Over the past few years, most of the public conversation around SARS-CoV-2 has focused on ACE2 — the so-called “front door” receptor that allows the virus to enter cells. That explanation has been useful, but it is incomplete. There is another door. In my view, it may be central to understanding why so many people are experiencing recurrent infections, prolonged illness, lymphopenia, viral reactivations, and persistent immune dysfunction long after their initial encounter with COVID.
This is the story of CD147 — what I have called the trapdoor.
In my presentation, “The COVID Trapdoor: How Your Immunity Gets Depleted by Repeated Infections”, I explored a mechanism that helps connect several clinical patterns many of us have observed but struggled to fully explain.
The Spike Protein Is a Master Key
Viruses operate through keys and locks. For SARS-CoV-2, the spike protein is the key. ACE2 was thought to be the main lock. But spike is not a simple key; it behaves more like a master key. Beyond ACE2, it can bind to other receptors — including CD147. Unlike ACE2, which is concentrated primarily on epithelial surfaces such as lung cells, CD147 is expressed broadly across the immune system. CD4+ T cells, B cells, monocytes, macrophages, neutrophils, and NK cells all express CD147.
That matters because CD4+ T cells and B cells do not express ACE2. Yet early in the pandemic we consistently observed lymphopenia and immune dysfunction. The unresolved question was how the virus was affecting immune cells that lacked the “main” entry receptor. CD147 provides a biologically plausible route.
The Virus Can Open More Doors from the Inside
What makes CD147 particularly concerning is not simply that it can act as an alternative entry point. It is inducible. In the paper titled “Inducible CD147 upregulation boosts extended SARS-CoV-2 infection triggering severe COVID-19 independent of ACE2”, researchers demonstrated that infection increased CD147 expression while downregulating ACE2. In other words, the virus appears capable of shifting the balance from the front door to the back door.
Wang, Ke, et al. "Inducible CD147 up-regulation boosts extended SARS-CoV-2 infection triggering severe COVID-19 independent of ACE2." Signal Transduction and Targeted Therapy 11.1 (2026): 42.
