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14-3-3? protein expression in eosinophilic meningitis caused by Angiostrongylus cantonensis infection.

ABSTRACT: BACKGROUND: Angiostrongylus cantonensis is a parasite endemic in the Southeast Asian and Pacific regions. Humans are incidentally infected either by eating uncooked intermediate hosts or by consuming vegetables containing the living third-stage larvae. The 14-3-3? protein is a cerebrospinal fluid (CSF) marker of neuronal damage during the development of Creutzfeldt-Jakob disease. In addition, increased 14-3-3? protein is also found in CSF from patients with a variety of neurological disorders. The goal of this study is to determine the roles of serum/CSF14-3-3? protein in patients with eosinophilic meningitis. METHODS: In a cohort study among nine Thai laborers with eosinophilic meningitis due to eating raw snails (Pomacea canaliculata), we examined the CSF weekly while patients were still hospitalized and followed up the serum for 6 months. The levels of 14-3-3? protein in CSF were analyzed by western blot and an in-house 14-3-3? enzyme-linked immunosorbent assay (ELISA) measurement was established and tested in an animal model of eosinophilic meningitis. RESULTS: The elevated 14-3-3? level was detected in the CSF from eight out of nine (81%) patients After 2 weeks of treatment, all patients showed a declined level or cleared of 14-3-3? protein in the CSF. By developing an in-house ELISA for measurement of 14-3-3? protein, it was found that the serum 14-3-3? level was significantly increased in patients during initial visit. . This finding was consistent to the animal experiment result in which there was severe blood brain barrier damage three weeks after infection and increased 14-3-3? protein expression in the CSF and serum by western blot and in house ELISA. After treatment, the serum 14-3-3? level in meningitis patients was rapidly returned to normal threshold. There was a correlation between initial CSF 14-3-3? level with severity of headache (r?=?0.692, p?=?0.039), CSF pleocytosis (r?=?0.807, p?=?0.009) and eosinophilia (r?=?0.798, p?=?0.01) in the CSF of patients with eosinophilic meningitis (Spearman's correlation test). CONCLUSIONS: The serum 14-3-3? concentrations may constitute a useful marker for blood brain barrier damage severity and follow up in patients with eosinophilic meningitis caused by A. cantonensis.

SUBMITTER: Tsai HC

PROVIDER: S-EPMC3932789 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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14-3-3β protein expression in eosinophilic meningitis caused by Angiostrongylus cantonensis infection.

Tsai Hung-Chin HC Huang Yen-Lin YL Chen Yao-Shen YS Yen Chuan-Min CM Tsai Rachel R Lee Susan Shin-Jung SS Tai Ming-Hong MH

BMC research notes 20140220

<h4>Background</h4>Angiostrongylus cantonensis is a parasite endemic in the Southeast Asian and Pacific regions. Humans are incidentally infected either by eating uncooked intermediate hosts or by consuming vegetables containing the living third-stage larvae. The 14-3-3β protein is a cerebrospinal fluid (CSF) marker of neuronal damage during the development of Creutzfeldt-Jakob disease. In addition, increased 14-3-3β protein is also found in CSF from patients with a variety of neurological disor ...[more]

PMID: 24555778

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Project description:The 14-3-3 proteins are cerebrospinal fluid (CSF) markers of neuronal damage during infectious meningitis and Creutzfeldt-Jakob disease. Little is known about dynamic changes in the individual isoforms in response to parasitic eosinophilic meningitis. The purposes of this study were to determine the 14-3-3 protein isoform patterns, examine the kinetics and correlate the severity of blood brain barrier (BBB) damage with the expressions of these markers in mice with eosinophilic meningitis. Mice were orally infected with 50 A. cantonensis L3 via an oro-gastric tube and sacrificed every week for 3 consecutive weeks after infection. The Evans blue method and BBB junctional protein expressions were used to measure changes in the BBB. Hematoxylin and eosin staining was used to analyze pathological changes in the mice brains following 1-3 weeks of infection with A. cantonensis. The levels of 14-3-3 protein isoforms in serum/CSF and brain homogenates were analyzed by Western blot, and immunohistochemistry (IHC) was used to explore the different isoform distributions of 14-3-3 proteins and changes in BBB junctional proteins in the mice brain meninges. Dexamethasone was injected intraperitoneally from the seventh day post infection (dpi) until the end of the study (21 dpi) to study the changes in BBB junctional proteins. The amounts of Evans blue, tight junction and 14-3-3 protein isoforms in the different groups of mice were compared using the nonparametric Kruskal-Wallis test. There were significant increases in 14-3-3 protein isoforms ? and ? in the CSF in the second and third weeks after infection compared to the controls and first week of infection, which were correlated with the severity of BBB damage in brain histology, and Evans blue extravasation. Using IHC to assess the distribution of 14-3-3 protein isoforms and changes in BBB junctional proteins in the mice brain meninges, the expressions of isoforms ?, ?, ?, and ? and junctional proteins occludin and claudin-5 in the brain meninges increased over a 3-week period after infection compared to the controls and 1 week after infection. The administration of dexamethasone decreased the expressions of BBB junctional proteins occludin and claudin-5 in the mice brain meninges. Our findings support that 14-3-3 proteins ? and ? can potentially be used as a CSF marker of neuronal damage in parasitic eosinophilic meningitis caused by A. cantonensis.

Project description:BACKGROUND:Angiostrongylus cantonensis, an important foodborne parasite, can induce serious eosinophilic meningitis in non-permissive hosts, such as mouse and human. However, the characteristics and mechanisms of the infection are still poorly understood. This study sought to determine the key molecules and its underlying mechanism in inducing brain eosinophilic infiltration caused by Angiostrongylus cantonensis. METHODS:Mathematical models were established for prediction of significantly changing genes and the functional associated protein with RNA-seq data in Angiostrongylus cantonensis infection. The expression level of Chi3l3, the predicted key molecule, was verified using Western blotting and real-time quantitative PCR. Critical cell source of Chi3l3 and its relationship with eosinophils were identified with flow cytometry, immunohistochemistry, and further verified by macrophage depletion using liposomal clodronate. The role of soluble antigens of Angiostrongylus cantonensis in eosinophilic response was identified with mice airway allergy model by intranasal administration of Alternaria alternate. The relationship between Chi3l3 and IL-13 was identified with flow cytometry, Western blotting, and Seahorse Bioscience extracellular flux analyzer. RESULTS:We analyzed the skewed cytokine pattern in brains of Angiostrongylus cantonensis-infected mice and found Chi3l3 to be an important molecule, which increased sharply during the infection. The percentage of inflammatory macrophages, the main source of Chi3l3, also increased, in line with eosinophils percentage in the brain. Network analysis and mathematical modeling predirect a functional association between Chi3l3 and IL-13. Further experiments verified that the soluble antigen of Angiostrongylus cantonensis induce brain eosinophilic meningitis via aggravating a positive feedback loop between IL-13 and Chi3l3. CONCLUSIONS:We present evidences in favor of a key role for macrophave-derived Chi3l3 molecule in the infection of Angiostrongylus cantonensis, which aggravates eosinophilic meningitis induced by Angiostrongylus cantonensis via a IL-13-mediated positive feedback loop. These reported results constitute a starting point for future research of angiostrongyliasis pathogenesis and imply that targeting chitinases and chitinase-like-proteins may be clinically beneficial in Angiostrongylus cantonensis-induced eosinophilic meningitis.

Dataset Information

14-3-3? protein expression in eosinophilic meningitis caused by Angiostrongylus cantonensis infection.

Publications

14-3-3β protein expression in eosinophilic meningitis caused by Angiostrongylus cantonensis infection.

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