Natural killer cell receptor expression in patients with severe and recurrent Herpes simplex virus-1 (HSV-1) infections
Introduction
Herpes simplex virus-1 (HSV-1) is an important human pathogen with epidemiological studies demonstrating that by mid-life 80–90% of all individuals have antibodies to the virus [1]. It is well adapted to the human host causing mild or asymptomatic primary infection in a majority of immunocompetent individuals with subsequent latent persistence in neurological tissues for the life-time of a host. Certain stimuli, such as stress, menstruation and UV light, may lead to viral reactivation and around 25% of HSV-1 seropositive people develop recurrent infections. The majority of these have only one or two reactivation episodes per year. A small minority, however, (less than 10%), with no defined defect in their immunology have more frequent attacks, with more then one symptomatic reactivation a month [2].
Dissection of the immune response to HSV has centered on the adaptive arm of immunity (both T cell and antibody dependent). Neutralising antibodies prevent extra cellular spread of the virus and thus limits lesion size and Neuronal infection [3]. In addition, cellular responses (both CD4 and CD8) are necessary for the resolution of the peripheral lesions [1], [4]. In murine models HSV-1 specific CD8+ T cells have been shown to make direct contact with infected neurons resulting in the generation of interferon γ which controls viral reactivation [5]. It has been recently reported that Herpes simplex induced encephalitis in humans is caused by a mutation in the intracellular protein UNC-93B leading to reduced levels of interferon-α/β and lambda in response to viral infection [6].
The role of innate immunity, and in particular NK (Natural Killer) cells, in controlling Herpes infections, has also recently received greater attention. NK cells are large granular lymphocytes with the phenotype of CD3− CD16+, CD56+. Previous studies have indicated that NK cells can be subdivided into two subpopulations defined by the expression of CD56 [7]. The CD56dim population accounts for approximately 95% of NK cells and are cytolytic but generate relatively low levels of cytokines. CD56bright NK cells conversely are poorly cytolytic but high cytokine producers [8].
It is now recognised that NK cells use a complex array of inhibitory and activating receptors to bind to targets (reviewed in [9], [10]). NK cells detect the down-regulation of MHC Class I molecules, which some viruses including HSV-1 use to avoid detection by cytotoxic T cells. Decreased class 1 expression leads to reduced binding to NK inhibitory receptors such as killer Ig-like receptors (KIRS) ultimately leading to the disengagement of inhibitory signals and potentially leading to NK cell activation [11]. In addition, NK cells can also detect the expression cell surface proteins which are only present in times of cellular stress or viral infections. Binding to these ligands stimulate NK cells by engaging activating receptors such as NKp30, NKp44, NKp46 and NKG2D [12], [13]. NK cell activation therefore may be the result of suspended inhibition or engagement of activating receptors or a combination of both [9], [14].
Reports suggest that NK cells play an important role in controlling infections caused by Herpes viruses. Herpes viruses have evolved a number of mechanisms to avoid detection by NK cells [15]. Additionally, NK cell deficient hosts, such as genetically modified mice, or in rare patients with primary or secondary NK deficiencies, are particularly vulnerable to Herpes viruses [16], [17], [18]. Conditions such as familial Erythrophagocytic Lymphohistiocytosis (FELH), Chediak-Higashi syndrome (CHS) and Griscelli syndrome (GS) are characterised by impairments of CTL and NK cytotoxicity [19], [20], [21] and results in increased susceptibility to a number of infections including HSV.
On the basis of this evidence and the observation that certain individuals (despite apparently intact immune response to HSV-1) continue to have frequent and troublesome infections caused by HSV-1, we postulated that such individuals may have subtle, but yet to be identified, NK cell defects that renders them susceptible to this pathogen. To investigate this idea further, we studied NK cell phenotype and receptor cell expression in patient with frequent HSV-1 infections. In particular, we examined the ratio of different NK cell populations, such as CD3− CD56dim and CD3− CD56bright NK cells and also determined the surface expression of a number of inhibitory and activating receptors in patients and healthy controls.
Section snippets
Selection of patient and healthy volunteers (HV)
Eighteen patients with history of recurrent HSV-1 infections and twelve healthy volunteers of similar age and sex were recruited for the study. Local ethics approval was obtained and all subjects gave written informed consent prior to their inclusion in this study. All patients had previous normal baseline immunological investigations, which included immunoglobulin profile, serological evidence of previous HSV-1 infection, lymphocyte subsets and proliferation response to PHA. Patients and
Patient details
The clinical details associated with the patients recruited into this study are shown in Table 1. All patients, apart from patient 12 and 18 had recurrences of HSV at a single site (orolabial Herpes), with Patient 12 also having extensive involvement of her chin. The diagnosis of orolabial HSV was made clinically and on the basis of their response to treatment. Some but not all patients had been investigated and found to have serological evidence of previous exposure/infection with HSV-1 and
Discussion
This study was designed to examine whether abnormal NK receptor expression accounted for the frequent HSV-1 recurrences experienced by a number of individuals, with apparently normal immunology. Previous immunological investigations performed in our laboratory indicated the presence of HSV-1 specific IgG as well as normal lymphocyte numbers and proliferation responses to PHA in all patients included in this study. The possibility that NK cell impairment may be responsible was suggested by
Acknowledgments
The authors thank Chloe Wager for secretarial help, Nicola Ruddock for help with figures and Dr. Graham Cook and Dr. Josie Mead for helpful discussions.
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These authors contributed equally to this work.