Toll-Like Receptor-2 Arg753Gln Polymorphism and Herpes Virus Infections in Transplantation

Abstract

Toll-like receptors (TLR) mediate a phylogenetically primitive, nonclonal mechanism of pathogen recognition based on binding to structurally conserved pathogen-associated molecular patterns (1). Stimulation of TLR by its ligand results in the secretion of cytokines that mediate the innate immune control of infections while pathogen-directed adaptive immunity is established (1). Functional single nucleotide polymorphisms in TLRs are therefore hypothesized to influence the pathogenesis of infectious diseases (2). We conducted this hypothesis- generating study to determine the clinical relevance of TLR2 Arg753Gln polymorphism in transplant recipients. This particular TLR2 polymorphism predisposes to staphylococcal infections in humans (2). Ninety-five patients, consisting of 80 solid organ transplant (predominantly liver recipients [80%]) and 15 allogeneic hematopoietic stem cell transplant recipients, were screened for TLR2 Arg753Gln polymorphism using a LightCycler polymerase chain reaction assay (3). Five of 95 transplant recipients possessed the TLR2 Arg753Gln polymorphism (Table 1). Collectively, all five patients with the TLR2 Arg753Gln polymorphism developed at least one herpes infection during the first five years after transplantation: cytomegalovirus (CMV), n=4, including two CMV disease and two asymptomatic CMV infection; herpes simplex virus (HSV), n=2; Epstein-Barr virus (EBV), n=1; varicella zoster virus (VZV), n=1. Except for one patient with recurrent pneumonia due to presumed bacterial pathogen, there were no significant bacterial infections. By comparison, only two herpes infections (one asymptomatic CMV infection and one CMV disease) occurred in a group of five patients without TLR2 Arg753Gln polymorphism that were selected and matched to the cases based on age, gender, allograft type, CMV serostatus, and length of follow-up.TABLE 1: Clinical characteristics of five patients with toll-like receptor 2 Arg753Gln polymorphismThis study demonstrates that herpes virus infections are common among transplant recipients with TLR2 polymorphism. This clinical observation is supported by experimental data demonstrating the role of TLR2 in herpes virus pathogenesis (4). In experimental models, TLR2 was demonstrated as immune sensor for HSV, CMV, and VZV (5–9). Because cells with TLR2 Arg753Gln polymorphism have impaired response to its ligand (4), it is plausible that this could have predisposed to herpes infections. However, this study also demonstrates that the spectrum of illness due to herpes viruses among patients with TLR2 polymorphism varied from asymptomatic primary infection to recurrent and tissue-invasive reactivation disease. Of particular interest is the clinical course of CMV in patients four and five (Table 1). Characteristically, CMV-naïve recipients of allografts from CMV-seropositive donors are at highest risk of CMV disease. With TLR2 polymorphism, one would expect a defective immune response that leads to uncontrolled viral replication and CMV disease. On the contrary, the patients developed asymptomatic CMV infection, implying that TLR2 polymorphism does not by itself completely impede CMV-specific immunity. Indeed, the patients developed humoral responses within three months after transplantation. Although this study is novel since it is the first to assess the clinical relevance of TLR2 Arg753Gln polymorphism on infections after transplantation, it is limited from drawing substantive conclusions because of the small number of subjects. Nonetheless, the intriguing observations in this hypothesis-generating study should encourage further investigations aimed at assessing the impact of TLR polymorphisms on herpes and other infections after transplantation. Albert J.Eid Robert A. Brown Raymund R. Razonable Division of Infectious Diseases Mayo Clinic College of Medicine Rochester, MN