The Brazilian Zika virus strain can cross the placenta and cause growth restriction — including signs of microcephaly — in mice, according to findings published in Nature this week.
These are the first experimental proof that ZIKVBR causes birth defects in an animal model.
The paper also finds that ZIKVBR can infect human brain organoids in culture, inducing cell death and disrupting layers of neural tissue known as cortical layers.
In Brazil, the recent increase in the number of infants born with malformations — including microcephaly and other neurological diseases — has been linked to the outbreak of a Zika virus strain originating from a strain of Asian lineage and spread by Aedes aegypti mosquitoes. However, direct evidence from an animal model that ZIKVBR causes birth defects has been lacking.
Alysson Muotri, Patricia Beltrão Braga, Jean Pierre Peron and colleagues used ZIKVBR isolated from a clinical case in northeast Brazil to infect two different strains (SJL and C57BL/6) of pregnant mice (two to six mice across several experiments).
They evaluated the pups immediately after birth and found that those born from SJL ZIKVBR-infected females displayed clear evidence of whole-body growth delay — or intrauterine growth restriction — and showed signs of microcephaly, such as cortical malformations, compared to controls. In contrast, no significant changes were observed in pups born from C57BL/6 ZIKVBR-infected females, which may be due to the robust anti-viral immune response of this mouse strain.
They also showed that the virus was capable of inducing cell death in mouse neural tissue and that it could infect human brain organoids, inducing cell death and disrupting cortical layers.
Their analyses suggest that ZIKVBRcrosses the placenta and causes microcephaly by targeting cortical progenitor cells, inducing cell death and impairing neurodevelopment.
These results reinforce existing evidence linking the ZIKVBR outbreak to growing numbers of clinical cases of congenital malformations and may aid future pre-clinical studies, including vaccine development.
Associate Professor Sanjaya Senanayake, a practising infectious diseases physician at the Australian National University Medical School, says the World Health Organization and the US CDC have already announced that they believe that Zika virus infection in pregnancy can lead to a birth defect called microcephaly.
“There is a lot of supportive evidence for this from human studies,” she says.
“At a human level, immune differences, such as with interferon, could explain why some pregnant women infected with Zika develop babies with microcephaly while others do not.
“The investigators also demonstrated that the Brazilian strain of Zika could damage human brain organoids (which is like a microscopic organ). These findings further add support to the association in humans of Zika and birth defects as well as neurological complications in adults from Zika, like Guillain-Barre syndrome.
“The study also compared the original African strain of Zika to the current Brazilian strain. They are very similar (87-90%), but not identical.
“They seemed to show that the Brazilian strain seemed to have more of an impact on nerve cells; but, the African strain could infect nerve cells too.
“Although not discussed in the paper, one possibility for why the African strain hasn’t been associated with birth defects is not because it can’t affect foetal nerve cells, but possibly because it can’t cross the placenta – that may be a new adaptation of the newer strain.
“Alternatively, the African strain may have caused birth defects previously, but it may not have been recognized due to the limited surveillance resources in those developing nations.”