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Medical research: First experimental proof that Brazilian Zika virus causes birth defects in an animal model
The Brazilian Zika virus strain (ZIKVBR) can cross the placenta and cause growth restriction — including signs of microcephaly — in mice. These findings, which are published in Nature this week, 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.
**The paper will be free to access until further notice, per an agreement among publishers and research funders to ensure that the global response to public health emergencies is informed by the best available research evidence and data. A dedicated hub hosting all Springer Nature Zika content can be found here.**
Expert Reaction
These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.
The study by Cugola and colleagues builds upon the growing evidence that Zika virus is able to cross the placenta and cause fetal infections, and that these infections can lead to developmental problems in the growing fetal brain. The authors found that when pregnant mice were infected with the virus, their pups have delayed or reduced growth and their brains display abnormalities that are suggestive of reduced development. The authors also found that Zika virus infection leads to problems in gene expression in the developing mouse brain that are involved in cell death. When repeated with early human brain cells in a petri dish, viral infection also led to significant cell death. Therefore this is a very significant paper that demonstrates a clear association between Zika virus infection and brain cell death, supporting the growing evidence in multiple studies to date and also presenting a model organism in which to test new therapeutics and vaccines.
Associate Professor Jason Mackenzie is from the Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity and the University of Melbourne
Zika virus infection can result in fetal neurological complications exacerbating in microcephaly, something that is unique to this virus. Very little is known how Zika virus replicates and causes disease as research has been lacking in this area. This report has revealed a new approach to investigate the pathological outcomes of Zika infection in innovative experimental models and is the first of its kind and is a tremendous step forward. It has shown the experimental models used can reflect the clinical presentation of Zika infection and thus serve as an excellent basis to understand the disease process and evaluate strategies for prevention. These findings are significant, as while the connection of microcephaly with Zika infection has been generally accepted, there has been a lack of definitive evidence. This study has confirmed this association and now highlights the global concerns with respect to Zika infection in pregnant mothers and strengthens the awareness of Australian travellers that may visit areas with current Zika outbreaks. Research such as this study needs to be supported to drive development in awareness and prevention to new emerging diseases.
Associate Professor Sanjaya Senanayake is a specialist in Infectious Diseases and Associate Professor of Medicine at The Australian National University
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. In this prospective interventional animal study, scientists infected two different strains of mice with the Brazilian strain of Zika. They were able to demonstrate that pups from one strain of mouse developed microcephaly and had growth restriction. Pups from the other strain of mouse were not affected, probably because it had higher levels of interferon, which is part of the immune system that targets viruses. 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.
Professor Alexander Khromykh is an NHMRC Senior Research Fellow and Professor of Molecular Virology at the University of Queensland
The upcoming study in Nature describes the first mouse model for foetal abnormalities induced by infection of pregnant mums with Zika virus. Although a number of questions remain unanswered in this publication, the presented model may be useful in testing new vaccines and antivirals for preventing foetal abnormalities occurring at alarming rates in the current outbreak of Zika virus infection in the Americas.
Professor Cheryl Jones is a Professor of Paediatrics at The University of Sydney and Marie Bashir Institute for Infectious Diseases and Biosecurity. She is also President of the Australasian Society for Infectious Diseases (ASID)
This paper uses a mouse model to demonstrate that transmission of zika virus across the placenta to the developing fetus can directly cause birth defects including microcephaly. It is the first study to directly provide a causal link between zika virus infection ion pregnancy and microcephaly in offspring.
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