Around the world, hundreds of women infected with the Zika virus have given birth to children suffering from microcephaly or other brain defects, as the virus attacks important cells responsible for generating neurons and building the brain because the embryo develops. Studies have suggested that Zika enters these types of cells, called neural progenitor cells or NPCs, simply by grabbing onto a specific protein called AXL on the cellular surface. Now, scientists at the Harvard Stem Cell Company (HSCI) and Novartis have shown that this is not the only path of infection for NPCs.
The scientists demonstrated that Zika infected NPCs even if the cells did not produce the AXL surface receptor proteins that is widely thought to be the main vehicle of entry for that virus.
“Our finding really recalibrates this particular field of research, because it tells us we still have to look and find out how Zika is getting into these cells, inch said Kevin Eggan, principal faculty member at HSCI, professor of stem cell and regenerative biology from Harvard University, and co-corresponding author on a paper confirming the research in Cell Stem Cell .
“It’s very important for the research community to understand that targeting the AXL protein alone will not prevent Zika, ” agreed Ajamete Kaykas, co-corresponding author plus a senior investigator in neuroscience at the Novartis Institutes with regard to BioMedical Research (NIBR).
Previous studies have proven that blocking expression of the AXL receptor protein really does defend against the virus in a number of human cell types. Given that the particular protein is highly expressed on the surface of NPCs, many labs have been working on the hypothesis that AXL is the access point for Zika in the developing brain.
“We were thinking that the knocked-out NPCs devoid of AXL more than likely get infected, ” said Max Salick, a NIBR postdoctoral researcher and co-first author on the paper. “But we saw these cells getting infected just as much since normal cells. ”
Working in a service dedicated to infectious disease research, the scientists exposed two-dimensional cell cultures of AXL-knockout human NPCs to the Zika virus. They followed up by exposing three-dimensional mini-brain “organoids” containing such NPCs to the virus. In both instances, cells clearly displayed Zika infection. This finding has been supported by an earlier study that knocked out AXL in the brains of mice.
“We understood that organoids are great models for microcephaly and other situations that show up very early in development and have an extremely pronounced effect, ” said Kaykas. “For the first few weeks, the organoids do a really good job in recapitulating regular brain development. ”
Historically, human NPCs have been difficult to study in the lab because it would be extremely hard to obtain samples without damaging brain tissue. With the breakthroughs in induced pluripotent stem cell (iPS cell) technologies, a cell reprogramming process that allows researchers to cajole any cell in the body back into a stem cell-like condition, researchers can now generate these previously inaccessible human tissue in a petri dish.
The team could produce human iPS cells and then, using gene-editing technologies, modify the cells to knock out AXL expression, mentioned Michael Wells, a Harvard postdoctoral researcher and co-first author. The scientists pushed the iPS cells to be NPCs, building the two-dimensional and three-dimensional models which were infected with Zika.
The Harvard/NIBR collaborators started working with the virus in mid-April 2016, only 6 months before they published their findings. This unusual acceleration of research reflects the urgency of Zika’s worldwide challenge, as the virus has spread to more than seventy countries and territories.
“At the genesis of the project, my wife was pregnant, ” Eggan said. “One can’t read the newspapers without being concerned. ”
The collaboration grew out of interactions at the Wide Institute of MIT and Harvard’s Stanley Center with regard to Psychiatric Research, where Eggan directs the stem cellular program. His lab already had developed cell lifestyle systems for studying NPCs in motor neuron plus psychiatric diseases. The team at Novartis had made brain organoids for research on tuberous sclerosis complicated and other genetic neural disorders.
“Zika appeared to be a big issue where we could have an impact, and we all distributed that interest, ” Eggan said. “It’s been excellent to have this public, private collaboration. ”
The researchers are studying other receptor proteins which may be open to Zika infection, in hopes that their basic research ultimately will help in the quest to develop vaccines or other medications that defend against the virus.
Components provided by Harvard University . Original authored by Hannah Robbins and Eric Bender. Take note: Content may be edited for style and length.