How Zika went from a mild virus to a lethal one

Sin­gle ge­netic change pin­pointed as step where dis­ease turned fear­some

Baltimore Sun Sunday - - NEWS - By Melissa Healy

When the Zika virus was first iso­lated from a Ugan­dan for­est mon­key in 1947 and found in mildly ill hu­mans a few years later, it was hardly worth a men­tion in the an­nals of hu­man dis­ease. What a difference a mu­ta­tion can make. In a new round of ge­netic sleuthing, Chi­nese re­searchers have pin­pointed the sin­gle ge­netic change that has made the Zika virus a fear­some plague to preg­nant women and their ba­bies across the Amer­i­cas, re­spon­si­ble for thousands of cases of mi­cro­cephaly and other griev­ous brain ab­nor­mal­i­ties that some­times re­sult in death.

The Chi­nese re­searchers also came close to pin­point­ing the time at which the Zika virus grad­u­ated from un­wel­come pest sta­tus to an in­ter­na­tional scourge. That change, they sur­mised, oc­curred around May 2013, a few months be­fore the start of a two-year out­break in French Poly­ne­sia and three other Pa­cific is­lands.

By March 2015, the Zika virus had ar­rived in Brazil and was cir­cu­lat­ing widely there. As of last week, it had caused mi­cro­cephaly and other griev­ous brain ab­nor­mal­i­ties in at least 3,589 ba­bies born to women in­fected dur­ing preg­nancy, in­clud­ing 2,952 in Brazil.

The find­ings were re­ported Thurs­day in the jour­nal Sci­ence.

As Zika hop­scotched across the world, borne by soc­cer play­ers and other world trav­el­ers, its ge­netic blue­print — RNA — un­der­went a number of changes. The new re­search un­der­scores how that en­tirely normal process of ge­netic “drift” can, at any mo­ment, change the tra­jec­tory of hu­man his­tory.

Ge­netic mu­ta­tions picked up along its jour­ney can dis­arm a virus as a threat to hu­mans. Or, they can equip it with vir­u­lent new pow­ers to sicken. Of­ten, these mu­ta­tions do nothing at all.

The recorded his­tory of the Zika virus posed a mys­tery for mod­ern-day public health re­searchers and of­fi­cials.

Upon en­ter­ing a hu­man body, had the long-un­her­alded fla­vivirus al­ways had the power to at­tack any de­vel­op­ing brain tis­sue in­side its hu­man host and wreak a spe­cial kind of havoc? Had that de­struc­tive power sim­ply not been picked up be­cause pre­vi­ous out­breaks were too small, or in­cluded too few preg­nant women?

Or had the Zika virus ac­quired an omi­nous mu­ta­tion be­fore hit­ting the Amer­i­cas?

To find out, re­searchers from the Chi­nese Acad­emy of Sci­ences tested a collection of Zika virus sam­ples taken over time to see how their ge­netic struc­ture had changed.

Com­par­ing strains har­vested in 2015 with one col­lected in Cam­bo­dia in 2010, they iden­ti­fied seven sites where the virus’ RNA had changed. Each change al­tered Zika’s sur­face pro­tein by just one fea­ture — a sin­gle amino acid.

Team mem­bers cre­ated cloned cells bear­ing each of those ge­netic al­ter­ations and used the re­sult­ing strains to in­fect fe­tal and new­born mice.

The re­searchers sus­pected they had their cul­prit when a cloned Zika strain bear­ing a mu­ta­tion at po­si­tion S139N of the virus’ RNA caused “strik­ingly” greater de­struc­tion in the brain cells of new­born mice, whose neu­ral de­vel­op­ment mim­ics that of hu­man ba­bies dur­ing the sec­ond trimester.

Then they in­fected hu­man neu­ral pro­gen­i­tor cells — the fore­run­ners of ma­ture hu­man brain cells — with the Zika strain bear­ing that sin­gle mu­ta­tion. Compared to the 2010 Zika strain, the mu­tated ver­sion grew and mul­ti­plied more pro­lif­i­cally, becoming a ruth­less killer of brain cells.

The re­searchers had found their mu­ta­tion.

“The fact that this change in be­hav­ior can be al­most wholly at­trib­uted to a sin­gle amino acid change in one of the virus’ sur­face pro­teins is re­mark­able,” said Jonathan Ball, a molec­u­lar vi­rol­o­gist at the Univer­sity of Not­ting­ham who has probed ge­netic shifts in the Ebola virus.

“This data, as well as ev­i­dence from other viruses like Ebola, shows us that the small­est of ge­netic changes can have a ma­jor im­pact on virus be­hav­ior,” Ball added.

Ear­lier this month, a team of U.S. re­searchers pub­lish­ing in the Jour­nal of Ex­per­i­men­tal Medicine found that Zika may spare normal adult brain tis­sue, even as it seeks and de­stroys the prim­i­tive cells which, in a fe­tus, give rise to the brain’s di­ver­sity of cells.

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