When most people think of the immune system, they think of white blood cells that fight invading bacteria in the bloodstream. But now, according to research published June 4 in the journal Cell Press, molecular cellScientists detail another, but equally important, route by which our bodies fight infections: directly inside already infected cells. In the report, the authors define a previously undescribed method of bacterial resistance, a term they coined “antibody-directed xenophagy” (ADX). This method allows cells to digest bacteria and viruses that pass through the cell membrane. Salmonella and adenovirus.
Viral xenophagy has been talked about as a concept in the past, but looking at the literature, there are no good examples showing that it strongly blocks infection. In our single study, we went from discovering a completely unknown entity (ADX) to its molecular mechanism, its function in cells, and animals, and demonstrating its physiological importance. ”
Mr. Leo James of MRC Molecular Biology Laboratory
Normally, when you get an infection, your body produces antibodies that trap the invader in your blood and alert immune cells, such as white blood cells, to destroy the invader. However, this doesn’t always work. In some cases, pathogens that bind to these antibodies can bypass immune cells and infect healthy cells. This is where antibody-directed xenophagy comes into play. Using CRISPR-Cas9 and quantitative imaging, the research team found that when a pathogen labeled with an antibody enters a cell, ADX begins with a special protein called TRIM21. TRIM21 flags pathogens with a marker called ubiquitin, which signals cells that a pathogen has invaded.
“TRIM21 is unique in that it uses antibodies attached to invading viruses and bacteria to alert cells,” James says. “So in this case, the virus comes in and the cell doesn’t notice it at first, but because the virus has antibodies, TRIM21 recognizes it and decides, ‘Oh, this is a virus, this is a pathogen,’ and it labels the virus so that the cell can break it down.”
The immune effects of TRIM21 and ADX appear to be widespread, as they can mark and destroy both adenoviruses and bacteria. Salmonella from infected cells. “In our paper, we showed that in addition to non-enveloped viruses, we can also target bacteria along the same pathway,” says co-author Tyler Reinsmith, also from the MRC Institute of Molecular Biology. “TRIM21 appears to trigger the ubiquitination of pathogens that have surrounding antibodies, which is an important step leading to autophagy in bacteria and viruses.”
This ability of cells to fight back from within does not seem to be limited to specific cells in our bodies. The research team tested the presence and action of TRIM21 on adenoviruses using various human cell lines and, in the case of adenoviruses, a live mouse model. salmonella. These experiments demonstrated that ADX-mediated immunity may be ubiquitous throughout the human body.
“TRIM21 is expressed from a so-called ‘interferon-stimulated gene,’ which means it is upregulated during infection, so the body produces TRIM21 everywhere and at all times,” Leo says. “And the reason it’s so ubiquitous is because it has the potential to protect any cell or tissue.”
ADX may sound like a “backup” for the immune system when pathogens evade our first line of defense, but the authors point out that this may be an equally important primary mode of protective immunity.
“Our data show that without TRIM21, a key component of protective immunity, alive You will lose your antivirus. In reality, immunity works because a variety of mechanisms work together,” says James.
TRIM21 is the first intracellular protein discovered to stimulate ADX immunity, but there may be other proteins that similarly target a broad range of or specific pathogens. Part of the research team’s next steps will be to determine whether other ADX-stimulating proteins exist and what limitations there are on TRIM21’s function.
The discovery of the ADX pathway may have future medical implications. Antibodies or small molecule therapeutics can be used to treat infections by marking pathogens in the blood, allowing TRIM21 to recognize pathogens that have entered cells and activate ADX. Still, more research needs to be done before treatment options become a reality.
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Reference magazines:
Reinsmith, T. Others. (2026). TRIM21 induces selective autophagy in viruses and bacteria. molecular cell. DOI: 10.1016/j.molcel.2026.04.031. https://www.sciencedirect.com/science/article/pii/S1097276526002856?via%3Dihub
