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Evidence of Human Parvovirus B19 Infection in the Post-Mortem Brain Tissue of the Elderly.

ABSTRACT: After primary exposure, the human parvovirus B19 (B19V) genome may remain in the central nervous system (CNS), establishing a lifelong latency. The structural characteristics and functions of the infected cells are essential for the virus to complete its life cycle. Although B19V has been detected in the brain tissue by sequencing PCR products, little is known about its in vivo cell tropism and pathogenic potential in the CNS. To detect B19V and investigate the distribution of its target cells in the CNS, we studied brain autopsies of elderly subjects using molecular virology, and optical and electron microscopy methods. Our study detected B19V in brain tissue samples from both encephalopathy and control groups, suggesting virus persistence within the CNS throughout the host's lifetime. It appears that within the CNS, the main target of B19V is oligodendrocytes. The greatest number of B19V-positive oligodendrocytes was found in the white matter of the frontal lobe. The number was significantly lower in the gray matter of the frontal lobe (p = 0.008) and the gray and white matter of the temporal lobes (p < 0.0001). The morphological changes observed in the encephalopathy group, propose a possible B19V involvement in the demyelination process.

SUBMITTER: Skuja S

PROVIDER: S-EPMC6267580 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Evidence of Human Parvovirus B19 Infection in the Post-Mortem Brain Tissue of the Elderly.

Skuja Sandra S Vilmane Anda A Svirskis Simons S Groma Valerija V Murovska Modra M

Viruses 20181025 11

After primary exposure, the human parvovirus B19 (B19V) genome may remain in the central nervous system (CNS), establishing a lifelong latency. The structural characteristics and functions of the infected cells are essential for the virus to complete its life cycle. Although B19V has been detected in the brain tissue by sequencing PCR products, little is known about its in vivo cell tropism and pathogenic potential in the CNS. To detect B19V and investigate the distribution of its target cells i ...[more]

PMID: 30366357

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Project description:BackgroundHuman parvovirus B19 (HPV B19) is a single-stranded DNA virus. The detection rate of HPV B19 in the blood of healthy blood donors using PCR technology was reported to be 6.323/100000. However, that among hospitalized patients suspected of being infected with a pathogenic microorganism is unknown.MethodsA retrospective analysis was conducted on 2,182 high-throughput NGS results for 1,484 inpatients admitted to the First Affiliated Hospital of Zhengzhou University from January 2020 to October 2021 who were suspected of being infected with a pathogenic microorganism, as well as on clinical data of some HPV B19-positive patients.ResultsHuman parvovirus B19 was detected in 39 samples from 33 patients. The positivity rate was 2.22% among patients and 1.78% among samples. HPV B19 was detected in 20 cerebrospinal fluid samples, 13 blood samples, 3 alveolar lavage fluid samples, 2 tissue samples, and 1 throat swab. Based on clinical symptoms and NGS results, 16 patients were diagnosed with HPV B19 infection. The number of HPV B19 sequences in these patients was greater than 6, and the patients showed common symptoms such as fever (14 cases), anemia (11 cases), and severe nervous system symptoms such as meningoencephalitis (9 cases) and Guillain-Barré syndrome with peripheral motor and sensory nerve axon damage (4 cases). All 16 patients had experienced events likely to lead to decreased immunity (11 had a history of trauma/surgery/major disease, 4 had a history of precursor infection, and 3 had used immunosuppressants) and 7 had a history of blood transfusion during hospitalization. After treatment with antiviral drugs (12 cases) and intravenous human immunoglobulin (3 cases), of the 16 patients, 14 patients improved.ConclusionThe HPV B19 infection rate in hospitalized patients suspected of microbial infection was 2.22%. Most patients with HPV B19 infection had a history of low immunity and blood transfusion. HPV B19 could be detected in various bodily fluids and tissues (especially cerebrospinal fluid) using NGS. Patients with severe HPV B19 infection may have nervous system damage such as Guillain-Barré syndrome and meningoencephalitis. Early diagnosis using NGS and treatment with antiviral drugs and immunoglobulin can improve prognosis.

Project description:Parvovirus B19 (B19V) infection can cause hematological disorders and fetal hydrops during pregnancy. Currently, no antivirals or vaccines are available for the treatment or prevention of B19V infection. To identify novel small-molecule antivirals against B19V replication, we developed a high-throughput screening (HTS) assay, which is based on an in vitro nicking assay using recombinant N-terminal amino acids 1 to 176 of the viral large nonstructural protein (NS1N) and a fluorescently labeled DNA probe (OriQ) that spans the nicking site of the viral DNA replication origin. We collectively screened 17,040 compounds and identified 2,178 (12.78%) hits that possess >10% inhibition of the NS1 nicking activity, among which 84 hits were confirmed to inhibit nicking in a dose-dependent manner. Using ex vivo-expanded primary human erythroid progenitor cells (EPCs) infected by B19V, we validated 24 compounds that demonstrated >50% in vivo inhibition of B19V infection at 10 μM, which can be categorized into 7 structure scaffolds. Based on the therapeutic index (half-maximal cytotoxic concentration [CC50]/half-maximal effective concentration [EC50] ratio) in EPCs, the top 4 compounds were chosen to examine their inhibitions of B19V infection in EPCs at two times of the 90% maximal effective concentration (EC90). A purine derivative (P7) demonstrated an antiviral effect (EC50 = 1.46 μM) without prominent cytotoxicity (CC50 = 71.8 μM) in EPCs and exhibited 92% inhibition of B19V infection in EPCs at 3.32 μM, which can be used as the lead compound in future studies for the treatment of B19V infection-caused hematological disorders. IMPORTANCE B19V encodes a large nonstructural protein, NS1. Its N-terminal domain (NS1N) consisting of amino acids 1 to 176 binds to viral DNA and serves as an endonuclease to nick the viral DNA replication origins, which is a pivotal step in rolling-hairpin-dependent B19V DNA replication. For high-throughput screening (HTS) of anti-B19V antivirals, we miniaturized a fluorescence-based in vitro nicking assay, which employs a fluorophore-labeled probe spanning the terminal resolution site (trs) and the NS1N protein, into a 384-well-plate format. The HTS assay showed high reliability and capability in screening 17,040 compounds. Based on the therapeutic index (half-maximal cytotoxic concentration [CC50]/half-maximal effective concentration [EC50] ratio) in EPCs, a purine derivative demonstrated an antiviral effect of 92% inhibition of B19V infection in EPCs at 3.32 μM (two times the EC90). Our study demonstrated a robust HTS assay for screening antivirals against B19V infection.

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Evidence of Human Parvovirus B19 Infection in the Post-Mortem Brain Tissue of the Elderly.

Publications

Evidence of Human Parvovirus B19 Infection in the Post-Mortem Brain Tissue of the Elderly.

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