"Long before it's in the papers"
March 04, 2016

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New signs that Zika virus may cause microcephaly

March 4, 2016
Courtesy of Johns Hopkins Medicine
and World Science staff

Work­ing with lab-grown hu­man stem cells, re­search­ers sus­pect they have found out how the Zika vi­rus probably causes mi­cro­ceph­a­ly, or ab­nor­mally small heads, in fe­tus­es.

The vi­rus seems to se­lec­tively in­fect cells of the brain’s out­er lay­er, the cor­tex, the in­ves­ti­ga­tors say, mak­ing them more likely to die and less likely to di­vide nor­mally and make new brain cells. The re­search­ers say their ex­pe­ri­ments al­so sug­gest the lab-grown cells could serve to screen for an­ti-Zika drugs.

The vi­rus be­gan spread­ing through­out the Amer­i­cas last year at about the same time as a jump in cases of fe­tal mi­cro­ceph­a­ly, as well as oth­er brain ab­nor­mal­i­ties. This led the World Health Or­gan­iz­a­tion to de­clare Zika a global pub­lic health emer­gen­cy.

But proof of a Zika-mi­cro­ceph­aly link has been lack­ing.

The vi­rus is­n’t new; it was dis­cov­ered in Ugan­da in the 1940s. Since then, small out­breaks have ap­peared in Asia and Af­ri­ca, but symp­toms were gen­er­ally mild and did­n’t seem to have long-term ef­fects. Zika largely spreads through bites of Ae­des ae­gypti mosquitoes, but al­so sex­u­ally and through in­tra­u­terine in­fection.

The new work “does­n’t def­i­nitely prove that Zika vi­rus causes mi­cro­ceph­a­ly,” said neu­rol­o­gist Guo-li Ming at Johns Hop­kins Un­ivers­ity In­sti­tute for Cell En­gi­neer­ing in Bal­ti­more, one of the study lead­ers. But “it’s very tell­ing that the cells that form the cor­tex are po­ten­tially sus­cep­ti­ble to the vi­rus, and their growth could be dis­rupted by the vi­rus.” 

Fur­ther­more, Ming said, “s­tud­ies of fe­tus­es and ba­bies with the tell­tale small brains and heads of mi­cro­ceph­a­ly in Zika-affected ar­eas have found ab­nor­mal­i­ties in the cor­tex, and Zika vi­rus has been found in the fe­tal tis­sue.” 

The sci­en­tists re­ported their find­ings on­line March 4 in the jour­nal Cell Stem Cell. Work­ing quickly in light of the glob­al threat, they com­pared Zika’s ef­fect on cells known as cor­ti­cal neu­ral pro­gen­i­tor cells to two oth­er cell types.

Hengli Tang, a vi­rol­o­gist at Flor­i­da State Un­ivers­ity who co-led the study with Ming, said that three days af­ter vi­rus ex­po­sure, nine in ten cor­ti­cal neu­ral pro­gen­i­tor cells were in­fected, and had been hi­jacked to churn out new cop­ies of the vi­rus. Fur­ther­more, the genes needed to fight vi­ruses had not switched on, which is highly un­usu­al, he added. Many of the in­fected cells died, and oth­ers showed dis­rupted ex­pres­sion of genes that con­trol cell di­vi­sion, in­di­cat­ing that new cells could not be made ef­fectively.

Us­ing spe­cif­ic, known types of cells al­lowed the re­search­ers to see where the de­vel­op­ing brain is most vul­ner­a­ble, said Hongjun Song, a third lead­er of the re­search team, al­so at Johns Hop­kins. 

He and Ming are now us­ing the cells to find out more about the ef­fects of Zika in­fection on the de­vel­op­ing cor­tex. “Now that we know cor­ti­cal neu­ral pro­gen­i­tor cells are the vul­ner­a­ble cells, they can likely al­so be used to quickly screen po­ten­tial new ther­a­pies for ef­fectiveness,” Song said.


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Working with lab-grown human stem cells, researchers suspect they have found out how the Zika virus probably causes microcephaly, or abnormally small heads, in fetuses. It seems the virus selectively infect cells of the brain’s outer layer, the cortex, the investigators say, making them more likely to die and less likely to divide normally and make new brain cells. The researchers say their experiments also suggest the lab-grown cells could serve to screen for anti-Zika drugs. The virus began spreading throughout the Americas last year at about the same time as a jump in cases of fetal microcephaly, as well as other brain abnormalities. This led the World Health Organization to declare Zika virus an international public health emergency. But proof of a Zika-microcephaly link has been lacking. The virus isn’t new; it was discovered in Uganda in the 1940s. Since then, small outbreaks have appeared in Asia and Africa, but symptoms were generally mild and didn’t seem to have long-term effects. Zika largely spreads through bites of Aedes aegypti mosquitoes, but also sexually and through intrauterine infection. The new work “doesn’t definitely prove that Zika virus causes microcephaly,” said neurologist Guo-li Ming at Johns Hopkins University Institute for Cell Engineering in Baltimore, one of the study leaders. But “it’s very telling that the cells that form the cortex are potentially susceptible to the virus, and their growth could be disrupted by the virus.” Furthermore, Ming said, “studies of fetuses and babies with the telltale small brains and heads of microcephaly in Zika-affected areas have found abnormalities in the cortex, and Zika virus has been found in the fetal tissue.” The scientists reported their findings online March 4 in the journal Cell Stem Cell. Working quickly in light of the global threat, they compared Zika’s effect on cells known as cortical neural progenitor cells to two other cell types. Hengli Tang, a virologist at Florida State University who co-led the study with Ming, said that three days after virus exposure, nine in ten cortical neural progenitor cells were infected, and had been hijacked to churn out new copies of the virus. Furthermore, the genes needed to fight viruses had not switched on, which is highly unusual, he added. Many of the infected cells died, and others showed disrupted expression of genes that control cell division, indicating that new cells could not be made effectively. Using specific, known types of cells allowed the researchers to see where the developing brain is most vulnerable, said Hongjun Song, a third leader of the research team, also at Johns Hopkins. He and Ming are now using the cells to find out more about the effects of Zika infection on the developing cortex. “Now that we know cortical neural progenitor cells are the vulnerable cells, they can likely also be used to quickly screen potential new therapies for effectiveness,” Song said.