VirusBank

html`
  <h3>${virus}</h3>
  <p>&nbsp;</p>
`

Zika virus (ZIKV)

Zika virus infections are usually asymptomatic, but when symptoms do occur, they commonly include fever, joint pain, red eyes, headache, and a maculopapular rash.

The disease has been associated with Guillain-Barre syndrome.

Complication in pregnant woman include microcephaly and other brain malformations.

Data reported from 2022 https://wwwnc.cdc.gov/travel/page/zika-information

ZIKV was first isolated in Africa, 1947.

2013 Outbreak in Americas, French Polynesia associate Guillain-Barre syndrome , defect birth , microcephaly.

Include in the Blueprint priority diseases of WHO.

2018 and 2019 number of cases decline, although cases of ZIKV persists at low levels in several countries.

In 2022 was reported 3000 cases, and 4 ZIKV-related deaths.

There are no approved vaccines or antivirals available at the moment for the prevention or treatment ZIKV infection.

renderVirusToolbox("flaviviruses", "ZIKV")

Cell-based assays

CPE reduction assay

This antiviral assay measures the ability of a tested compound to protect infected cells from virus-induced cytopathic effects (mostly virus-induced cell death). The cell viability can be determined in a colorimetric assay using MTS/PMS method.

Virus yield assay

This antiviral assay measures the ability of a tested compound to inhibit the viral replication in an infected cell culture through quantifying the viral RNA and the infectious virus loads released in the supernatant. This assay can be used for validation of compounds that show efficacy in CPE-reduction assays and to confirm that the compounds have direct effect on viral replication (not only cytoprotective).

Delay of treatment assay (Time-of-addition)

This a test to determine the stage(s) of the viral replication cycle at which the compound exerts its antiviral effect. Briefly, cells are treated with the compound at different time points prior or after the infection with the virus then cells are incubated for example until the end of one or 2 replication cycles. At the end of incubation, the intracellular and extracellular viral RNA loads at each time point are quantified by qRT-PCR to determine at which stage(s) the compound is still effective and when it loses its antiviral efficacy.

Plaque assay

This assay is a standard method to quantify infectious virus titers in a sample. Briefly, the test sample is serially diluted then aliquot of each dilution is added to a well in a cell culture plate with incubation to allow virus attachment followed by removal of the viral input and adding overlay of agarose or similar viscous material that limit the spread of viral infection. Under this condition, the attached virion will start to replicate producing more virions that will kill surrounding cells to generate a hole or plaque in the cell monolayer. By removal of the overlay and staining the live cells for e.g. by Crystal violet or methylene blue, this will provide a dark background for clear visualization of plaques. By counting the plaques at certain dilution(s), the plaque forming units (PFU)/mL can be calculated.

High-throughput screening

High throughput screening (HTS)

HTS is an approach in antiviral drug discovery involving the use of automated equipment to rapidly test huge libraries of chemical or biological materials with the aim of identifying hit molecules against specific viruses. HTS is usually done in culture plates with 384 or 1536 wells format using high performance liquid/plate handling devices.

Recombinant viruses

Reverse genetic system

A reverse genetic system is mostly a plasmid-based system that can be used to insert the desired mutations in the viral genome to study the effect of these mutations on viral replication, virulence, sensitivity to antiviral compounds in vitro and in vivo.

Reporter viruses

Reporter viruses are recombinant viruses engineered to carry reporter genes such as the one coding for fluorescent or luminescent proteins for development of high throughput antiviral assays or easily detection method for in vivo replication.

Animal infection models

Rodent models

Rodent models such as mice, rats and hamsters have been widely used to study viral infections. Such models allow to study host response and pathogenicity for wide variety of viruses. Moreover, these models are beneficial to assess the preclinical efficacy and safety of potential antivirals identified in cell culture assays.

Zebrafish models

Zebrafish (Danio rerio) are optically-transparent tropical freshwater fish of the family Cyprinidae that are widely used as vertebrate models of disease. They have remarkable genetic, physiologic and pharmacologic similarities to humans. Compared to rodents, the maintenance and husbandry costs are very low. Interestingly, zebrafish larvae have been shown to be susceptible to infection with some human viruses (herpes simplex virus type 1, influenza A virus, and chikungunya virus, human norovirus). Therefore, such a model can be used to study the pathogenesis as well as test antiviral drugs for specific human viruses in higher capacity and less cost compared to rodent models.

import { encodeTool } from '/_js/functions.js'

FA = FileAttachment

// Load the toolbox
families = await FA("/families.json").json()
_toolbox = await FileAttachment("/toolbox/toolbox.json").json()
toolbox = _toolbox.map( tool => encodeTool(tool) )

// console.log(toolbox)

addEncodedTools = (virus) => {
  return ({ ... virus, tools: toolbox.flatMap( tool => virus[tool.encoded] ? tool.id : []) }) 
}

// Load all Newick tree file and create a dictionary `family -> tree`
nwks = await Promise.all(
  families.map(async (family) => { 
    let tree = await FA("/"+ family + "/tree.newick").text()
    return ({ family: family, nwk: tree })
  }))
nwksAsMap = Object.fromEntries(nwks.map( el => [el.family, el.nwk] ))

// console.log(nwks)

// Load annotations for viruses for each family
_annotations = await Promise.all(
  families.map( async (family) => {
    let xls = await FA("/"+ family + "/family.xlsx").xlsx()
    let _annotations = xls.sheet(0, { headers: true, range: ":L" })

    let _trimmed = _annotations.map( virus => {
      let trimmed = {}
      Object.keys(virus).forEach( key => {
        trimmed[key] = virus[key].trim()
      })
      return trimmed
    })

    return _trimmed.map( virus => ({... virus, family: family }) )
  }))

// console.log(_annotations)

// Add tools information, just the list of tools ids
annotations = _annotations
  .flat()
  .map( virus => addEncodedTools(virus) )

familyAnnotations = annotations
  .filter(virus => virus.family == virusFamily)

function virusInfo(_family, _virus) {
  const info = 
    familyAnnotations.filter(row => row.abbreviation == _virus && row.family == _family)
  return info[0]
}

// Handle grouped viruses by extending the model with isGroup: false/true
addGrouped = (virus) => {
  const isGroup = (typeof virus.group_abbreviation !== "undefined") && (virus.group_abbreviation !== "")
  const virus_pointer = (isGroup) ? virus.group_abbreviation : virus.abbreviation 
  return (
    { ... virus,
      isGroup: isGroup,
      virusPointer: virus_pointer,
      resVirusId: (isGroup) ? virus.group_abbreviation : virus.abbreviation,
      resAbbreviation: (isGroup) ? virus.group_abbreviation : virus.abbreviation,
      resVirusName: (isGroup) ? virus.group_virus_name : virus.virus_name 
    }
  )
}

// Create a list of all viruses of interest in the Excel file
// Add group information early on
annotatedViruses =
  familyAnnotations
    .filter(virus => virus.virus_of_interest == "Yes")
    .map(virus => addGrouped(virus))

// Create a sublist of viruses with toolbox
// Take into account groups by selecting unique entries
toolboxAnnotatedViruses =
  annotatedViruses
    .filter(virus => virus.availability_in_toolbox == "Yes")
    .filter((value, index, self) => {
      return self.findIndex(v => v.resAbbreviation === value.resAbbreviation) === index;
    })

// Derive a virus object from the ID
// The ID can be either a virus_id (from the ictv tree) or a group_abbreviation
virusIdToVirus = (virus_id) => {

  // lookup the virus_id in the full list of viruses
  const fullList =
    annotatedViruses
      .filter(v => v.virus_id.replace(/^'+|'+$/g, '') == virus_id || v.abbreviation == virus_id)
      //.filter(v => v.virus_id == virus_id || v.abbreviation == virus_id)

  // lookup the abbreviation for the group
  const groupList =
    toolboxAnnotatedViruses
      .filter(v => v.group_abbreviation == virus_id)

  if (fullList.length > 0) {
    return fullList[0]
  }
  if (groupList.length > 0) {
    return groupList[0]
  }
}

// Return all matches for a virus ID
virusIdToViruses = (virus_id) => {
  // lookup the virus_id in the full list of viruses
  const single_virus =
    annotatedViruses
      .filter(v => v.virus_id.replace(/^'+|'+$/g, '') == virus_id || v.abbreviation == virus_id)
      [0]

  if (single_virus.isGroup) {
    return annotatedViruses
      .filter(v => v.group_abbreviation == single_virus.group_abbreviation)
  } else {
    return [ single_virus ]
  }
}

function renderVirusToolbox(family, virus_id) {

  // First extract the virus object from the ID or abbreviation
  // This takes into account the groups
  const virus = virusIdToVirus(virus_id)

  if (typeof virus.tools !== "undefined" && virus.tools.length > 0) {
    return html`
      ${toolbox.filter(tool => virus.tools.includes(tool.id) ).map(tool => 
        html`
        <h2 id="${tool.id}-section">${tool.name}</h2>
        <div class="container grid">
          <div class="g-col-12 g-col-md-3 toolbox one-tool" style="text-align:center;">
            <div id="toolbox-contents" class="tool-container">
              <a href="/toolbox/index.html#${tool.id}-section">
                <div class="tool-wrapper">
                  <div id="${tool.id}" class="tool">
                    <div class="tool-tooltip-text">${tool.name}</div>
                    ${tool.icon.map( i =>
                    html`<img class="tool-icon" height="${(tool.icon.length > 1) ? 150/tool.icon.length : 100}%" src="${i}"/>`
                    )}
                  </div>
                </div>
              </a>
            </div>
          </div>
          <div class="g-col-12 g-col-md-9">
            <p>${tool.description}</p>
          </div>
          <div class="g-col-1" style="text-align:center;">
          </div>
        </div>
        <div class="col-xs-12" style="height:20px;"></div>
        `
      )}
    `
  }
   else {
    return html`
      <p>&nbsp;</p>
    `
   }
}