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Genetic Influence of Toll-Like Receptors on Non-HIV Cryptococcal Meningitis: An Observational Cohort Study

39 Pages Posted: 24 Sep 2018

See all articles by Li-Ping Zhu

Li-Ping Zhu

Fudan University - Department of Infectious Diseases

Ying-Kui Jiang

Fudan University

Ji-Qin Wu

Fudan University

Xuan Wang

Fudan University

Rui-Ying Wang

Fudan University

Ling-Hong Zhou

Fudan University

Ching-Wan Yip

Fudan University

Li-Ping Huang

Fudan University

Jia-Hui Cheng

Fudan University; Fudan University - Department of Ophthalmology and Vision Science

Ya-Hong Chen

Fudan University

Hua Li

Government of the People's Republic of China - People's Liberation Army (PLA)

Li-Ping Zhu

Fudan University

Xin-Hua Weng

Fudan University

More...

Abstract

Background Cryptococcal 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 compare single nucleotide polymorphisms (SNPs) of Toll-like receptor (TLR) in non-HIV CM patients with those of healthy controls, and to assess the links among TLR SNPs, cytokine concentrations in cerebrospinal fluid (CSF), and clinical severity.

Methods This observational cohort study was done in 2 stages: a discovery stage and a validation stage. We conducted a case-control genetic association study between 159 non-HIV CM patients and 468 healthy controls. TLR SNPs significantly related to susceptibility were further validated in a second cohort of 583 subjects from a certain district. Cytokine concentrations in CSF were used to evaluate the in situ immune response of CNS after infection. Correlations among TLR SNPs, CSF cytokine concentrations, and clinical severity were validated in a third prospective cohort of 99 previously untreated non-HIV CM patients. Logistic regression model was used to determine the independent predictors for disease severity.

Findings In the discovery stage, the genotype distributions of 8 TLR SNPs in non-HIV CM patients exhibited a significant difference in comparison with controls, of which 3 SNPs remained statistically significant in patients without predisposing factors. In the validation stage, 5 of the 8 nominated TLR SNPs were found to influence CSF cytokine expression. Eighteen cytokines were significantly up-regulated in severely ill patients, among which 12 were affected by TLR2 rs3804099. The rs3804099 was also found in relation to disease severity. High IL-10 levels 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.

Interpretation TLR participate 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. Our findings inform of an opportunity for early evaluation and treatment of non-HIV CM. TLR might also become a potential target on which to base host-directed immunotherapy.

Funding: National Natural Science Foundation of China and National Key Basic Research Program of China (973 Program).

Declaration of Interest: We declare no competing interests.

Ethical Approval: Ethical approval was obtained from the medical ethics committee of Huashan Hospital, Mengchao Hepatobiliary Hospital, Fujian HIV/AIDS Diagnosis and Treatment Center, and No. 476 Hospital of Fuzhou General Hospital.

Keywords: Toll-like receptor, genetic polymorphism, non-HIV cryptococcal meningitis, CSF cytokine

Suggested Citation

Zhu, Li-Ping and Jiang, Ying-Kui and Wu, Ji-Qin and Wang, Xuan and Wang, Rui-Ying and Zhou, Ling-Hong and Yip, Ching-Wan and Huang, Li-Ping and Cheng, Jia-Hui and Chen, Ya-Hong and Li, Hua and Zhu, Li-Ping and Weng, Xin-Hua, Genetic Influence of Toll-Like Receptors on Non-HIV Cryptococcal Meningitis: An Observational Cohort Study (August 14, 2018). , EBioMedicine, Volume 37, November 2018, Pages 401-409, https://doi.org/10.1016/j.ebiom.2018.10.045, Available at SSRN: https://ssrn.com/abstract=3234888 or http://dx.doi.org/10.2139/ssrn.3234888

Li-Ping Zhu (Contact Author)

Fudan University - Department of Infectious Diseases ( email )

12 Central Urumqi Road
Shanghai, 200040
China

Ying-Kui Jiang

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

Ji-Qin Wu

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

Xuan Wang

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

Rui-Ying Wang

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

Ling-Hong Zhou

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

Ching-Wan Yip

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

Li-Ping Huang

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

Jia-Hui Cheng

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

Fudan University - Department of Ophthalmology and Vision Science ( email )

United States

Ya-Hong Chen

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

Hua Li

Government of the People's Republic of China - People's Liberation Army (PLA)

Fujian
China

Li-Ping Zhu

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

Xin-Hua Weng

Fudan University

Beijing West District Baiyun Load 10th
Shanghai, 100045
China

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