I don’t know about you, but when I picture red blood cells, I imagine them as Spaghetti-O’s. I know that they “carry hemoglobin” and “facilitate oxygen transfer” and other “important things,” but I can’t get the image from the Magic School Bus out of my mind where they are essentially just innertubes coasting through your blood stream.
 
Surf’s up.
 
Luckily, Mangalmurti and a team of researchers at the University of Pennsylvania have no such preconceptions and have been delving deeper into a different function of red blood cells: immunity.  First of all, it’s important to recognize that your whole body is only made up of around 37 trillion cells, and 20-30 trillion of those are red blood cells. While it may be difficult to perceive a number in the trillions, just know that if you select a cell from your body at random, 7 times out of 10 it will be a red blood cell.
 
Red blood cells are unique in mammals because they don’t have organelles or nuclei. These are expelled from the cells before they enter the blood stream (and did you know your red blood cells are born in your bone marrow?). Not having this equipment means they aren’t doing what other cells do: making DNA and other proteins. They live for 120 days carrying around a signal that tells the body’s immune system “don’t eat me.” Once they are too old or too damaged to function they remove this sign and macrophages in the spleen gobble them up to remove them from the blood stream. Their whole lifespan they don’t make anything, so they’ve got to just be transport vehicles for oxygen, right? Mangalmurti says otherwise.
 
In non-mammalian species—birds, fish, reptiles, amphibians—red blood cells DO have nuclei. This means that when external stimulus like a bacteria, virus, or fungus are present in the blood stream, the red blood cells can upregulate genes or create proteins to mount a defense. The active role of red blood cells in immune defense is not unheard of in biology, but it’s just not really explored or understood in humans because our red blood cells can’t upregulate genes or create proteins in defense.
 
Despite their lack of internal equipment, our trusty Spaghetti-O cells can, after all, help defend our bodies from intruders.
 
Bacteria and microbes have their own set of DNA, and their DNA comes in a range of patterns. Typically, immune cells have receptors on their surface that attract and respond to a particular pattern of DNA. Once this fatal attraction has begun and the immune cells have bound themselves to the bacteria, the immune cells (typically white blood cells) either lead the bacteria to their demise, kill it themselves, or prevent it from reproducing.  It turns out that red blood cells have a receptor that can act as an immune signal and target a certain pattern of microbial DNA.
 
The immune receptor that Mangalmurti recently found on red blood cells can bind to microbial DNA. Previously, this receptor had only been observed in white blood cells, which we know are the main players in immune response in humans. On red blood cells, when this receptor is not bound to invasive microbial DNA, the “don’t eat me” sign that the red blood cells carries throughout its life is proudly displayed. When the receptors bind the DNA, the red blood cells change shape and the “don’t eat me” sign is hidden and removed. As a result, the red blood cells ferry an invasive bacteria or virus around the body and through the spleen, where both are gulped down by a macrophage. If the cells are not destroyed in the spleen, it’s possible that the red blood cell presents its captive pathogen to white blood cells, who are able to mount a more direct immune response. Although one red blood cell sacrificed its life, it was able to take out an invading pathogen in the process.
 
Most of the time, this process is largely insignificant and serves to minimize inflammation on a day-to-day basis. However, in cases of severe infection there is an overwhelming amount of microbial DNA in the blood stream, leading to increased binding by red blood cells. This amplifies the destruction of red blood cells and dramatically decreases the number present in circulation. The signaling and cellular interactions described here are associated with anemia in critically ill patients with sepsis, a disease characterized by an extreme immune response to infection. Long-term anemia in patients who have recovered from COVID-19 has also been observed, and Mangalmurti’s group believe their findings, and what they hope to learn in the future, can contribute to minimizing effects like this.
 
This new discovery is only the beginning of a better understanding of infection and immune response in the human body.
   
– Kalen Johnson
 
Kalen is a doctoral candidate in the College of Veterinary Medicine and Biomedical Sciences.