Illustration by Kimberly Carney / Fred Hutch News Service
Pregnancy is weird, in so many ways. Perhaps most bizarre of all is the fact that women grow an entirely new organ for short-term use, the placenta.
This large, liver-colored organ has multiple jobs, providing both nourishment and protection to the growing fetus. It allows easy entry for some passengers — oxygen and nutrition — and keeps others out, such as some infectious agents. And it allows a unique exchange of cells between mother and child, known as “microchimerism.”
Now comes a suggestion of a new role, at least in mothers infected with malaria during pregnancy. When the mosquito-borne parasite known as malaria infects the placenta, it can have lasting, unexpected effects, according to a new study from researchers at Fred Hutchinson Cancer Research Center and their colleagues.
The research team, led by University of Washington and Seattle Children’s Hospital pediatric infectious disease specialist Dr. Whitney Harrington working with Fred Hutch microchimerism researcher Dr. J. Lee Nelson, looked at how malaria can alter the mother-child cell sharing that happens during pregnancy. While most of us carry a very small number of foreign cells acquired from our mothers — on the order of a few maternal cells per every 100,000 of our own — the researchers found that babies born to Tanzanian mothers infected with malaria during pregnancy and whose infections had traveled to their placentas had evidence for far more maternal cells on board at the time of their births.
The researchers examined the babies’ microchimerism levels by looking at the amount of maternal DNA in their cord blood — babies born to mothers with placental malaria had an average of about 1 percent maternal DNA in their cord blood at the time they were born, and three of them had more than 5 percent maternal DNA in their blood. At that level, it’s not even accurate to describe the children’s chimerism as “micro” any more, Nelson said.
And that increased maternal microchimerism affected the babies’ risk of contracting malaria after birth, the researchers found. Babies with higher levels of their mothers’ cells were more likely to get malaria in the future — but their infections were much milder than average, suggesting that the cells transferred from their mothers might confer some protection against the disease, the researchers said.
What they’ve uncovered — that a mother’s cells could directly act as part of her child’s immune system, even after birth — is “fascinating biology and super important to explore,” said Harrington, who conducted her research in Nelson’s clinical research lab at Fred Hutch. Harrington was first author on the study published recently in the Journal of Infectious Diseases.
“We’ve always considered the effect of a vaccine or an infection as being the product of one person’s immune system,” Harrington said. “What we’re basically proposing is that it’s actually the product of two different immune systems that are interacting.”
Photo by Robert Hood / Fred Hutch News Service
How mom’s cells might be teaching her children
Malaria is a leading cause of death in low- and middle-income countries, especially among children. An estimated 429,000 people die of the infection every year, according to the World Health Organization, and the majority of those deaths occur in sub-Saharan Africa.
To understand how maternal microchimerism and malaria might interact, the researchers examined 53 umbilical cord blood samples from pregnant women and their babies enrolled in a previous study in Muheza, Tanzania, from 2002 to 2006. Malaria is incredibly common in this region, Harrington said, and first-time pregnancies are more likely to result in placental infection with the parasite. About half of the 53 women in their study had placental malaria, and about half of those infected women had what’s called inflammatory placental malaria, where the placenta gets very diseased and can stop functioning properly. (But it does still seem to protect fetuses — none of the babies in this study contracted malaria in utero, although that does happen on occasion, Harrington said.)
The researchers looked for the amount of maternal DNA in the babies’ umbilical cord blood. This is representative of the level of maternal microchimerism the children had at the moment they were born, Harrington said, although it’s not known how long that level may persist after birth. Women with placental malaria gave birth to babies with higher-than-average maternal microchimerism. Three of the babies in their study had more than 5 percent maternal DNA, and one had 17 percent maternal DNA, the highest level of maternal microchimerism their team has found, Nelson said.
On average, the researchers saw higher levels of maternal microchimerism in babies whose mothers had inflammatory placental malaria. That group had an average of about 2 percent maternal cells present in their blood.
That increase of mother’s cells present in baby’s blood was a surprise to the researchers. “It’s really striking,” Harrington said. She hypothesizes that the infection led to alterations in placental proteins that control cell trafficking, which allowed more maternal cells to enter the fetuses.
But the lasting effect of this change was especially interesting to the researchers. When they looked at the health records of the babies in that Tanzanian study, they found that babies with higher levels of maternal microchimerism were twice as likely to be infected with malaria during childhood — but half as likely to get sick from that infection.
These results are just the first hint of what’s going on, Harrington said, citing two possibilities: Either mom’s immune cells are directly recognizing and acting on the malaria parasite in her child’s body, or they’re acting indirectly by teaching the child’s immune system how to recognize and react to the pathogen.
Photo by Robert Hood / Fred Hutch News Service
Their next steps are to tease out how the maternal and infant cells interact to affect future malaria risk. In one experiment, they plan to isolate mothers’ cells from the babies’ blood and ask whether those cells can directly react to malaria in the lab. They also aim to take the babies’ immune cells and ask whether the presence or absence of maternal cells changes how the child’s cells recognize and react to malaria.
They also want to ask whether and for how long the high levels of maternal cells persist during the children’s lives. Past research from other teams has suggested that maternal cells do last, possibly for life, but they don’t know whether that tenet applies to the huge boost of mother’s cells in this group of children. Harrington and her colleagues are now broadening their studies to look at mothers and children in Mali and Uganda, two other African countries with high levels of malaria.
The researchers also want to ask more generally how people’s microchimerism status affects their susceptibility to other childhood infections. As Nelson puts it, there’s a growing appreciation through many fields of research that our body is made up of many foreign parts — for example, there’s our microbiome, the complex communities of often-helpful bacteria that inhabit every nook and cranny of our body. Nelson would like us to think too about what some researchers dub our “microchiome,” cells from our mothers — and for some women, their children, because the sharing goes both ways — that make up our body but weren’t ours at the time we were first conceived.
Just like we need a healthy microbiome for our overall health, “we also need our microchiome,” Nelson said. “We’re better off with it.”
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Rachel Tompa, a staff writer at Fred Hutchinson Cancer Research Center, joined Fred Hutch in 2009 as an editor working with infectious disease researchers and has since written about topics ranging from nanotechnology to global health. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Reach her at email@example.com or follow her on Twitter @Rachel_Tompa.
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