Antibody-Directed Xenophagy Pathway Blocks Intracellular Infections From Spreading

Scientists have revealed the process by which cells can internally digest bacteria and viruses. The research, published in the Cell Press journal Molecular Cell, outlines a novel method of germ resistance termed ‘antibody-directed xenophagy’ (ADX).

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When people think about the immune system, they often picture white blood cells circulating through the bloodstream and defending the body against harmful pathogens.

However, scientists at the Medical Research Council Laboratory of Molecular Biology (MRC LMB) have discovered that individual cells can also engulf microbes that breach the cell membrane, including pathogens such as Salmonella bacteria and adenoviruses.

Molecular Mechanism

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. 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.

Leo James, Group Leader, MRC LMB

Specialized Proteins

The body produces antibodies that attach to the invaders present in the bloodstream, signaling immune cells, such as white blood cells, to eliminate them when an infection occurs.

There are instances when these antibody-bound pathogens manage to evade immune cells and infect healthy cells.

Employing CRISPR-Cas9 technology and quantitative imaging techniques, the research team discovered that once an antibody-tagged pathogen infiltrates a cell, the process of ADX is initiated by a specialized protein known as TRIM21.

TRIM21 marks the pathogen with a molecule called ubiquitin, which indicates to the cell that it has been compromised.

Super-resolution image of an LC3-positive autophagosome engulfing a TRIM21 and antibody-coated adenovirus. Image Credit: Claudia Puri, Matthew J. Gratian, Anna Albecka, and Tyler Rhinesmith.

Labeling Cells

TRIM21 is unique because it uses the antibodies attached to the invading virus or bacteria to alert the cell. So, in this case, 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.

Leo James, Group Leader, MRC LMB

The immune response mediated by TRIM21 and ADX seems to be extensive, as it is capable of tagging and eliminating both adenoviruses and the bacterium Salmonella from infected cells.

Wide-Ranging

The capacity of cells to mount an internal defense does not seem to be restricted to particular cell types within the human body.

The research team investigated the presence and functionality of TRIM21 in response to adenovirus across various human cell lines, and also in living mouse models concerning Salmonella.

The results of these experiments suggest that ADX-mediated immunity is probably widespread throughout the human body.

Primary Mode of Defense

TRIM21 is produced from what is referred to as an 'interferon-stimulated gene,' indicating that its expression increases during infections, resulting in its constant production throughout the body.

This mechanism allows the body to potentially safeguard any cell or tissue.

While ADX might appear to serve as a 'backup' for the immune system when pathogens bypass the initial defenses, the authors emphasize that it could also represent a crucial primary mode of protective immunity.

TRIM 21

The study indicates that the absence of TRIM21 results in the loss of a crucial element of protective immunity in vivo against viral infections. In practical terms, immunity functions through the collaboration of various mechanisms.

TRIM21 is the first intracellular protein identified to enhance ADX immunity; however, it is possible that additional proteins exist with similarly broad or specific targets against pathogens. 

One of the forthcoming objectives of the research team is to ascertain the presence of other proteins that stimulate ADX and to explore any potential limitations associated with the function of TRIM21.

Key Step

We show in the paper that on top of non-enveloped viruses, it’s also able to target bacteria along the same pathway. 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.

Tyler Rhinesmith, Study Co-author, MRC LMB

Future Treatments

The identification of the ADX pathway holds significant potential for future medical applications.

Therapeutics, whether antibody-based or small molecules, may be employed to combat infections by tagging pathogens in the bloodstream, enabling TRIM21 to identify and activate ADX upon their entry into cells.

Extensive research is required before these therapeutic alternatives can be realized.