In medicine, whether we’re researchers or clinicians, discoverers or the people applying discoveries, we all prefer clear mechanisms to mere correlations and connections, especially with novel issues like the COVID spike protein. As this article notes, mast cell activity (a part of the immune system) has been correlated with a wide variety of immune processes besides just allergic ones. While more well-known for contributions to anaphylaxis, hives, and similar conditions, more recent research has demonstrated that as these mast cells sit on the surfaces between our bodies and our environment, they serve to direct immune responses against a variety of infections. This study sheds light on the actual mechanisms of how COVID spike proteins trigger mast cell reactions. It thus spurs us on to search for therapies to harness this response for good, rather than just suffering its unwanted effects.
The article by Zhang et al from April 2025 focused on identifying the mechanisms by which mast cells might play a role in acute COVID. Building on other prior research linking mast cells and the severe respiratory syndrome of COVID infection, they worked to identify the exact molecular process by which COVID or its parts triggers an inflammatory reaction in our immune system. This connection should not be surprising; as the article mentions, mast cells have been linked to responses against other pathogens like bacteria, parasites, and other viruses.
Even the study authors own prior research said that the COVID spike protein triggered “rapid degranulation”, meaning release of further active mediators, a process that contributed to inflammation in various organs. They even mention an article by Weshsler et al in Allergy from 2022 that linked long COVID and mast cell activation. Still, we all want to find the actual mechanism, both for confirmation and to help find therapies.
In this study, the researchers identify the receptors which bound the COVID spike protein, setting in motion the actual inflammatory process. They trace this through several steps so that they can confidently assert that COVID spike proteins have a clear mechanistic pathway from receptor binding to degranulation of the mast cells, passing on signals for ongoing inflammation.
With a clearer understanding of how this happens, beyond a simple knowledge that it does happen, we can begin searching for ways to harness this process. The process itself is meant to allow the body to respond to infectious threats and should not necessarily be turned off completely. Doing so would likely cause more ultimate harm than good. Yet, allowing the process to run amok may be behind some of acute COVID’s severity and maybe even long COVID’s thorn in our sides.
As we await further research, we can feel confident in trying the mast cell therapies we already have available. These include natural and pharmaceutical mast cell stabilizers and anti-histamines. We aim first to prevent mast cell activation and then try to decrease its intensity and duration to appropriate levels when it does happen. Helping our patients live healthier more abundant lives requires the best of both worlds of medicine applied wisely to their individual situation with close watch over them to see how each respond. Ultimately, it is both what therapies we use and how we apply them, just like a painter in how they use the same paints as others to create works of art by their skills. Caring for patients is as much an art as a science.
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Original Article:
Zhang, S., Xu, C.-L., Wang, J., Xiong, X., & Wang, J.-H. (2025). Spike proteins of coronaviruses activate mast cells for degranulation via stimulating Src/PI3K/AKT/Ca2+ intracellular signaling cascade. Journal of virology, 99(5), e0007825. https://doi.org/10.1128/jvi.00078-25
Sanctuary Functional Medicine, under the direction of Dr Eric Potter, IFMCP MD, provides functional medicine services to Nashville, Middle Tennessee and beyond. We frequently treat patients from Kentucky, Alabama, Mississippi, Georgia, Ohio, Indiana, and more... offering the hope of healthier more abundant lives to those with chronic illness.
Dr. Eric Potter graduated from Vanderbilt Medical School and then went on to specialize in internal medicine (adult) and pediatric care, spending significant time and effort in growing his medical understanding while caring for patients from all walks of life.
