Dr. Indira Mysorekar is an associate professor in the departments of obstetrics and gynecology and pathology and immunology at Washington University. Her research is aimed at understanding how infections can trigger preterm birth, using cell culture models, mouse models, and human placental tissues. She received an Investigator Award in Reproductive Sciences from the Burroughs Wellcome Fund in 2011. Here she explains her efforts to understand how the placenta protects the fetus from bacteria and viruses, and what happens when they make their way across that normally impenetrable barrier.
Q: A few years ago, you were involved in a seminal study that found the placenta is home to a variety of bacteria. How has that discovery influenced the field and its long-held view of the placenta as a germ-free organ?
A: Historically, scientists thought that the placenta was sterile, and therefore if they detected any bacteria then that must be indicative of an infection that would need to be treated by antibiotics. Along those same lines, it was common practice for women who might be at risk for infection to be put on a low dose of prophylactic antibiotics. They did a randomized control trial several years ago where they did just that and they found that women who were put on antibiotics had a slightly higher risk of going into labor early and giving birth prematurely, which was the exact outcome they were trying to prevent. That confused everyone.
Then we found the placenta naturally harbored bacteria, not just a few random bacteria floating around, but entire communities, living within placental cells. As a microbiologist, I knew that when you have a subset of bacteria that are intracellular and are consistently found a certain type of cell, then they’re there for a purpose, it’s usually not random. It may be that these bacteria play some kind of important role, which gets eliminated by antibiotics. We've now done much more extensive work trying to understand where the bacteria in the placenta came from and what they are doing there.
Q: What other aspects of the placenta do you study?
A: I am interested in how the placenta normally protects the fetus. The placenta is amazing in how it provides nutrition and oxygen, and shields the fetus from environmental impacts like stress or infections. There are millions of us on earth, and for the most part we're born at term, and we’re born without infections, so how does the placenta manage that? As part of that, I want to understand how bacteria and viruses overcome the placenta’s natural barrier to either help or harm the fetus.
Specifically, my laboratory studies a process called autophagy. It's a biological process of recycling cellular components, and we have found that the placenta uses it to chop up and recycle invading pathogens. But it doesn’t always work like it should, and some bacteria and viruses are able to avoid autophagy or actually use it to gain access to the placenta. We have been looked at different genes and proteins involved in this process to determine how changing or removing them might alter the infectious capacity a specific viruses. Now we're doing those studies with the Zika virus, and hope to have some exciting results soon.
Q: How did you become involved in Zika research?
A: I had heard a lot about Zika from a colleague down the hall, an obstetrician who is on a short sabbatical from Brazil. Then in January I had a chance dinner with my colleague and fellow BWF awardee Mike Diamond, a flavivirus expert. He mentioned that he was receiving all these strains of the Zika virus strains from different parts of the world as they were being isolated from people, and that he had several strains from Brazil. He was manipulating mice to create models that could be infected with these strains, because it’s not normally a mouse virus. A couple of days later, I emailed him to say that he should think about looking at what happens during pregnancy in the mouse models. I mentioned my expertise in studying placenta biology and infections, and that I would be happy to help. We set up this collaboration and it went at a breakneck speed, it was very intense and our results were published recently in Cell. My postdoctoral fellow, who is a first author on this paper, literally worked 24/7 to get it done.
Q: That is an amazing feat, to conceive a project in January and then publish it in Cell five months later. What did your study entail, and what did you find?
A: Mike generated two mouse models of infection, by either genetically knocking out important immune molecules called interferons or chemically blocking them with antibodies. We then impregnated the mice, infected them, and isolated their placentas to assess the effects of the virus. We found that the virus is physically going through the layers of cells that make up the placenta, not simply bypassing the barrier. It starts in the maternal circulation and goes into the placental trophoblasts that reside in a region called the junctional zone. There, the virus replicates tremendously before going through another region called the labyrinth zone and then into the fetal endothelial cells, which are the cells that line the blood vessels of the fetus. Next we actually see it in the circulation, and directly after that we see it going up into the fetal brain. We see damage to the placental cells all along the way.
A previous paper noted in the pregnant women infected with Zika, that there is placental insufficiency, meaning that because of the virus shrinks the size of the blood vessels, reducing the oxygen and nutrient exchange between the mother and the fetus and leading to the fetus being much smaller. Clinically it's called "intrauterine growth restriction," or simply small fetuses. In general, the fetuses that are born from these infected moms are smaller. We were able to recapitulate those same findings in our animals.
Q: What kind of studies are you planning to conduct, now that you have these animal models of Zika infection?
A: I think this one project could hopefully generate many more years of more research, for our lab and others. These mouse models could be used to study the transmission of the virus from mother to child, as well as to test new drugs and vaccines. Specifically, my laboratory would like to test additional variations of Zika infection, such as changing the dose, route of administration, virus strain, time of infection during pregnancy, and time of analysis, to see how they might affect its infectivity and impact on the placenta and the fetus. And of course, we want to explore what kind of a role autophagy plays in the ability of the virus to breach the placental barrier.
Q: In your paper in Cell, you concluded that placental infection may be a larger phenomenon than previously realized. Do you care to expand on that statement?
A: I would qualify that by saying that I think a better understanding of what an infection is will be hugely critical. Researchers who are studying the placenta might suspect an infection when they find some microbes, some immune response, and some immune markers in the maternal plasma or serum, or in the placenta itself. But we need to be careful to think in terms of the location of these factors, that these things might have a signal of normal development and not infection. Each location of the placenta has different biology, different function, and each location also has differential susceptibilities or resistance to infection. If we find something in an area where it has bypassed the barrier, then you it likely there to do bad things, as opposed to other areas, where it might not.
I think a better, deeper, and more spatial and temporal understanding of placental development will enable us to differentiate between situations where a woman actually has an infection that is going to affect the fetus and should be treated accordingly and a woman who doesn’t have an infection, but may have other things going on. As with so many other aspects of clinical care, the misdiagnosis of infection or misuse of antibiotics could lead to more harm than good. I think more understanding right now is the key.
Q: How do you think the current Zika outbreak is affecting research in your field?
A: I think this epidemic is shedding light on an understudied area and I hope that Congress will pass a spending measure to fund more studies on the placenta and Zika. Hopefully more people will study the placenta, and appreciate it and understand it better.
My training was in a different field, I spent graduate school studying the gut and my post-doc studying the urinary tract, so I came to study the placenta as an adult. I have a different kind of appreciation than others who have grown up with the tissue. It's like coming as an immigrant to a country at the age of 21.
From that perspective, I have been amazed at how interesting a tissue it is, and how it's just generally considered a bloody mess by most people, but if you actually look into it, it's an extraordinary organ. It's functioning as your lung, your gut, your endocrine system, your urinary system, and everything for this relatively short period of time, and then it's made again for the next person. I have a 13-year old, and when I gave birth, I was remotely interested in the placenta. It had already done its job, my baby was born. Now I look at it with a lot of respect.