by Tess Whitwam
figures by Daniel Utter
Imagine for a moment that you’re at a concert, standing close to a large loudspeaker—you can feel the vibrations from the loud music coursing through your body. Then, your friend behind you taps your shoulder, so you turn around, just as someone walks by and steps on your foot, causing you to jump back in pain. All the while, you can sense the internal pressure from your full bladder, indicating to you that you will need to find a bathroom soon. How did your body sense all of these things? While seemingly different stimuli, they all rely in part on the ability of your body to sense mechanical force. In addition to impacting our daily lives, the body’s ability to sense mechanical forces plays an unexpected role in human disease and disease resistance, impacting the contraction of malaria worldwide.
First, some terminology
Mechanical force is a force that requires physical contact. For example, if you want to open a door, you will need to apply physical force by pushing or pulling to open or close it. Mechanical force is highly prevalent in many aspects of life; it is utilized by the body to regulate many sensations and processes, including blood pressure, hearing, sensing touch, pain, and even the pressure from a full stomach or bladder. So, how does the body sense mechanical force? Mechanosensitive ion channels mediate one aspect of this sensation.
Ion channels are proteins that sit in the outer layer, or membrane, of cells. They have the ability to open and close, allowing charged molecules known as ions (such as calcium and sodium) to enter and exit the cell. These ions communicate messages, signaling to the cell how it should respond to stimuli. In mechanosensitive ion channels, force causes changes in cell membrane tension, causing these channels to open and allowing ions to flow through the channel. Different mechanosensitive ion channels sense different types of tension. For example, some respond to poking, while others respond to stretching. This allows the body to respond to a diverse range of forces. In 2010, one of the most prevalent mechanosensitive ion channels was discovered: Piezo1.
Piezo1 is present primarily in tissues that respond to fluids and pressure—places like the kidneys and red blood cells (RBCs). When Piezo1 senses force, it opens to allow sodium and calcium ions to enter the cell (Figure 1). While there are still many unknowns about Piezo1, researchers have begun making great strides towards better understanding its function and importance to many diseases. The remainder of this article will focus on just some of the many ways Piezo1 is important for human health, including its role in malaria resistance.
Piezo1 in Malaria
When RBCs circulate, they experience significant mechanical forces that can influence their structure and function as they pass through tight blood vessels in their journey throughout the body. Incorrect regulation of any of these mechanical forces acting on the RBCs can negatively impact their function and survival. One example of this is seen in hereditary xerocytosis (HX), a disease that can cause symptoms such as fatigue and jaundice in patients. This disease is primarily caused by mutations in Piezo1 that make RBCs shrink from fluid loss and become dehydrated. This occurs because the mutant Piezo1 ion channels can stay open longer, allowing more ions into the RBC and ultimately causing water to flow out, dehydrating the cell. Interestingly, prior studies have demonstrated that while dehydrated or misshapen RBCs can cause multiple different diseases (like HX), these mutations can also be protective against malaria. Now, how does this work? To understand, we’ll need a little background on how malaria infection occurs.
Malaria is caused by an infection of the parasite Plasmodium, typically transmitted to humans through mosquito bites. Once inside the body, the parasite can infect RBCs and travel throughout the bloodstream. Sometimes, as the disease progresses, it compromises the blood-brain barrier: a mostly impenetrable barrier that separates the brain from the blood stream, protecting the brain from harmful foreign agents. This enables the infected RBCs to enter the brain, leading to cerebral malaria, which is often fatal (Figure 2). Interestingly, malaria has greatly influenced the human genome through evolutionary selective pressure, in that genetic mutations that provide any assistance against Plasmodium infection are often passed on between generations of people. In 2018, researchers from The Scripps Research Institute found a new example of how Plasmodium has influenced the human genome: Piezo1.
In this study, the authors tested mice that express the same Piezo1 mutation found in HX patients. As expected, they saw that RBCs from mutant mice were dehydrated, as they are in human patients. Because RBC dehydration and/or malformation has previously been linked to malaria protection, the authors decided to test Plasmodium infection in the mouse model of HX. While normal infected mice died within 8 days, the Piezo1 mutant mice were amazingly able to survive for as long as 24 days—three times longer! This increased survival is in part because Plasmodium infects RBCs more slowly in Piezo1 mutant mice, leading to overall decreased infection rates. These observations indicate that the Piezo1 mutation is protective against Plasmodium infection of RBCs in mice, leading to longer survival rates. Furthermore, while the normal mice infected with malaria had malaria-infected RBCs in their brains, the mutant mice did not, indicating that Piezo1 mutant mice are protected against cerebral malaria.
Since the HX Piezo1 mutation is protective against malaria in mice, the authors wondered if it was also protective against malaria in humans. By looking at genetic sequence databases, the authors discovered that a mutation in Piezo1 is present in 1/3 of the African population (a group very susceptible to malaria infection). The authors were then able to obtain blood samples from African American volunteers with and without the Piezo1 mutation so that they could test if the mutation is in fact preventative as they hypothesized. They found that the RBCs from the donors with the Piezo1 mutation had decreased Plasmodium infection, just as they had seen in mice (Figure 3)! As such, despite the fact that Piezo1 mutations can be detrimental (as in HX), the benefit of malaria resistance has allowed these mutations to persist in the human population throughout evolution.
These findings of a novel role for mechanosensation in HX and malaria demonstrate new ways to study and potentially treat malaria. It is fascinating to consider the ways in which evolution has allowed organisms to develop resistance to certain diseases. A better understanding for how adaptations have evolved to combat disease naturally has the potential to provide new insight into manmade treatments for these diseases. For example, if a drug treatment were able to reproduce the protective aspects of the Piezo1 mutation, this could provide a preventative malaria treatment for at-risk populations. Further studies will need to look at how exactly this Piezo1 mutation is able to provide malaria resistance, as well as research ways to potentially utilize this finding for novel malaria treatments. It is exciting to think that basic science research initially looking to better understand the basic biological function of mechanosensation has the potential to lead to treatments for a disease that impacts millions of people around the world!
Tess Whitwam is a Ph.D. student in the Program in Neuroscience at Harvard University. You can reach her at twhitwam@g.harvard.edu
Dan Utter is a 4th year PhD student in Organismic and Evolutionary Biology at Harvard.
For more information:
- To read the original research described in this article, see this Cell article
- For more information about malaria, check out the website from the CDC
- For another take on this research and interviews with the scientists, check out this article
- To check out other research from the Patapoutian lab at The Scripps Research Institute, see here