Transcriptomic signatures in whole blood of patients who acquire a chronic inflammatory response syndrome (CIRS) following an exposure to the marine toxin ciguatoxin.

James C Ryan,Ritchie C Shoemaker,Qingzhong Wu

doi:10.1186/s12920-015-0089-x

James C Ryan, Ritchie C Shoemaker + Show 1 more

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https://doi.org/10.1186/s12920-015-0089-x

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Abstract

BackgroundCiguatoxins (CTXs) are polyether marine neurotoxins found in multiple reef-fish species and are potent activators of voltage-gated sodium channels. It is estimated that up to 500,000 people annually experience acute ciguatera poisoning from consuming toxic fish and a small percentage of these victims will develop a chronic, multisymptom, multisystem illness, which can last years, termed a Chronic Inflammatory Response Syndrome (CIRS). Symptoms of ciguatera CIRS include fatigue, cognitive deficits, neurologic deficits, pain and sensitivity to light. There are few treatment options for ciguatera CIRS since little is known about its pathophysiology.MethodsThis study characterizes the transcriptional profile in whole blood of 11 patients with ciguatera-induced CIRS and 11 normal controls run in duplicate using Agilent one color whole genome microarrays. Differential expression was determined by using a combination of moderated t-test p-value and fold change (FC). Significant genes were subjected to gene ontology, principal component analysis and SVM classification. Seven significant genes found by microarray were validated by PCR.ResultsUsing a low stringency (p < 0.05 and FC > 1.4) and a high stringency (p < 0.01 and FC > 1.5) filter, the resulting gene sets of 185 and 55, respectively, showed clear separation of cases and controls by PCA as well as 100% classification accuracy by SVM, indicating that the gene profiles can separate patients from controls. PCR results of 7 genes showed a 95% correlation to microarray data. Several genes identified by microarray are important in wound healing (CD9, CD36, vWF and Factor XIII), adaptive immunity (HLA-DQB1, DQB2, IL18R1 and IL5RA) and innate immunity (GZMK, TOLLIP, SIGIRR and VIPR2), overlapping several areas shown to be disrupted in a mouse model of acute exposure to ciguatoxin. Another area of interest was differential expression of long, non-coding sequences, or lncRNA.ConclusionsDisruptions of innate and adaptive immune mechanisms were recorded at both the genomic and proteomic level. A disruption in the HLA-T cell receptor axis could indicate HLA haplotype sensitivity for this chronic syndrome, as noted in many autoimmune conditions. Taken together, these indicators of illness provide additional insights into pathophysiology and potential therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0089-x) contains supplementary material, which is available to authorized users.

Highlights

Ciguatoxins (CTXs) are polyether marine neurotoxins found in multiple reef-fish species and are potent activators of voltage-gated sodium channels
The fold change (FC) cut-off is considered the best indicator of true differential gene expression [15,16] and quantitative real-time PCR (qPCR) validation of Agilent microarray results at a minimum threshold of 1.4 FC has been robust at this specific genomic core [17]
Most differential gene expression remained under a 2 fold change, the little studied sialic acidbinding immunoglobulin-type lectin, SIGLEC14 exhibited by far the greatest degree of change at 7.5 FC

Summary

Introduction

Ciguatoxins (CTXs) are polyether marine neurotoxins found in multiple reef-fish species and are potent activators of voltage-gated sodium channels. As reviewed by Lewis [3], families of ciguatoxins have been isolated from the Pacific and Indian Oceans, along with the Caribbean Sea, and suites of CTX congeners have been distinguished by minor differences in their cyclic polyether backbone and different toxicities These heat stable, lipid soluble, cyclic polyether toxins are potent activators of voltage-gated sodium channels, and the consumption of toxic levels is characterized by acute gastrointestinal and neurological symptoms, including vomiting, diarrhea, abdominal pain, headache, tachycardia, prostration, severe localized itching, tingling of extremities and lips, and temperature reversal [4]. These long term symptoms can include fatigue, pain, weakness, depression and cognitive deficits, as well as hypersensitivity to inflammagen exposure [5]

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