Researchers have learned how Listeria crosses the placenta from mother to baby.
For the first time, researchers have learned how the dangerous foodborne pathogen Listeria crosses the placenta from mother to baby.
Listeria bacteria are found in unpasteurized cheeses, uncooked meat, and raw vegetables. Pregnant women are advised not to eat those foods, as they are 20 times more susceptible to Listeria infection than other healthy adults, and effects can be devastating: miscarriage, stillbirth, premature delivery, or meningitis in newborns. The higher risk for mothers-to-be was long blamed on the fact that a woman's immune response is dampened during pregnancy to prevent her body from rejecting the fetus. However, several years ago researchers performed experiments that suggested that Listeria may actively target and invade human placenta.
Now, Marc Lecuit; Pascale Cossart, an Howard Hughes Medical Institute international research scholar; and their colleagues at the Pasteur Institute and Inserm in Paris have worked out the molecular trick that makes the bacteria so dangerous to pregnant women. Knowing which molecular interactions are involved in placental infection will allow researchers to develop new ways to prevent infection.
The work was published in the September 17, 2008, issue of the journal Nature.
Listeria monocytogenes is unique among human pathogens in its ability to invade three normally impermeable internal barriers: the intestinal lining, the placenta, and the blood-brain barrier. Lecuit and Cossart had previously found that Listeria invades the intestine by relying on the interaction between internalin (InlA), a protein on the surface of the bacteria, and E-cadherin, a receptor on human epithelial cells.
To find out how Listeria invades the placenta, the researchers infected pieces of human placenta. That analysis indicated that InlA also had a role in the placental infections, along with a member of In1A's extended family, another internalin called InlB. To verify that both In1A and In1B were involved, they turned to traditional animal models of Listeria infection—mouse, rat and guinea pig—and immediately ran into a problem. InlA and InlB played no role in placental infections in those animals.
“Several groups, including ours, have now shown that InlA isn't required for Listeria to cross the placental barrier in guinea pigs,” Cossart says. “So there is some discrepancy between the human and guinea pig results.” Clearly the researchers' animal models weren't working, so they set out to find new animal models in which both InlA and InlB could mediate entry into the corresponding cultured cells. A likely candidate was the gerbil, which is naturally susceptible to Listeria infection.
The researchers found that mutant bacteria that lacked InlA, InlB, or both could not infect cultured gerbil intestinal cells. “Now we had an animal cell that—in contrast to mouse, rat, or guinea pig cells—was behaving like human cells, because both internalins had an effect,” Lecuit says. “We knew we were on the right track.” The next step was to explore these interactions in the placenta. When they infected pregnant gerbils with the mutant strains of Listeria, those bacteria could not infect the placenta either.
The team then created a genetically engineered mouse that expressed a version of human E-cadherin throughout their bodies. A previous transgenic mouse that expressed human E-cadherin only in its intestine was resistant to placental infection with Listeria, but in this new mouse, the placenta was susceptible to the bacteria.
Combined, these experiments showed that both InlA and InlB were needed for placental invasion to occur. If either was missing, the placental infection couldn't happen. Now that they know how Listeria invade the placenta, the researchers can look for a way to prevent placental infection. The findings might also be relevant to other pathogens, such as toxoplasmosis, that pose a threat to pregnant women and their babies..
Lecuit and Cossart think that the unique nature of the cell covering the placenta's surface may cause the bacteria to resort to a double-barrelled molecular attack. The epithelial interface between mother and fetus consists of a single cell layer called a syncytiotrophoblast. This highly specialized cell, which is large and contains multiple nuclei, has a structure that is very different from classical epithelial cells. One consequence is that E-cadherin (the “E” stands for epithelial) is organized differently on its surface.
That E-cadherin is not anchored on the placental surface in the same way would make it difficult for InlA to mediate entry, so that interaction alone may not be sufficient to allow Listeria to both bind to the cell and enter it. “One hypothesis is that the interaction between InlA and E-cadherin mediates adhesion, and the interaction between InlB and (its receptor) Met triggers entry,” Cossart says.
Now Lecuit and Cossart are trying to figure out how Listeria monocytogenes crosses the blood-brain barrier. The barrier contains E-cadherin at some locations, so some of the same mechanisms could be at play as in the placenta and intestine. However, they say, “It could also be something totally different again. That's the next big question,” Cossart says.