Saturday, 5 March 2016

Lab virus in lab cells, kill lab cells...


Tang and colleagues from Johns Hopkins University School of Medicine and other Universities have just described what Zika virus (ZIKV) can do to cells in culture.[1] That is, cells that have been tweaked to appear and behave like human brain cells - of a sort. Some very complex, expensive and expert work is needed to chemically drive cells to become other cells. But the question is - how much does this reflect what happens in a developing foetus whose cells harbour ZIKV?

The human neural progenitor cells (hNPCs) in this study were developed from human induced pluripotent stem cell (iPSC) lines that had previously been generated from skin biopsy material. This is an interesting origin because we do know that ZIKV can grow in skin cells (dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells).[2] The authors do not address whether the new hNPCs inherit any skin cell features that may help ZIKV infect them and perhaps give an inaccurate picture of the ZIKV in the developing human brain. I'm no expert on these methods however and may well be missing many issues.

These new laboratory findings may begin to unearth some possible mechanisms by which ZIKV infects and damages brain tissue in humans, but they are one step on a long path to understanding the mechanism in humans and should be considered with care and in context. The use of "primary" human tissues would be a useful addition to this study-cells or tissue not chemically matured, but as found in foetal tissues. No, I do not know how those tissues could be obtained-it would certainly require a lot of effort.

The particular ZIKV used in this study, which the authors identify as the MR766 variant (which originates from a sentinel primate from Uganda in 1947),  has been extensively grown in animals, mosquitoes and cell culture [3] although to what extent is unclear from the authors or from the information provided by the company they bought the virus preparation from.[1,3] It is unclear whether this lab-adapted virus still "behaves" in the same way as do ZIKVs currently circulating in Brazilian mosquitoes and infected humans. It may be an accurate ZIKV representative, or it may infect cells more easily, cause cellular damage or changes more effectively - or it may do the opposite.

Cell culture studies are a fast and relatively easy starting point to understand which cell types may host a virus and to see what the virus does in those cells and under those laboratory conditions. Certainly compared to clicnial studies. Cell cultures derived from one tissue type that have then been extensively manipulated and chemically treated in the laboratory to develop in certain ways, to be prepared for infection and possibly requiring ongoing chemical care to retain their state or health, may not yield infection results that accurately reflect disease processes in humans or other animals.

While this article is a useful insight into ZIKV and human-derived immature neural cells, a lot of work remains to be done to understand how ZIKV could cause the brain injuries or diagnoses with which it is being presumptively associated, predominantly in Brazil.

And that work appears to be proceeding apace.

NOTE #1: this post was based around bullet points I wrote in response to a request for comment by The Scientist.[4]

NOTE #2: There was another paper in this space that went online at PeerJ Reprints 04MAR2016 [5] - it has yet to be peer reviewed and does not have the detail describing the development and maturation of the stem cells that the paper reviewed above does. My thanks to @Ammer_B for pointing this out.

References...
  1. Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth
    http://www.cell.com/cell-stem-cell/pdfExtended/S1934-5909(16)00106-5[Extended article contains information of the laboratory maturation of the human stem cells]
  2. Biology of Zika Virus Infection in Human Skin Cells
    http://jvi.asm.org/content/89/17/8880.long
  3. ZIKA VIRUS Infectious Culture Fluid
    http://www.zeptometrix.com/docs/PI0810092CF.pdf?1457038294
  4. Zika Infects Neural Progenitors
    http://www.the-scientist.com/?articles.view/articleNo/45506/title/Zika-Infects-Neural-Progenitors/
  5. Zika virus impairs growth in human neurospheres and brain organoids
    https://peerj.com/preprints/1817/