Dataset Information

Enrichment of Retroviral Sequences in Brain Tissue from Patients with Severe Demyelinating Diseases.

ABSTRACT: Background:Our group has used deep sequencing to identify viral RNA signatures in human brain specimens. We have previously used this method to detect HSV1, GBV-C, and measles virus sequence in brain tissue from deceased donors. Deep sequencing was performed on brain specimens from a cohort of patients who died with progressive forms of MS, revealing evidence of increased expression of some human endogenous retrovirus (HERV) domains. Objectives:Identify RNA sequences and new antigens involved in the pathogenesis of MS. Methods:Deep sequencing was performed on RNA extracted from 12 progressive MS, 2 neuromyelitis optica (MS/NMO = demyelination group), 14 normal control, and 7 other neurologic disease (OND) control frozen brain specimens. The resulting single-ended 50 bp sequences (reads) were compared to a non redundant viral database representing (NRVDB) all 1.2 M viral records in GenBank. A retroviral gene catalog (RVGC) was prepared by identifying human genetic loci (GRCh37.p13) homologous to domains contained in the Gypsy 2.0 retro element database. Reads were aligned to the RVGC and human transcriptome with Bowtie2. The resulting viral hit rates (VHRs) were normalized by the number of high quality reads. The expression of human genes, including HERVs, was determined using Cufflinks. Comparisons between the groups were performed using the false discovery rate. Results:Fifty to 131 million high quality reads per specimen were obtained. Comparison of the reads to the NRVDB suggested that the demyelination and OND specimens had higher VHRs against some retroviral sequences compared with the controls. This was confirmed by retroviral domain averaging. Gene expression analysis showed differential expression among some HERV sequences. Single read mapping revealed one envelope and one reverse transcriptase sequence record that were significantly enriched among the demyelination samples compared to the normal controls. Less restrictive (comprehensive) read mapping showed that 2 integrase, 2 core, 2 envelope, and 3 KRAB sequences that were overexpressed in the demyelination group. Conclusions:These data demonstrate that some endogenous retroviral sequences are significantly overexpressed in these demyelination brain tissue specimens, but the magnitude of this overexpression is small. This is consistent with the concept of HERV activation as a part of the innate immune response.

SUBMITTER: Kriesel JD

PROVIDER: S-EPMC5707126 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Enrichment of Retroviral Sequences in Brain Tissue from Patients with Severe Demyelinating Diseases.

Kriesel J D JD Bhetariya P J PJ Chan B K BK Wilson T T Fischer K F KF

Journal of emerging diseases and virology 20170716 2

<h4>Background</h4>Our group has used deep sequencing to identify viral RNA signatures in human brain specimens. We have previously used this method to detect HSV1, GBV-C, and measles virus sequence in brain tissue from deceased donors. Deep sequencing was performed on brain specimens from a cohort of patients who died with progressive forms of MS, revealing evidence of increased expression of some human endogenous retrovirus (HERV) domains.<h4>Objectives</h4>Identify RNA sequences and new antig ...[more]

PMID: 29202119

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Project description:A panel of 10 IgG enzyme-linked immunosorbent assays (ELISAs) were developed for the detection of anti-microbial immune responses in the cerebrospinal fluid (CSF) of patients with demyelinating diseases (DD). The anti-microbial ELISA assays follow on prior human brain tissue RNA sequencing studies that established multiple sclerosis (MS) microbial candidates. Lysates included in the ELISA panel were derived from Akkermansia muciniphila, Atopobium vaginae, Bacteroides fragilis, Lactobacillus paracasei, Odoribacter splanchnicus, Pseudomonas aeruginosa, Cutibacterium (Propionibacterium) acnes, Fusobacterium necrophorum, Porphyromonas gingivalis, and Streptococcus mutans. CSF responses from patients with demyelinating diseases (DD, N = 14) were compared to those with other neurological diseases (OND, N = 8) and controls (N = 13). Commercial positive and negative control CSF specimens were run with each assay. ELISA index values were derived for each specimen against each of the 10 bacterial lysates. CSF reactivity was significantly higher in the DD group compared to the controls against Akkermansia, Atopobium, Bacteroides, Lactobacillus, Odoribacter, and Fusobacterium. Four of the 11 tested DD group subjects had elevated antibody indexes against at least one of the 10 bacterial species, suggesting intrathecal antibody production. This CSF serological study supports the hypothesis that several of the previously identified MS candidate microbes contribute to demyelination in some patients. KEY MESSAGES: A panel of 10 IgG enzyme-linked immunosorbent assays (ELISAs) were developed for the detection of anti-microbial immune responses in the cerebrospinal fluid (CSF) of patients with demyelinating diseases, including multiple sclerosis and acute disseminated encephalomyelitis. CSF reactivity was significantly higher in the demyelination group compared to the controls against the bacteria Akkermansia, Atopobium, Bacteroides, Lactobacillus, Odoribacter, and Fusobacterium. Several of the demyelination subjects had elevated antibody indexes against at least one of the 10 antigens, suggesting at least limited intrathecal production of anti-bacterial antibodies. This CSF serological study supports the hypothesis that several of the previously identified MS candidate microbes contribute to demyelination in some patients.

Project description:BACKGROUND: Endogenous retroviral sequences (ERVs) are integral parts of most eukaryotic genomes and vastly outnumber exogenous retroviruses (XRVs). ERVs with a relatively complete structure were retrieved from the genetic archives of humans and chickens, diametrically opposite representatives of vertebrate retroviruses (over 3300 proviruses), and analyzed, using a bioinformatic program, RetroTector, developed by us. This rich source of proviral information, accumulated in a local database, and a collection of XRV sequences from the literature, allowed the reconstruction of a Pol based phylogenetic tree, more extensive than previously possible. The aim was to find traits useful for classification and evolutionary studies of retroviruses. Some of these traits have been used by others, but they are here tested in a wider context than before. RESULTS: In the ERV collection we found sequences similar to the XRV-based genera: alpha-, beta-, gamma-, epsilon- and spumaretroviruses. However, the occurrence of intermediates between them indicated an evolutionary continuum and suggested that taxonomic changes eventually will be necessary. No delta or lentivirus representatives were found among ERVs. Classification based on Pol similarity is congruent with a number of structural traits. Acquisition of dUTPase occurred three times in retroviral evolution. Loss of one or two NC zinc fingers appears to have occurred several times during evolution. Nucleotide biases have been described earlier for lenti-, delta- and betaretroviruses and were here confirmed in a larger context. CONCLUSION: Pol similarities and other structural traits contribute to a better understanding of retroviral phylogeny. "Global" genomic properties useful in phylogenies are i.) translational strategy, ii.) number of Gag NC zinc finger motifs, iii.) presence of Pro N-terminal dUTPase (dUTPasePro), iv.) presence of Pro C-terminal G-patch and v.) presence of a GPY/F motif in the Pol integrase (IN) C-terminal domain. "Local" retroviral genomic properties useful for delineation of lower level taxa are i.) host species range, ii.) nucleotide compositional bias and iii.) LTR lengths.

Dataset Information

Enrichment of Retroviral Sequences in Brain Tissue from Patients with Severe Demyelinating Diseases.

Publications

Enrichment of Retroviral Sequences in Brain Tissue from Patients with Severe Demyelinating Diseases.

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