Genetic influence of Toll-like receptors on non-HIV cryptococcal meningitis: An observational cohort study

Abstract

BackgroundCryptococcal meningitis (CM) is a significant source of mortality, the pathogenesis of which has not been fully understood, especially in non-HIV infected populations. We aimed to explore the potential genetic influence of Toll-like receptor (TLR) on non-HIV CM.MethodsThis observational cohort study was done in two stages: a discovery stage and a validation stage. A case-control genetic association study was conducted between 159 non-HIV CM patients and 468 healthy controls. TLR SNPs significantly related to susceptibility went further validation in a second cohort of 583 subjects from a certain district. Associations among TLR SNPs, cerebrospinal fluid (CSF) cytokine concentrations, and clinical severity were explored in a third cohort of 99 previously untreated non-HIV CM patients. Logistic regression model was used to determine the independent predictors for disease severity.FindingsIn the discovery stage, eight TLR SNPs exhibited significant genetic susceptibility to non-HIV CM, one of which was validated in a population validation of HIV-infected cases while none survived in non-HIV cases. CSF cytokine detections showed that 18 cytokines were significantly over-expressed in severely ill patients. Two of the 8 SNPs (rs5743604 and rs3804099) were also significantly associated with disease severity. Specifically, the rs3804099 C/T genotype was further found to be correlated to 12 of the 18 up-regulated cytokines in severe patients. In addition, high levels of interleukin (IL)-10 in CSF (OR 2·97, 95% CI 1·49–5·90; p = 0·002) was suggested as an independent predictor for severity after adjusted for possible confounders.InterpretationTLR participates in both the occurrence and the pathogenesis of non-HIV CM. The in situ immune responses of CM were under genetic influence of TLR and contributed to disease severity.FundNational Natural Science Foundation of China and National Key Basic Research Program of China (973 Program).

Risk-Based Estimate of Human Fungal Disease Burden, China

“…In contrast to other countries, where CM is often diagnosed in patients with HIV or immunocompromised patients, in China, a high proportion of cryptococcosis was reported in immunocompetent persons (34). Jiang et al reported on 159 HIV-negative patients with CM, of whom 85 were normal hosts; however, whether these persons were immunocompetent is unknown, because several genetic predisposition factors for CM have been found in the ethnic Chinese population (46). Most large-scale studies have been conducted in adults; few were dedicated to pediatric populations.…”

Association of cytokine gene polymorphisms with chronic hepatitis C virus genotype 1b infection in Chinese Han population

“…IL-10 belongs to Th2-type anti-inflammatory cytokine, acts in highly coordinated cytokine network and interferes with innate and adaptive protective immunity in infectious diseases. [ 25 , 26 ] IL-10 also interferes with the balance of Th1/Th2 cells, negatively regulates the response of Th1 lymphocytes, and prevents immunologic injury caused by exacerbated immune responses. [ 27 ] It is believed that ∼50% to 70% of the observed variation in IL-10 production contributes to genetic factors, mainly the polymorphisms in the promoter region of IL-10 gene, those were rs1800896, rs1800871, and 1800872.…”

Host Genetics Takes a Toll on Immunity to Cryptococcus

“…In this issue of EBioMedicine , Jiang and colleagues report on the association of genetic variants in Toll-like receptors (TLRs) and the risk of non-HIV cryptococcal meningitis (CM) [ 1 ]. CM represents a major cause of morbidity and mortality in HIV-infected patients, especially in sub-Saharan Africa.…”

“…These receptors have been vastly implicated in anti-cryptococcal immunity [ 5 ], however the question remains as to which TLR-ligand interaction is actually required for the recognition, phagocytosis, and subsequent fungal killing. In this study, Jiang and colleagues provide both genetic and immunological evidence highlighting the pivotal role of TLR-dependent mechanisms of cryptococcal recognition and cytokine production in defining susceptibility to human CM in HIV-uninfected individuals [ 1 ].…”

“…Although recent advances have contributed to an expanding number of genetic variants associated with the risk of fungal disease, little is known about their functional consequences through effects on defined biological processes. The study by Jiang and colleagues correlated the presence of genetic variants in TLRs with the levels of cytokines detected in the cerebrospinal fluid (CSF) of infected patients [ 1 ]. Besides providing functional validation to the association studies, these findings uncover the potential usefulness of CSF cytokines as diagnostic biomarkers for CM, particularly if combined with fungal surrogate markers and integrating the genetic risk profile of the patient [ 8 ].…”