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

Abstract

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.

Granzyme B is a novel interleukin-18 converting enzyme

“…GrB and IL-18 have been reported to be important for host defense against herpes simplex virus (HSV)-1 [37]. HSV-1 preferentially replicates in host non-hematopoietic cells, such as epithelial cells and nerve cells.…”

Imbalanced production of IL-18 and its antagonist in human diseases, and its implications for HIV-1 infection

“…The pathogens include viruses (HSV-1), bacteria (Salmonella, Mycobacteria, Listeria; Streptococcus pyogenes, Lactobacilli, etc. ), protozoa (Leishmania, malaria) and fungi (Cryptococcus and Candida; [51][52][53][54][55]). Several poxviruses have usurped the gene encoding IL-18BP, an endogenous antagonist of IL-18, to neutralize the host's IL-18 response.…”

IL-12p40 and IL-18 Play Pivotal Roles in Orchestrating the Cell-Mediated Immune Response to a Poxvirus Infection

“…For instance IL-18, but not IL-12, was shown to play an antiviral role in HSV-1 (14) and influenza A/X/31 (15) virus infections in C57BL/6 (B6) mice. In contrast, neutralization of IL-12p40 in BALB/c mice was found to significantly diminish the antiviral CTL response to the more virulent A/PR/8 strain of influenza virus (16).…”