With global health officials warning that millions of people in the Americas could contract Zika infections this year, the virus might not seem like a choosy pathogen. But one group that’s eluded the virus: lab mice.
But on Monday, a group from the University of Texas Medical Branch in Galveston reported a break: a genetically altered mouse capable of contracting the virus that scientists from academia and biopharma companies can now use to screen potential Zika therapies.
“It’s a good initial model to test the effects of antivirals and any vaccine,” said UTMB infectious disease researcher Nikos Vasilakis, a coauthor of the study published in the American Journal of Tropical Medicine and Hygiene.
Before the ongoing outbreak in the Americas seized the world’s attention last year, only a thin stack of Zika research existed, much of which was published a decade before man walked on the moon. That lack of attention meant no good animal models for Zika had been cultivated — something that frustrated UTMB virologist Shannan Rossi.
“It’s frustrating to us as scientists because we don’t have answers,” said Rossi, “and it’s frustrating to the public because they have all these questions and they turn to the scientists and we just shrug our shoulders.”
By studying how viruses affect lab animals, scientists can more quickly, cheaply, and ethically glean insights into what might happen when a person contracts the disease. Plus, any vaccines or antiviral therapies need to be extensively tested on animals before they can move into human trials.
Not every animal serves as an accurate stand-in for how a virus behaves in a human, though. And not every animal can get the diseases that sicken people.
So scientists around the world have been scurrying to uncover representative animal models for Zika, hoping to examine what kind of tissue the virus targets and how the virus could be inducing miscarriages or birth defects such as microcephaly — outcomes that global health officials increasingly suspect Zika can trigger.
For the study published Monday, Rossi, Vasilakis, and their colleagues used a Zika strain closely related to the one now circulating in the Americas. They tried to infect standard lab mice, but the virus failed to replicate or cause disease.
The researchers therefore honed in on two types of genetically altered mice known as A129 and AG129 that had shown susceptibility to related viruses like dengue. The former had one interferon receptor knocked out, and the latter had an additional receptor disabled. In both mice, the researchers found that the immune-weakening changes made the animals able to contract the virus.
In a paper published online earlier this month before being peer reviewed, scientists from Public Health England also reported that A129 mice could be good models for Zika infection.
These mice aren’t perfect stand-ins for what the virus does in people, though, because they’re engineered to lack receptors that people have. And some experts say even the best mouse models could never truly aid in the most pressing Zika investigation: if and how the virus can cause problems in pregnancy.
With mice, “you’re out of luck because the amnion and where the fetal development takes place is not representative” of people, Vasilakis said.
Still, studying pregnant mice might spill some secrets about how the virus is transmitted from mother to fetus, so Utah State University virologist Justin Julander said he is working on developing both mouse and hamster models for that.
For small animals, a better model might be guinea pigs — which have placentas that, biologically speaking, are not all that different from women’s. But like mice, guinea pigs don’t naturally contract Zika, and these animals are harder to genetically manipulate than mice.
Of course, the closest animal model to humans would be another primate. Testing on monkeys is slower and more expensive than with rodents, and such experimentation comes with more regulations and ethical quandaries. But scientists have already infected a number of rhesus macaques with Zika, including at least one pregnant monkey.
At the University of Wisconsin, Madison, infectious disease researcher David O’Connor — who described the reaction among scientists when Zika first made news as, “Oh my gosh, we know nothing about this” — started infecting macaques last month and has been sharing his data online as it arrives.
The research is preliminary, but suggests that the monkeys see a similar disease pattern to what people experience, and that the Asian strain of the virus responsible for the Zika outbreak in the Americas produces higher levels of virus in the monkeys’ blood than the African strain.
O’Connor and his colleagues have infected one pregnant macaque, during the equivalent of her mid-first trimester, and so far the ultrasounds appear normal. They hope to time future infections to different stages of pregnancy. (One problem with rhesus macaques as models: They typically reproduce for only part of the year.)
“The question is when during pregnancy is there a risk to a fetus,” said O’Connor, the chair of the Wisconsin National Primate Research Center’s global infectious disease division.
Dr. Koen Van Rompay and his colleagues at the California National Primate Research Center — a part of the University of California, Davis — have also infected a small number of rhesus macaques with Zika, and plan to move to pregnant monkeys soon. Van Rompay, who like O’Connor has studied HIV in monkey models, hopes to learn how frequently an infected mother transmits the virus across the placenta to the fetus, and whether an antiviral therapy could reduce that rate like it can with HIV.
The primate studies could also help answer the question of whether Zika causes microcephaly and other defects. Case studies from Brazilian infections suggest that the virus infects the fetal brain, but uncertainty remains about if the infection alone causes the defects, if a past dengue infection exacerbates the response, or if an immune reaction in the mother prompted by a Zika infection creates problems inside the womb.
“Is it the virus?” Van Rompay said. “Or is it the virus plus something else needed to cause microcephaly?”