effective than pDC in promoting NK cell IFN-γ expression. In contrast, the potent stimulation of NK cells by pDC was dependent on IL-18 as pDC from IL-18-deficient mice only activated a similar proportion of NK cells as conventional DC. These data identify IL-18 as a crucial factor for pDC-mediated NK cell regulation.

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-γ 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.

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