Courtesy of
Washington University School of Medicine, St Louis
‘Malaria
drug (Hydroxychloroquine) protects fetuses from Zika infection
Treatment
prevents virus from crossing placenta to infect fetus, mouse study shows
BIN CAO
Human placental cells (blue) infected with Zika virus (green) responded to the
malaria drug chloroquine (left). The drug prevented the virus from growing,
unlike the drug rapamycin, which prompted the virus to grow rapidly (right).
Studying pregnant mice, researchers at Washington University School of Medicine
in St. Louis found that Zika virus manipulates the body’s normal barrier to
infection, and that hydroxychloroquine, a malaria drug related to chloroquine,
interferes with this process, protecting the fetus from viral infection.
Devastating
consequences of Zika virus infection are suffered in the womb, where the virus
can cause brain damage and sometimes death. Studying pregnant mice,
researchers at Washington University School of Medicine in St. Louis have
learned that the Zika virus infects the fetus by manipulating the body’s normal
barrier to infection. Moreover, they showed that a malaria drug that interferes
with this process protects the fetus from viral infection. That drug already is
approved for use in pregnant women for other medical purposes.
“We found
that the malaria drug hydroxychloroquine effectively blocks viral transmission
to the fetus,” said senior author Indira Mysorekar, PhD, an associate professor of obstetrics
and gynecology, and of pathology and immunology. “This drug already is used in
pregnant women to treat malaria, and we suggest that it warrants evaluation in
primates and women to diminish the risks of Zika infection and disease in
developing fetuses.”
The findings
are published July 10 in The Journal of Experimental Medicine.
In late
2015, doctors in Brazil began to notice a surge in the number of babies born
with microcephaly, or unusually small heads, an indicator of neurological
damage. The epidemic soon was linked to the mosquito-borne Zika virus, which
was spreading through the tropical parts of the Americas. Doctors advised
pregnant women to avoid mosquito bites by wearing bug spray and long-sleeved
clothing, but had little other advice to offer. There were, and still are, no
drugs or vaccines approved for use in pregnant women to protect them or their
fetuses from Zika infection.
The
developing fetus is uniquely vulnerable to damage from infection, so the body
mobilizes robust defenses to keep microbes from ever reaching the fetus in the
first place. The placenta is the last line of defense. Mysorekar and
others have shown that a process known as autophagy – the
cellular waste-disposal pathway by which cells grind up debris, unwanted
organelles and invading microbes – is an important part of the formidable
placental barrier to infection. However, previous studies by Mysorekar and others have shown
that Zika not only can invade the placenta, but multiply there.
To learn
more about how Zika breaches the placenta, Mysorekar, postdoctoral fellow Bin
Cao, PhD, and colleagues infected human placental cells with Zika virus. They
found that exposure to the virus activated genes related to autophagy.
However,
when the researchers treated the cells with drugs to ramp up the autophagy
pathway, the number of cells infected with Zika virus increased. Drugs that
suppressed autophagy resulted in fewer placental cells infected with Zika
virus. In other words, the virus multiplied and spread more effectively when
the researchers dialed up the barrier response, and performed more sluggishly
when they dialed it down. The virus seemed to be doing a form of microbial
martial arts, turning the body’s weapons to its own advantage.
Mysorekar
and colleagues verified these findings using mice whose autophagy response was
hobbled by low levels of a key autophagy protein. They infected two groups of
pregnant mice with Zika: one in which the autophagy process was disrupted and
the other in which it worked normally.
Five days
after infection, the mothers with a weak autophagy response had about the same
amount of virus in their bloodstreams as the mice with a normal response.
However, in mice with a weak autophagy response, the researchers found 10 times
fewer viruses in the placenta and the heads of the fetuses and less damage to
the placentas.
“It appears
that Zika virus takes advantage of the autophagy process in the placenta to
promote its survival and infection of placental cells,” Cao said.
Since
hydroxychloroquine suppresses the autophagy response, the researchers
questioned whether it also could protect fetuses against Zika.
To find out,
they repeated the mouse experiment using only mice with a normal autophagy
response. Female mice at day nine of pregnancy were infected with Zika and then
dosed with hydroxychloroquine or placebo every day for the next five days.
Following
treatment, the researchers found significantly less virus in the fetuses and
placentas from the mice that had received hydroxychloroquine. In addition,
these placentas showed less damage and the fetuses regained normal growth. Both
the untreated and the treated mothers had about the same amount of Zika virus
in their bloodstreams, indicating that hydroxychloroquine was able to protect
fetuses even when the virus was circulating through the mother.
Although
hydroxychloroquine has been used safely in pregnant women for short periods of
time, the researchers caution that further studies are needed before it can be
used in pregnant women to fend off Zika. Pregnant women living in areas where
Zika circulates may need to take the drug for the duration of their
pregnancies, and the safety of hydroxychloroquine for long-term use is unknown.
“We would
urge caution but nevertheless feel our study provides new avenues for feasible
therapeutic interventions,” said Mysorekar, who is also co-director of the
university’s Center for Reproductive Health Sciences. “Our study
suggests that an autophagy-based therapeutic intervention against Zika may be
warranted in pregnant women infected with Zika virus.”
Joseph Ana.
Africa Center for Clin Gov Research &
Patient Safety
@ HRI West Africa
Group - HRI WA
Consultants in
Clinical Governance Implementation
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