C7 genotype of the donor may predict early bacterial infection after liver transplantation

Owing to improved surgical techniques and new immunosuppressive drugs, recipient survival after liver transplantation (LT) has increased steadily, with a current 5-year survival rate of between 70% and 80%1. However, post-transplantation infection causes high mortality and remains a significant challenge; 50–90% of deaths within six months of LT are linked to infection2. Bacterial infections are the most frequently (70%) occurring infectious complications post-transplantation, followed by viral (20%) and fungal infections (8%), and are the leading cause of morbidity and mortality in liver transplant recipients3,4,5. Bacterial infections can occur at any time after LT, but most bacterial infections occur less than 6 months after LT6. Therefore, identification of risk factors to allow prediction of early bacterial infection is a pivotal measure for improving the survival of LT recipients by facilitating early, specific treatment and clinical combinational interventions. High-risk factors for bacterial infection in recipients include critical illness, prolonged operation time, overall level of immunosuppression, postoperative care, and technical complexity of the LT surgery, as well as the occurrence of invasive diagnostic procedures within 6 months of transplantation7,8. In accordance with this, our previous studies also demonstrated that these were high-risk factors for bacterial infection9,10. Thus, by shortening the operation time, improving postoperative care, appropriately reducing the dose of immunosuppressive drugs, and limiting invasive diagnostic procedures, the incidence of bacterial infection in LT recipients can be significantly reduced. However, for some recipients, bacterial infections are inevitable11, which indicates that these patients are inherently susceptible to infection. It is conceivable that this susceptibility may be related to the genetics of the donor or the recipient. Many studies have focused on the role of genetic factors in the recipient, such as IL28β12, and TLR413, in relation to infection; however, the impact of donor genetics on infection after LT has been underestimated. After LT, the donor liver replaces the recipient liver to perform a variety of crucial physiological functions, including the detoxification of various metabolites, the production of biochemicals necessary for digestion, and protein synthesis. Specifically, the liver is responsible for biosynthesis of between 80% and 90% of plasma complement components14. The complement system plays an important role in mediating both acquired and innate responses against microbial infections14. The complement system can be activated by the classical, lectin and alternative pathways. Each of these leads to activation of the terminal pathway and formation of the membrane attack complex (MAC or C5b-9) to lyse foreign entities14. In addition, because the genetic backgrounds of the donor and recipient are different, the functionality of the donor liver in the recipient and interaction of the donor liver with the recipient immune system will play essential roles in the determination of recipient immunity against bacterial infection. In support of this, an early study using specific target gene sequences has demonstrated that donor polymorphisms in the gene encoding mannose-binding lectin (MBL2), a critical component for lectin pathway activation, influence the risk of potentially life-threatening infections after LT15,16. To fully understand the susceptibility to infection of liver transplant recipients, we investigated the genetic contributions of the donor liver to the incidence of infection after LT in a genome-wide genetic variation analysis of donor liver gene expression; this approach is known as expression quantitative trait loci (eQTL) analysis17. Genome-wide association studies (GWAS) have found that the majority of allelic variants linked with disease states are located in non-coding regions of the genome, suggesting that complex pathologies are primarily influenced by genetic control of gene expression. Such non-coding genomic regions with the capacity to affect specific mRNA expression levels are termed eQTLs17, and their characterization may thus facilitate an improved understanding of disease susceptibility and identification of important molecular drivers of pathology. Furthermore, acquisition of the eQTL dataset of the donor liver may extend our understanding of the mechanisms by which donor genetics can influence the etiology of recipient infection. Therefore, using this approach, we analyzed 77 donor livers; 32 of the recipients had an infection within six months of transplantation and the other 45 did not. The most significant differences between these two groups were found in the complement genes. Complement is an important component of the innate immune system and mediates the initial response to infections by pathogenic microorganisms14. Subsequently, we confirmed these results in an extended validation group of 113 patients and found that polymorphisms in two complement component genes, C7 (for MAC formation) and MBL2, were significantly associated with bacterial infection. Specifically, we found that the donor C7 rs6876739 CC genotype was associated with lower levels of recipient C7 protein expression, soluble MAC, and IL-1β compared with the donor C7 rs6876739 TT genotype. In vitro, the MAC significantly triggered NLRP3 inflammasome activation and IL-1β release, suggesting that C7 might defend against bacteria by inducing MAC formation, leading to NLRP3 inflammasome activation and IL-1β release. Our findings may be helpful in identifying transplantation recipients at risk of bacterial infection prior to surgery and may contribute to novel infection prevention strategies and improvement of postoperative outcomes.