An association between single nucleotide polymorphisms within TLR and TREM-1 genes and infective endocarditis
Introduction
Infective endocarditis (IE) is a septic inflammation of the endocardium, which generally involves the lining of the heart chambers and heart valves [1]. Bacteria are believed to be the most common etiological agents in IE; in particular, the genera of Staphylococci, Streptococci and Enterococci, which are responsible for virtually all cases of the disease [1]. Other infectious agents, such as fungi, have also been reported to play a significant, albeit lesser role in the etiology of IE [2], [3]. In almost all cases, IE is accompanied by malaise, fever, chills, fatigue, and heart murmur. Other major symptoms of IE include anemia, abnormal urine color, Roth‘s spots, joint pain, Janeway lesions, excessive sweating and Osler‘s nodes [1]. Although the annual incidence of IE is relatively low (2–4 cases per 100,000 in the US and 15–60 cases per 1,000,000 in the world), the treatment of this pathology is currently a difficult task for clinicians. Despite substantial improvement in the detection and surgical management of IE during the last decades, the prognosis of patients with IE remains poor [4]. Currently, case fatality rates range from 10% in cases of IE caused by Streptococci to 30–40% in cases of acute IE due to Staphylococci, Streptococci aureus [5], [6]. Mortality may increase to up to 70% in certain high-risk populations [4].
The development of IE depends in many respects on how properly and effectively the immune system responds to infective agents. Accumulating evidence suggests a role for the inherited variation in genes of the immune system in the etiology of multiple diseases [7]. For instance, one of the most significant and promptly investigated types of inherited variation, called single nucleotide polymorphism (SNP), has long been studied as a potential predictive genomic biomarker [7]. The consequences of SNPs include alteration of expression or structure of proteins and enzymes, introduction of an alternative translation initiation codon or stop codon, and destabilisation of exonic mRNA [7]. Therefore, it could be suggested that SNPs in key immune system genes may alter susceptibility to IE occurrence development.
Toll-like receptors (TLRs) constitute a family of proteins which play a critical role in immunity. TLRs ensure recognition of pathogen-specific molecules (so-called pathogen-associated molecular patterns) and therefore lead to the activation of innate immune response [8]. Moreover, TLRs are known to participate in the activation of adaptive immune responses through T-helper and antigen-presenting cells [8]. Additionally, TLRs contribute to the stimulation of phagocytosis, synthesis of a plethora of cytokines, and expression of cell adhesion molecules [8]. Thereby, the efficacy of a proper immune response greatly depends on TLR-mediated recognition of a pathogen and further TLR-driven activation of intracellular signaling pathways. TLR’s form the focus of numerous research groups in the fields of biomedicine, molecular biology and immunology; numerous studies report that impaired TLR function and TLR signaling pathways due to SNPs may result in the elevated risk of occurrence of various pathologies, including autoimmune diseases, cancers and cardiovascular disorders [9], [10], [11].
Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) provides neutrophil and monocyte-mediated inflammatory responses launched by bacterial or fungal infection. In contrast to the TLR family, TREM-1 has been less extensively studied, however it plays a crucial role in the immune response nonetheless. Activation of TREM-1 leads to the neutrophil degranulation, the respiratory burst, and phagocytosis [12]. In addition, TREM-1 was associated with release of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, and numerous chemokines, including IL-8 and MCP-1. Moreover, it was recently demonstrated that TREM-1 has complex signal integration with certain TLRs; in particular, it was observed that TREM-1 repeatedly amplifies TLR-induced inflammatory responses during the course of infection [13]. Furthermore, there is evidence that TREM-1 synergises with bacterial lipopolysaccharide in the induction of expression of multiple genes, including IL-6 and TNF-α. Thus, the cross-talk between TREM-1 and TLRs appears complex [14]. To date, more than 200 polymorphic variants of TREM-1 gene are known [15]; however, almost all of them have not been investigated yet. Here, we speculate that inherited variation in the TREM-1 gene may bring alterations to the efficacy of the inflammatory response, and, consequently, modulate the susceptibility to various diseases.
In our study, we investigated whether eight SNPs within TLR (TLR1, TLR2, TLR4, and TLR6) genes and eight SNPs within the TREM-1 gene are associated with the susceptibility to IE.
Section snippets
Participants
In the present study we enrolled 110 consecutive Caucasian (Russian) individuals who underwent heart valve replacement surgery due to IE between 2009 and 2013 at the Kemerovo Cardiology Centre. All the IE cases were verified histologically and according to the modified Duke criteria (at least 1 major and 1 minor criteria or 3 minor criteria were fulfilled) [16], and all patients with IE underwent antibiotic therapy in the acute phase during the first admission to their district hospital.
Results
A total of 110 patients with IE and 300 healthy controls were enrolled in the study. The mean age was 48.5 (95%CI = 45.81–51.18, SD = 14.13) and 53.09 (95%CI = 51.61–54.57, SD = 13.06) for cases and controls, respectively. There were no significant differences in the baseline characteristics such as sex and age between cases and controls (Table 2). Native valve IE was diagnosed in 72.3% (n = 80) of subjects, with prosthetic valve IE being identified in the remaining 27.7% (n = 30) of individuals. There
Discussion
TLRs are commonly recognised as key regulators of susceptibility to both infectious and non-communicable diseases. Almost all TLRs are expressed in human cardiomyocytes and endothelial cells, and they are also known to play a role in various cardiovascular diseases, including atherosclerosis, ischaemia/reperfusion injury, cardiac dysfunction, viral myocarditis, and septic cardiomyopathy [19]. In addition, effective immune response driven by TLRs is dependent on the TREM-1 mediated amplification
Disclosure
The authors declare no conflict of interest. All the authors have read and approved the final article. Author contributions: A.S.G. and L.S.B. designed research, A.V.P., R.R.S., M.V.K., N.V.R., Yu.Yu.S., and A.E.Y. performed research, A.G.K. and A.E.Y. analyzed data, and A.E.Y. wrote the paper.
Acknowledgements
The authors are thankful to all who contributed to this study. Also, the authors want to express their gratitude to Dr. Alex Gordon-Weeks, a distinguished fellow of The Royal College of Surgeons of England, for his valuable commentaries and careful proofreading of the manuscript.
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