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Canine Meningoencephalitis of Unknown Origin-The Search for Infectious Agents in the Cerebrospinal Fluid via Deep Sequencing.

ABSTRACT: Meningoencephalitis of unknown origin (MUO) describes a group of meningoencephalitides in dogs with a hitherto unknown trigger. An infectious agent has been suggested as one possible trigger of MUO but has not been proven so far. A relatively new method to screen for viral RNA or DNA is next-generation sequencing (NGS) or deep sequencing. In this study, a metagenomics analysis of the virome in a sample is analyzed and scanned for known or unknown viruses. We examined fresh-frozen CSF of 6 dogs with MUO via NGS using a modified sequence-independent, single-primer amplification protocol to detect a possible infectious trigger. Analysis of sequencing reads obtained from the six CSF samples showed no evidence of a virus infection. The inability to detect a viral trigger which could be implicated in the development of MUO in the examined population of European dogs, suggests that the current techniques are not sufficiently sensitive to identify a possible virus infection, that the virus is already eliminated at the time-point of disease outbreak, the trigger might be non-infectious or that there is no external trigger responsible for initiating MUO in dogs.

SUBMITTER: Nessler JN

PROVIDER: S-EPMC8688736 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionNon-infectious inflammatory diseases of the central nervous system in dogs, such as steroid responsive meningitis-arteritis (SRMA) and meningoencephalitis of unknown origin (MUO), represent a common clinical challenge that needs extensive and multimodal work-up to reach a presumptive diagnosis. Both diseases are presumably caused by dysregulations of the immune system, but further research is needed in order to understand the molecular mechanisms behind each disease and to optimize treatment.MethodsBy next-generation sequencing and subsequent quantitative real-time PCR (qPCR) verification, we designed a prospective case-control pilot study to analyze the small RNA profiles of cerebrospinal fluid from dogs suffering from MUO (N = 5), dogs suffering from SRMA (N = 8), and healthy dogs (N = 5) presented for elective euthanasia used as the Control group.ResultsOur results showed an overall enrichment in Y-RNA fragments across all samples, followed by microRNAs (miRNAs) and ribosomal RNAs as the major findings. Additional traces of short RNA reads mapped to long non-coding RNAs and protein-coding genes were also found. From the detected canine miRNAs, miR-21, miR-486, miR-148a, miR-99a, miR-191 and miR-92a were among the most abundant. Dogs with SRMA showed higher differences in miRNA abundance than dogs with MUO when compared to healthy dogs, and miR-142-3p was consistently detected as differentially upregulated in both diseases, although at a low concentration. Moreover, miR-405-5p and miR-503-5p showed different profiles between SRMA and MUO dogs. Subsequent qPCR analyses confirmed miR-142-5p, miR-191-5p and miR-92a-3p as significantly upregulated miRNAs in dogs with SRMA and/or MUO.DiscussionCerebrospinal fluid is a challenging biological material to use for profiling miRNAs due to the low content of circulating RNAs. Despite this, we could confirm several miRNAs being differentially abundant when comparing healthy dogs and dogs with MUO and SRMA, respectively. The results of this study indicate a potential role of miRNAs in the underlying molecular mechanisms of these diseases and establish the basis for further studies.

Project description:Prospective study.To identify proteins with differential expression in the cerebrospinal fluid (CSF) from 15 clinically normal (control) dogs and 15 dogs with cervical spondylomyelopathy (CSM).Canine CSM is a spontaneous, chronic, compressive cervical myelopathy similar to human cervical spondylotic myelopathy. There is a limited knowledge of the molecular mechanisms underlying these conditions. Differentially expressed CSF proteins may contribute with novel information about the disease pathogenesis in both dogs and humans.Protein separation was performed with 2-dimensional electrophoresis. A Student t test was used to detect significant differences between groups (P < 0.05). Three comparisons were made: (1) control versus CSM-affected dogs, (2) control versus non-corticosteroid-treated CSM-affected dogs, and (3) non-corticosteroid-treated CSM-affected versus corticosteroid-treated CSM-affected dogs. Protein spots exhibiting at least a statistically significant 1.25-fold change between groups were selected for subsequent identification with capillary-liquid chromatography tandem mass spectrometry.A total of 96 spots had a significant average change of at least 1.25-fold in 1 of the 3 comparisons. Compared with the CSF of control dogs, CSM-affected dogs demonstrated increased CSF expression of 8 proteins including vitamin D-binding protein, gelsolin, creatine kinase B-type, angiotensinogen, ?-2-HS-glycoprotein, SPARC (secreted protein, acidic, rich in cysteine), calsyntenin-1, and complement C3, and decreased expression of pigment epithelium-derived factor, prostaglandin-H2 D-isomerase, apolipoprotein E, and clusterin. In the CSF of CSM-affected dogs, corticosteroid treatment increased the expression of haptoglobin, transthyretin isoform 2, cystatin C-like, apolipoprotein E, and clusterin, and decreased the expression of angiotensinogen, ?-2-HS-glycoprotein, and gelsolin.Many of the differentially expressed proteins are associated with damaged neural tissue, bone turnover, and/or compromised blood-spinal cord barrier. The knowledge of the protein changes that occur in CSM and upon corticosteroid treatment of CSM-affected patients will aid in further understanding the pathomechanisms underlying this disease.N/A.

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Canine Meningoencephalitis of Unknown Origin-The Search for Infectious Agents in the Cerebrospinal Fluid via Deep Sequencing.

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