Effects of using hydroxychloroquine in pregnant women over a long term remains to be assessed.
Commonly used malaria drug hydroxychloroquine can effectively block Zika virus from crossing the placenta and getting into the foetus and damaging its brain, say researchers from Washington University School of Medicine in St. Louis, US. The drug already has approval for use in pregnant women.
The placenta acts as a barrier to protect the developing foetus from disease-causing organisms. It prevents pathogens from reaching the foetus through a form of garbage recycling system that removes some components of cells, termed autophagy. While infections often ramp up this recycling system to get rid of any pathogens, the effects of autophagy on Zika infection and its impact on transmission of the virus past the placenta were earlier not known.
Zika manipulates autophagy
“We found that the Zika virus actually manipulates the garbage recycling system to its own advantage. The Zika infection ramps up autophagy. So when we use a drug that inhibits or suppresses this ramping up, we can block the virus from infecting the foetus,” says Indira U. Mysorekar from the Department of Obstetrics and Gynaecology, Washington University School of Medicine and the corresponding author of the study published in The Journal of Experimental Medicine.
To understand how the Zika virus crosses the placenta and infects the foetus, Prof. Mysorekar and her team infected human placental cells. They found the Zika virus activating the genes related to autophagy thereby heightening the destructive recycling system activity. But treating the cells with drugs that inhibit autophagy resulted in significant decrease in Zika virus replication about two days after infection. On the other hand, when drugs that promote the cell recycling process were administered, the virus multiplied and caused increased viral infection.
Similar results in mice
Prof. Mysorekar got similar results when her team repeated the experiments in mice. They infected two groups of pregnant mice — one which had reduced autophagy and mice that had normal autophagy. In the former group, the virus in the placenta was 10 times lower and placental damage was decreased compared with the normal mice. Also, the presence of Zika virus in the foetus was 15 times lower in mice with reduced autophagy. However, the virus load in the blood was the same in both groups of mice.
“The viral loads in maternal blood were not affected by loss of autophagy which is good because we don’t want whole body effects of loss of autophagy as that could lead to side effects. Adults with Zika virus can clear the infection without too much trouble; it’s the transmission to the foetus that is devastating,” Prof. Mysorekar says in an email.
Since the malaria drug hydroxychloroquine inhibits the cell recycling response, the researchers repeated the experiments using mice with a normal autophagy response. Pregnant mice infected with Zika virus were treated with the drug or a dummy for five consecutive days. Compared with the controls, there was significantly less virus in the placenta of mice that received the drug. The damage to placenta was also less in mice that were treated with the drug and foetus showed reduced Zika infection.
Duration of treatment
The drug has been approved for use in pregnant women but only for a shorter duration of time. But with Zika virus infection even during the third trimester causing foetal damage, the treatment has to be for a long time. “We do not know what the risk may be of long-term treatment with the drug [Hydroxychloroquine]. These tests have to be done and that will be the next step as the findings leave the lab and head to the clinic,” says Prof. Mysorekar.
“Carrying out a trial on pregnant women is always challenging. But given that the drug is already approved and Zika infections have such terrible consequences, there may be more chances of going forward,” she says.
While ramping down the autophagy by using the malarial drug can help protect the foetus from Zika infection, there is a risk of other pathogenic bacteria and virus taking advantage of the suppressed autophagy and crossing the placenta and infecting the foetus. “We have to test this. That is a caveat,” she says.
“I don’t know [how quickly the drug can be approved for use in pregnant women] but it should be faster than a vaccine,” she adds. With her lab focussing only on the mechanism of action, it for other agencies and physicians to take it to the next level.