Study Uncovers How Cells Digest Pathogens That Slip Past the Immune System

When pathogens enter the bloodstream, the immune system typically responds by producing antibodies that flag invaders for destruction by white blood cells. But sometimes antibody-bound pathogens evade immune cells and infect healthy cells anyway. Research published recently in Molecular Cell describes a previously unknown pathway by which the body fights back—directly inside already infected cells. 

The authors define this mechanism as “antibody-directed xenophagy” (ADX), a process by which cells can digest bacteria and viruses that cross the cell membrane, including Salmonella and adenoviruses.

“People have talked about viral xenophagy before as a sort of concept, but if you look in literature, there aren’t any good examples where people have shown this operating to potently block infection,” said senior author Leo James of the MRC Laboratory of Molecular Biology. “In our single study, we’ve gone from the discovery of something completely unknown [ADX], all the way through molecular mechanism, its function in cells into animals, and demonstrated physiological importance.”

Using CRISPR-Cas9 and quantitative imaging, the team determined that ADX begins with a specialized protein called TRIM21. Once an antibody-labeled pathogen enters a cell, TRIM21 detects the antibodies attached to the invader and flags it with a marker called ubiquitin—signaling the cell to degrade it. “TRIM21 is unique because it uses the antibodies attached to the invading virus or bacteria to alert the cell,” James said. “A virus comes in and the cell is initially not aware of it, but since there's an antibody on the virus, TRIM21 sees that and goes, ‘aha, that's a virus, that's a pathogen,’ then labels it so that the cell degrades it.”

The pathway appears to operate broadly. TRIM21 was shown to mark and destroy both adenoviruses and Salmonella through the same mechanism. “It seems that you trigger ubiquitination of whatever pathogen has antibodies around it through TRIM21, and this is the key step that leads to autophagy of the bacteria or the virus,” said co-author Tyler Rhinesmith.

ADX-mediated immunity also appears to function throughout the body, not just in specific cell types. The team tested TRIM21 activity against adenovirus across a range of human cell lines, and against Salmonella in living mouse models. Because TRIM21 is expressed from an interferon-stimulated gene, it is upregulated during infection and present across tissues. “The reason why you make it everywhere is so that you can potentially protect any cell or tissue,” James said. 

Rather than serving merely as a backup when primary defenses fail, ADX may function as an equally important primary mode of protection. “Our data shows that without TRIM21, a significant component of protective immunity in vivo against viruses is lost. In practice, immunity works because we’ve got different mechanisms operating together,” James added.

TRIM21 is the first intracellular protein found to stimulate ADX immunity, but the researchers suspect others may exist with equally broad or more specific pathogen targets. Identifying those proteins and defining the limits of TRIM21’s function are among the team's next steps.