Thread by @ZdenekVrozina

A bystander apoptosis. The study in Nature argues that Omicron can drive the death of nearby, uninfected T cells. This paper shows an HIV-like pattern of immunopathology.🧵

A new paper suggests something important about severe Omicron cases.
The damage may not come only from the cells the virus infects directly.
It may also come from the immune cells caught in the crossfire.

The study argues that Omicron can drive the death of nearby, uninfected T cells.
That matters, because T cells are central to immune defense.
So the story is bigger than how much virus is inside a given cell.

It may also be
what kind of self-amplifying immune damage gets triggered around it.
The authors describe - a bystander apoptosis.

Some T cells may die not because the virus took them over,
but because the surrounding infected tissue sends out signals that push them toward death.

For some critically ill patients, it could help explain why profound lymphopenia shows up alongside immune dysfunction.
The paper proposes this pathway
GDF15 - BCL2L13 - T-cell apoptosis

So Omicron-stimulated epithelial cells release signals,
those signals alter T-cell death programs,
and more T cells are lost - including cells that were never directly infected.

This is where an parallel to HIV becomes interesting.

With HIV, it has long been recognized that immune damage is not only about direct viral infection of target cells.
A meaningful part of the damage can come from the death of bystander immune cells too.

The study also brings up CD63 as a possible helper for SARS-CoV-2 entry into T cells,
which is interesting because CD63 has also been discussed in HIV-related viral entry biology.

Once you see it that way,
severe disease stops looking like a simple viral load story.
It starts looking more like a systems problem
signaling, tissue stress, immune cross-talk, and collateral damage.

Sum:
In severe Omicron disease,
part of the immune collapse may come not only from direct infection,
but from the induced death of surrounding, uninfected T cells.

Omicron more strongly increases T-cell apoptosis, and the leading candidate mediator is GDF15, which upregulates BCL2L13.

The authors support this with multiple layers of evidence. Proteomics, experiments with recombinant GDF15, BCL2L13 overexpression, a clinical association between plasma GDF15 and worse condition, SOFA scores, lower lymphocyte counts. Still, the core mechanism remains demonstrated mainly in vitro.

So it could help explain why some patients deteriorate immunologically in ways that seem bigger than direct viral tropism alone would suggest.

The study offers a strong model with experimental support. Article in Press

Gao at al., Variant-divergent death: Omicron intensifies bystander T-cell apoptosis via GDF15–BCL2L13. Nature. nature.com/articles/s4142…