Brief communicationMannose-binding lectin 2 gene polymorphism in recurrent herpes simplex virus 2 infection
Introduction
Herpes simplex virus 2 (HSV-2) is the most common cause of ulcerative genital infection [1]. Lifelong in nature, HSV-2 infection leads to a highly variable course during the entire life of the host, ranging from subclinical reactivations to frequent and severe clinical recurrences. Frequent recurrences substantially decrease the quality of individuals' lives. Furthermore, genital ulcers during recurrences predispose individuals to other sexually transmitted diseases, including HIV infection [1].
Cell-mediated immunity plays a central role in immune defense against HSV-2 reactivations [2]. However, its mechanisms act with a delay, but innate immunity and pre-existing antibodies offer immediate protection at the onset of reactivation [3]. Thus far, genetic polymorphisms leading to structural variation in innate pattern-recognition molecules, such as Toll-like receptor 2, and complement-fixing antibodies have been associated with the frequency of recurring clinical disease [4], [5]. In patients with pre-existing complement-fixing immunoglobulin (Ig)G1 and IgG3 anti-HSV-2 antibodies, the duration of HSV-2 excretion is shorter and the complement system probably intervenes through direct lysis of virions or by lysis of infected cells [6]. This suggests that antibody-dependent cellular cytotoxicity and the complement are important factors in the defense against HSV-2 reactivation.
Mannose-binding lectin (MBL), an innate pattern-recognition molecule and the first component of the complement lectin pathway, together with ficolins, is capable of binding to glycoprotein structures on the surface of HSV-2 virus, although the exact surface structure to which MBL binds on the virion is not known [7], [8], [9]. MBL insufficiency is, in turn, caused by polymorphisms in codons 52, 54, or 57 in exon 1 of the MBL2 gene [7], [10], [11], [12]. MBL concentration is also highly dependent on several promoter region polymorphisms, of which that at position −221 bp is clinically the most important [13], [14]. In previous studies in mice—which are a nonnatural host of HSV-2—MBL has been observed to modulate the response to HSV-2 infection either by neutralizing the virus or by providing the virion with an alternative route of entry into cells [15], [16]. In two small clinical studies, low MBL concentration was associated with symptomatic HSV-2 infection, and the codon 52 structural variant of MBL2 has been associated with the risk of recurring HSV-2 meningitis [15], [17]. In this study, we studied for the first time the effect of MBL2 structural and promoter polymorphisms reflecting MBL insufficiency on the risk of recurrent HSV-2 infection in 51 patients and 147 controls.
Section snippets
Patients
The study population comprised 57 consecutive Caucasian patients referred for evaluation to the Division of Infectious Diseases, Department of Medicine, Helsinki University Central Hospital, between April 2000 and June 2004. The study population has been described in detail elsewhere [4]. All patients were >18 years old, without any known immunodeficiency and with HSV-2 infection confirmed by a positive culture from an active genital or extragenital lesion. The first clinical episode of genital
Results
MBL2 structural and promoter gene polymorphisms in patients and controls are presented in Table 1. Genotype frequencies in both groups were in Hardy–Weinberg equilibrium. However, a significant difference in structural genotype frequencies was detected between the patients and controls (p = 0.015), and the structural variant genotype (A/O or O/O) was reported in 47% (24/51) of patients compared with 26% (38/147) of controls (OR 2.6, 95% CI 1.3–4.9; P = 0.005). The increase in frequency was
Discussion
This is the first study to investigate the effect of MBL2 structural and promoter polymorphisms on the risk of recurring genital HSV-2 infection. The carriage of MBL2 structural variant genotype (A/O or O/O) was more common among Caucasian patients with frequent recurrences compared with unselected controls or even with controls seropositive for anti-HSV-2 with unknown clinical activity of herpes. Surprisingly, the effect was mainly a result of the A/O genotype; in patients with the O/O
Acknowledgments
This study was financially supported by the Medical Research Fund of Tampere University Hospital and the Maud Kuistila Foundation. We thank Ms. Marjo Leponiemi for her expert technical assistance.
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