May 11, 2016

expert reaction to experimental evidence on Zika virus and birth defects in a mouse model

The Zika virus is still spreading through the Americas with information on its effects emerging, and a paper published in the journal Nature has reported experimental evidence for the first time that it can cause signs of microcephaly in mice.

All our previous output on this subject can be seen here. The SMC also produced a Factsheet on the Zika virus.

Prof. Daniel Altmann, British Society for Immunology spokesperson and Professor of Immunology at Imperial College London, said:

“The current Zika virus outbreak has been especially alarming due to the association with a sharp spike in foetal microcephaly. This has been the key feature distinguishing the recent experience in Brazil from previous encounters with Zika in Africa or French Polynesia. However, evidence that Zika is truly causal in this microcephaly spike and, if so, how it happens, has been building incrementally over the past months. Earlier evidence has been of virus isolation from placenta and from blood and brain tissue of affected foetuses as well findings on infection of human neural stem cells.

“Now, Cugola, Fernandes, Russo and colleagues in Sao Paulo have looked at this by injecting pregnant female mice, about halfway through gestation, with a Brazilian variant of the virus. The litters, while not displaying the full features of microcephaly per se, show many signs of cortical malformation reminiscent of findings in human foetuses. This opens the door to mechanistic studies to understand the mode of its attack on nerve cells of this virus and molecular pathways of this mode of pathogenesis.

“Meanwhile, the mouse studies leave many unknowns: Can this help to illuminate why, of Zika–exposed populations, increased cases of microcephaly are being reported largely from Brazil, and from some regions much more than others? What are the features of the viral sequences present in Brazil that account for differences in pathogenesis from the African sequences? And what lessons of variability in host susceptibility can be learnt from the fact that, in this study, one mouse strain was susceptible, the other absolutely resistant?”

Dr Nathalie MacDermott, Clinical Research Fellow, Imperial College London, said:

“The paper by Cugola et al adds further evidence to the growing literature demonstrating that the Zika virus strain currently circulating in South America has a propensity for invading neuronal tissue and can result in significant damage to the developing brain of the foetus when their mother is infected in pregnancy.

“The paper provides evidence in the form of animal models using mice and studies of infected human nerve cells, that the Zika virus kills developing nerve cells in the brain resulting in abnormally formed brains in the developing infant. This is consistent with the clinical findings from microcephalic infants born in Brazil, many of whom appear to have an abnormally formed brain cortex and cerebellum on brain scans.

“The study lends further support to the likelihood that the damage to the infant resulting in microcephaly, microencephaly and brain malformations occurs during the first and second trimesters of pregnancy, a time when the infant’s brain is rapidly developing and nerve cells are migrating to the correct regions.”

Dr Derek Gatherer, Lecturer in the Division of Biomedical and Life Sciences, Lancaster University, said:

“This new paper provides further evidence that Zika is the cause of microcephaly and other neurological and birth defects in humans. Cugola et al, writing in Nature, infected pregnant mice from two different lab strains with a Brazilian isolate of Zika virus, at a stage when the foetal brain is formed but not fully developed.  In one of the two strains, a range of birth defects was observed, including some, such as eye defects and thinning of the cortex (the outer layer of the brain), which have also been seen in human babies from Zika-infected mothers. They also found cellular and molecular changes that were consistent with damage to the mouse foetal nervous system by Zika virus. Cugola et al did not directly demonstrate microcephaly, but it should be remembered that mouse development is much faster than that of humans and we should not expect directly comparable results. Indeed, one of the two mouse strains tested appeared to be resistant to Zika virus. Interestingly, Cugola et al also found differences, in some but not all of their tests, between African and Brazilian strains of Zika, suggesting that the current Zika pandemic may involve a strain that is more dangerous in pregnancy, and possibly explain why Zika-associated birth defects were not observed before now.

“This paper adds to the weight of evidence that Zika virus is the cause of the apparent spike in microcephaly and other birth defects observed in Brazil, and suggests that other countries currently suffering from generalised Zika transmission may see similar spikes.  Previous studies of Zika’s pathological effects have used cells or organoids grown in the laboratory, so this direct demonstration of Zika’s neurological effects on developing mouse foetuses are very important.  However, the differences between mouse and human development mean that larger experimental animals that are more similar to humans – such as monkeys – must also be tested.  Additionally, the possibility that some African monkeys may be adapted to Zika via previous exposure, or that African and Asian/American strains of Zika have varying pathological properties, as suggested by Cugola et al, adds a new layer of complexity to the issue.”

‘The Brazilian Zika virus strain causes birth defects in experimental models’ by Fernanda R. Cugola et al. published in Nature on Wednesday 11 May 2016. 

Declared interests

Prof. Daniel Altmann: “No conflicts of interest to declare.”

Dr Nathalie MacDermott: “I am a paediatrician. I am also undertaking a PhD in Ebola virus disease at Imperial College London funded by the Wellcome Trust.”

Dr Derek Gatherer: “No conflict of interest.”