Raziskovalke in raziskovalci z Medicinske fakultete Univerze v Ljubljani (Inštitut za mikrobiologijo in imunologijo in Inštitut za patologijo) ter Univerzitetnega kliničnega centra Ljubljana (Klinični oddelek za perinatologijo Ginekološke klinike UKC Ljubljana in Klinični inštitut za radiologijo UKC Ljubljana) so pod vodstvom prof dr. Tatjane Avšič Županc v ugledni znanstveni reviji The New England Journal of Medicine pravkar objavili raziskavo, v kateri so potrdili povezavo med virusom zika in mikrocefalijo.
Povzetek ugotovitev študije
Virus Zika – flavivirus med ljudmi prenašajo pretežno v dnevnem času aktivni komarji iz rodu Aedes. Več kot 80 odstotkov primerov okužbe poteka brez simptomov, v ostalih primerih gre za razmeroma kratkotrajno vročinsko bolezen. V letu 2014 se je virus razširil na območje južne in srednje Amerike in povzročil drastične epidemije. Oktobra 2015 so brazilske zdravstvene oblasti poročale o nenavadnem porastu števila primerov mikrocefalije pri novorojenčkih v brazilski zvezni državi Pernambuco, nadaljnje retrospektivne analize pa so razkrile znatno povečanje primerov mikrocefalije glede na povprečje zadnjih let tudi v drugih zveznih državah, kar je sovpadalo z epidemijo Zike. Generalna sekretarka Svetovne zdravstvene organizacije je na priporočilo posebne komisije mednarodnega zdravstvenega odbora, ki je zasedala 1. februarja 2016, razglasila primere mikrocefalije in drugih okvar živčevja, o katerih so poročali iz Brazilije, za javnozdravstveno grožnjo mednarodnega pomena.Sumi o povezavi med okužbo z virusom Zika v nosečnosti in prirojenimi okvarami živčevja so se do tega trenutka množili, a neposredna vzročna povezava ni bila konkretno dokazana. Virus so nedavno odkrili v plodovnici dveh novorojenčkov z mikrocefalijo, kar kaže na možnost okužbe ploda med nosečnostjo. V poročilu, objavljenem na spletni strani revije The New England Journal of Medicine, pa je slovenska skupina raziskovalcev prvič doslej predstavila bolezenske spremembe v možganih ploda, ki so povezane z vertikalnim prenosom (to je z matere na plod) virusa Zika.
Raziskava temelji na primeru prej zdrave Evropejke, pri kateri se je med bivanjem in delom v Braziliji ob koncu prvega trimesečja nosečnosti pojavila vročinska bolezen z izpuščajem. Ultrazvočna preiskava je nepravilnosti ploda prvič prikazala v 29. tednu nosečnosti, v 32. tednu pa smo z ultrazvokom ugotovili zastoj rasti ploda, mikrocefalijo in kalcinacije (poapnitve) v možganih. Zato je mati zaprosila za prekinitev nosečnosti, ki sta jo potrdili Etična komisija in Komisija za prekinitve nosečnosti.
Avtopsija ploda po prekinitvi nosečnosti je potrdila hude strukturne okvare možganov (zelo majhni možgani, skoraj popolna odsotnost možganskih vijug, hidrocefalus, kalcinacije), mikroskopski pregled možganskega tkiva pa spremembe, ki so značilne za virusno okužbo. Elektronska mikroskopija je v vzorcih možganskega tkiva prikazala virusom podobne delce in delce z značilnostmi flavivirusnih replikacijskih kompleksov (kar nakazuje razmnoževanje virusa v možganih).
Virološke preiskave z verižno reakcijo s polimerazo z reverzno transkriptazo (RT-PCR) so potrdile prisotnost RNK virusa Zika in razmeroma veliko virusno breme (veliko število kopij virusne RNK na enoto tkiva) v vzorcih možganskega tkiva. Številne odvzete vzorce možganov in drugih organov ter tkiv smo testirali na prisotnost drugih flavivirusov (vključno z virusom denge in rumene mrzlice), drugih virusov (vključno z virusom chikungunye, citomegalovirusom in herpes virusi) in drugih možnih povzročiteljev bolezni. Virus Zika je bil edini prisoten povzročitelj, odkrili pa smo ga izključno v vzorcih možganskega tkiva. Prisotnost virusa smo potrdili z določitvijo nukleotidnega zaporedja celotne virusne RNK iz možganskega tkiva, ki je bila v 99,7 odstotka skladna s sevoma virusa Zika, ki so ju odkrili v Francoski Polineziji leta 2013 in Sao Paolu v Braziliji leta 2015.
(Vir: Sporočilo za medije: Slovenski znanstveniki prvi na svetu dokazali povezanost virusa Zika z okvaro možganov ploda okužene matere – pdf.)
»Naša raziskava je potrdila precejšnjo nevarnost za nosečnice, zlasti v prvem trimesečju, predvsem za tiste, ki se zadržujejo na območjih visoko endemičnega virusa,« je dejala dr. Tatjana Avšič Županc. Iz možganov zarodka so tudi pridobili celoten genom virusa zika. (Delo: Slovenski znanstveniki potrdili povezavo med ziko in mikrocefalijo )
“It looks like that Zika virus ‘likes’ brain tissue (e.g. neurotrophism) and likely the virus can replicate in neurons of the brain,” Avsic said by email. She said Zika virus may be able to stay in the brain longer than it does in other parts of the body, because the immune system is less able to reach it there. That way it can do more damage than it does to other tissues.
The fetus had no evidence of any other infection that could have caused the damage and the mother did not have any of the known genetic causes of microcephaly, Avsic’s team said.
“This really does strengthen the evidence that Zika virus is causing microcephaly,” Gordon, who was not involved in the study, told NBC news. (Vir: Zika Virus Found in Fetus With Severe Birth Defect – NBC News)
Brain samples tested positive for the Zika virus, and no other viruses in the same class, such as dengue, yellow fever or West Nile virus. The doctors also ruled out many other potential infectious causes of microcephaly, including rubella, cytomegalovirus and toxoplasmosis.
From the brain samples, the team was able to identify the complete genetic sequence of the Zika viral genome, which most closely matched a Zika virus strain isolated from a patient from French Polynesia in 2013 and a Zika virus strain isolated in Sao Paulo, Brazil, in 2015.
Importantly, the team found no presence of the virus and no other defects in any fetal organs other than the brain, which suggests the virus selectively attacks nerve tissue, Avšič Županc and colleagues wrote. But exactly how the virus does this is not clear.
The discovery of viral particles and a high load of Zika virus RNA in the brain samples, coupled with the absence of other possible pathogens, and a complete viral genome present “strong evidence” of the Zika virus’ potential for causing birth defects, Avšič Županc said in an email. (Researchers find new Zika clues to birth defect in fetus study | Reuters)
As well as the Zika genome, the researchers found high levels of viral RNA and viral particles in brain cells. There was no evidence of the presence of other pathogens that could have caused the brain damage, and no other organs were damaged suggesting the virus preferentially attacks the brain. “Microscopic examination revealed that brain cells were destroyed due to infection with the virus,” “While it can’t be definitive proof, it may present the most compelling evidence to date that congenital brain malformations associated with Zika virus infection in pregnancy are a consequence of viral replication in the fetal brain,” says Tatjana Avšič Županc of the University of Ljubljana in Slovenia, who was involved with the autopsy.(Vir: Whole Zika genome recovered from brain of baby with microcephaly | New Scientist)
“This is a huge step toward proving this virus causes microcephaly,” said Dr. Charles Chiu, director of a viral diagnostic laboratory at UC San Francisco. (Zika virus found in fetal brain – LA Times)
Seznam avtorjev in avtoric članka:
Raziskavo je vodila akad. prof. dr. Tatjana Avšič Županc, univ. dipl. biol. Ključni sodelavci so bili: Jernej Mlakar dr. med., zn. sod. dr. Miša Korva, univ. dipl. mikr., doc. dr. Nataša Tul, dr.med., prof. dr. Mara Popović, dr. med., strok. svet. asist. dr. Mateja Poljšak Prijatelj, univ. dipl. biol., Jerica Mraz, univ. dipl. mikr., Marko Kolenc, univ. dipl. mikr., Katarina Resman Rus, univ. dipl. bioteh., Tina Vesnaver Vipotnik, dr. med., Vesna Fabjan Vodušek, dr.med., zn. svet. dr. Alenka Vizjak, univ. dipl. biol., prof. dr. Jože Pižem, dr. med. in prof. dr. Miroslav Petrovec, dr. med.
Povzetek: A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 in South and Central America and the Caribbean. A major concern associated with this infection is the apparent increased incidence of microcephaly in fetuses born to mothers infected with ZIKV. In this report, we describe the case of an expectant mother who had a febrile illness with rash at the end of the first trimester of pregnancy while she was living in Brazil. Ultrasonography performed at 29 weeks of gestation revealed microcephaly with calcifications in the fetal brain and placenta. After the mother requested termination of the pregnancy, a fetal autopsy was performed. Micrencephaly (an abnormally small brain) was observed, with almost complete agyria, hydrocephalus, and multifocal dystrophic calcifications in the cortex and subcortical white matter, with associated cortical displacement and mild focal inflammation. ZIKV was found in the fetal brain tissue on reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay, with consistent findings on electron microscopy. The complete genome of ZIKV was recovered from the fetal brain. (Vir: Zika Virus Associated with Microcephaly — NEJM)
Posnetki tiskovne konference:
24ur.com – video: Virus Zika so našli le v možganskem tkivu ploda
RTV Slo – video: Dokazali povezavo med Ziko in mikrocefalijo
