Zika: From a bug to a mon­ster

Chi­nese-based sci­en­tists track mu­ta­tion that made the virus so dan­ger­ous

Waterloo Region Record - - LOCAL - William Wan

When the Zika virus be­came a global ter­ror two years ago — in­flict­ing se­vere birth de­fects on the ba­bies of preg­nant women who were in­fected with the virus and alarm­ing health of­fi­cials world­wide — sci­en­tists were mys­ti­fied.

How did such an ob­scure, rel­a­tively harm­less pathogen that had been known for more than half a cen­tury sud­denly blos­som into a mon­ster virus? Was it some­thing about Zika’s new hunt­ing grounds when it spread from Africa to South Amer­ica and the Caribbean? Were its new vic­tims in Brazil some­how more sus­cep­ti­ble to its ef­fects?

A group of sci­en­tists based in China may have fi­nally solved the mys­tery. Their re­search — pub­lished Thurs­day in the jour­nal Sci­ence — pin­points a small mu­ta­tion in Zika’s ge­netic makeup that made the virus much more dan­ger­ous.

Their re­search shows that a change of a sin­gle amino acid mol­e­cule — likely oc­cur­ring some­time in 2013 — cre­ated a new strain of Zika much more dan­ger­ous to de­vel­op­ing brain cells. Shortly af­ter, Zika was im­pli­cated in a dra­matic in­crease in cases of mi­cro­cephaly, in which ba­bies’ heads are ab­nor­mally small, and a range of other birth de­fects.

“This an­swers the ques­tion ev­ery­body has been want­ing to know. Why is it only in the last few years that Zika be­came so ex­plo­sive, not just in its vir­u­lence but in sever­ity of symp­toms,” said PeiYong Shi, a virus and ge­net­ics ex­pert at Univer­sity of Texas Med­i­cal Branch who is a co-au­thor of the new study.

While the preva­lence of Zika has been much lower this year com­pared to the out­breaks in 2015 and 2016, ex­perts say Zika could re­turn in waves in fu­ture years, based on the out­break cy­cles of sim­i­lar viruses.

The dis­cov­ery will be of some help to those now work­ing to de­velop a vac­cine for Zika. It also helps health of­fi­cials try­ing to pre­vent fu­ture out­breaks of other viruses by help­ing them un­der­stand how a rel­a­tively be­nign virus like Zika quickly be­came a global threat.

Sci­en­tists have known about Zika since 1947, when it was iso­lated in a mon­key in the Zika for­est of Uganda. But for decades, the virus seemed in­con­se­quen­tial, with symp­toms like a mild form of dengue fever.

In re­cent decades, there have been spo­radic spikes of in­fec­tion as the virus made its way from Africa to South­east Asia. There was an out­break in Micronesia in 2007, and in French Poly­ne­sia in 2013 and 2014.

But two years ago, when Zika fi­nally reached South Amer­ica, the speed at which it spread sky­rock­eted. Doc­tors also be­gan notic­ing the in­creas­ing rates of the alarm­ing mi­cro­cephaly and sus­pected a con­nec­tion to Zika. It took an in­ter­na­tional ef­fort to con­nect the birth de­fects con­clu­sively to Zika and be­gin to rein in the out­breaks.

Zika is pri­mar­ily spread by mos­qui­toes, but it can be sex­u­ally trans­mit­ted.

To iden­tify the small molec­u­lar change that gave Zika its sud­den vir­u­lence and power to in­flict birth de­fects, it took two dozen sci­en­tists, al­most all based in China, work­ing for more than a year to isolate the amino acid re­spon­si­ble.

The group took older strains of Zika from ear­lier out­breaks in Africa and Micronesia and com­pared it to the cur­rent strain in Brazil. Then, they slowly mod­i­fied the older strains, mak­ing one change to a pro­tein at a time and in­ject­ing it into preg­nant fe­male mice to see if the mod­i­fied strains dis­rupted brain de­vel­op­ment. Af­ter try­ing seven dif­fer­ent amino acids, they found the cul­prit.

It was a sin­gle amino acid called ser­ine that, when re­placed by an­other amino acid called as­paragine, caused the dev­as­tat­ing ef­fect.

Be­cause of the com­plex­i­ties in­volved in the re­search, the re­sult­ing pa­per car­ries the names of 23 co-au­thors, said Zhi­heng Xu, a brain de­vel­op­ment ex­pert at the Chi­nese Academy of Sciences, in a phone in­ter­view from Beijing. The in­ter­dis­ci­pli­nary crew in­cluded ex­perts in vi­rol­ogy, neu­rol­o­gists, fe­tal de­vel­op­ment, mouse spe­cial­ists and struc­tural bi­ol­o­gists as well as other fields.

Once the group iso­lated the pro­tein change re­spon­si­ble, they checked against strains from pre­vi­ous eras to see when the amino acid mu­ta­tion first ap­peared. The re­searchers be­lieve the mu­ta­tion oc­curred be­fore a 2013 out­break in French Poly­ne­sia and be­gan to dom­i­nate as that strain spread to the Amer­i­cas.

Part of what makes RNA viruses like Zika so suc­cess­ful is that their ge­netic ma­te­rial is un­sta­ble, giv­ing them an un­canny abil­ity to mu­tate quickly as they are trans­mit­ted over and over.

Scott Weaver, who heads the In­sti­tute for Hu­man In­fec­tions and Im­mu­nity at the Univer­sity of Texas Med­i­cal Branch in Galve­ston, called Thurs­day’s find­ings im­por­tant, but pointed out the Chi­nese group only tested the changed amino acid strain on mice. “I be­lieve that ad­di­tional work in hu­man cells, in­clud­ing cells from the pla­centa, as well as larger num­bers of donors are needed to con­firm the po­ten­tially very high sig­nif­i­cance of the study,” he said.

Be­fore Thurs­day’s an­nounce­ment, sci­en­tists had floated sev­eral the­o­ries for why Zika be­came so vir­u­lent in 2015. Some be­lieved it had to do with the im­mune sys­tems of Brazil­ians and South Amer­i­cans, who had not been ex­posed to Zika be­fore. Oth­ers thought Zika may have some­how in­ter­acted with the an­ti­bod­ies in the bod­ies of lo­cals who had pre­vi­ously ex­pe­ri­enced other viruses like dengue.

Some of those other ex­pla­na­tions may still have con­trib­uted to the out­breaks, said co-au­thor Pei. “This isn’t the an­swer to ev­ery­thing, but it’s one of the most im­por­tant pieces of the puz­zle,” he said.

Even with this new in­sight into Zika’s ori­gins, how­ever, sci­en­tists still have ques­tions about the virus. Their most ur­gent task now is to de­velop a work­ing vac­cine for Zika be­fore the next out­break oc­curs.

Roughly five to six vac­cines are al­ready in hu­man tri­als, said An­thony Fauci, head of the Na­tional In­sti­tute of Al­lergy and In­fec­tious Dis­eases. Be­cause Zika has be­come less ac­tive dur­ing the past year, it has be­come harder to test and fi­nal­ize a work­ing ver­sion of the vac­cine.

In U.S. states, there have been 268 con­firmed cases of Zika this year, com­pared with 5,102 last year, ac­cord­ing to the Cen­ters for Dis­ease Con­trol and Pre­ven­tion. U.S. ter­ri­to­ries have had 556 cases so far this year and had more than 36,000 cases in 2016, pri­mar­ily in Puerto Rico.

But if an­other out­break oc­curs in Brazil dur­ing that coun­try’s sum­mer (which oc­curs dur­ing win­ter in the United States), it would ac­tu­ally speed up the work of vac­cine de­vel­op­ers, who in that case might have a vac­cine ready by mid-2018, Fauci said. If an­other out­break doesn’t oc­cur, the vac­cine may not be ready un­til 2020.

Sci­en­tists are also try­ing to de­velop bet­ter ways to di­ag­nose whether some­one has been in­fected in the past.

ADRI­ANA ZEHBRAUSKAS, NEW YORK TIMES

Pe­dro Miguel Firmo de Lima, born with mi­cro­cephaly, re­ceives a kiss from his grand­mother, Fa­tima, in Paulista, Brazil. Sci­en­tists be­lieve the deadly strain of the Zika virus, which causes mi­cro­cephaly, might be traced to a sin­gle ge­netic mu­ta­tion that arose in the virus in 2013.

JEF­FREY ARGUEDAS/EFE, TNS

Chi­nese re­searchers have pin­pointed the sin­gle ge­netic change that made the Zika virus such a dan­ger to preg­nant women and their ba­bies.

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