If any doubts still existed, several teams of researchers have reported the first direct experimental evidence that both Asian and Brazilian strains of Zika virus can cause microcephaly when they infect pregnant mice.

Those findings in themselves are not a great surprise – public health authorities and researchers alike have been operating on the assumption that the virus is behind the explosion of microcephaly cases for months now.

Alysson Muotri, associate professor of pediatrics at the University of California at San Diego, told reporters at a press conference describing his team's findings that despite those assumptions, his group's report, which appeared in Nature, is "the first direct experimental proof that the circulating Brazilian [Zika virus] strain can actually cause birth defects" when mothers are infected during pregnancy.

Separately, researchers at Washington University in St. Louis published data in Cell showing that a 2013 French Polynesian strain of Zika virus caused both damage to the placenta and microcephaly in pups when mothers were infected during pregnancy.

A third paper published in Cell Stem Cell by scientists at the Chinese Academy of Sciences and the Beijing Institute of Microbiology and Epidemiology reported that an Asian strain of Zika virus also caused microcephaly-like symptoms in the brains of embryonic mice.

All three papers appeared in the May 11, 2016, online issues of their respective journals.

Michael Diamond, professor of internal medicine at Washington University and co-corresponding author of the Cell paper, called the confirmation of a causal link between Zika virus and microcephaly by three independent labs "remarkable."

"It's great for the field, and emblematic of the speed of discovery," he told BioWorld Today.

Mice are not natural Zika virus hosts, and the three mouse models used different methods to establish infections. The Brazilian group used very high levels of virus, administered intravenously, while the Washington University group used mothers that were deficient in interferon signaling – though their pups, Diamond noted, were not. The Chinese group established infections through direct infection of Zika virus into the embryonic brain.

Despite the high viral levels, one strain of pups reported in Nature was immune to Zika virus infection. Those strain differences, Muotri said, provide "a way to understand where resistance is residing."

Resistant mothers may have a stronger peripheral immune response, or resistance may reside in the placenta itself.

In addition to formal experimental proof, the models "can easily be used to evaluate therapeutics and vaccines," Diamond said, adding that while none of the three papers alone recapitulated all aspects of human Zika virus infection, among the three of them, "almost all of the clinical phenotypes are now seen."

They will also be useful for understanding factors that influence the course of clinical disease. "We believe that we have developed a model to study both mechanisms of CNS lesions . . . but also to study mechanisms of protection to the fetus and the mother," Nature co-author Jean Pierre Peron, professor of immunology and director of the laboratory for neuro-immune interactions at the University of Sao Paulo, told reporters.

Diamond's group is looking at the effects of prior immunity to dengue virus on the clinical course of Zika infection. Though the current papers establish conclusively that dengue virus co-infection is not necessary for the development of microcephaly, prior exposure to dengue could shape the immune response to the related Zika virus, either for better or worse. There is the possibility of crossover protection, but infection with one strain of dengue can make later infections with another strain more serious, and the same might be true for a Zika infection.

Unfortunately, one of the messages of the current studies may be that as serious as the situation already looks, it may be more serious still. Peron and his colleagues found that, although the virus was present in particularly high levels in the brains of mouse pups whose mothers had been infected during pregnancy, it was also present in other tissues.

The pups had changes to their brains that were consistent with microcephaly. But they also showed more general growth arrest, which suggests, Muotri said, that as bad as it is, microcephaly might be just "the tip of the iceberg. . . . The health effects of the Zika virus are likely to be more widespread than we are currently documenting."

Diamond was somewhat more circumspect, but also noted that in the milder of the two models his team used, where "the mothers were not symptomatic at all, as far as we could tell," they also saw general growth retardation of the pups beyond damage to the brain. His team is currently following those pups to see whether they are neurodevelopmentally normal.

"Time will tell," he said, "but it's certainly an area of concern."

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