Extracellular Vesicle-Delivered tRF-His-GTG-1 Reprograms Neutrophil Lipophagy and Triggers Inflammation in COVID-19, 2026, Liao et al.

[SNT Gatchaman]

Extracellular Vesicle-Delivered tRF-His-GTG-1 Reprograms Neutrophil Lipophagy and Triggers Inflammation in COVID-19

Spoiler: Authors

Tsai-Ling Liao; Po-Yu Liu; Yi-Ming Chen; Kuo-Tung Tang; Hung-Jen Liu; Der-Yuan Chen

Immunometabolism and neutrophil extracellular traps (NETs) play pivotal roles in the pathogenesis of coronavirus disease 2019 (COVID-19) and its postacute sequelae. However, the upstream regulators that reprogram neutrophil lipid metabolism and trigger excessive NET formation remain largely undefined. This study identifies a transfer RNA-derived fragment, tRF-His-GTG-1, enriched in platelet-derived extracellular vesicles, as a key driver of neutrophil lipophagy dysfunction and inflammation in COVID-19.

The use on neutrophils from 60 patients and 20 healthy controls, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–infected hamster model, and multiple in vitro assays shows that severe COVID-19 and long COVID are characterized by increased lipid droplet (LD) accumulation and NET release.

Mechanistically, tRF-His-GTG-1 activates Toll-like receptor 8 (TLR8)–mammalian target of rapamycin (mTOR) signaling and suppresses RAB7A expression, changes that impair lipophagic flux. This dual pathway impairs lipophagy and promotes NET formation and proinflammatory cytokine secretion. Importantly, ex vivo treatment with a tRF-His-GTG-1 inhibitor restores lipophagy, reduces LD and NET levels, and suppresses interleukin 1beta (IL-1β)/IL-8 production in patient-derived neutrophils.

These findings reveal a novel EV-mediated immunometabolic axis linking platelets to neutrophil dysfunction, and position tRF-His-GTG-1 as a promising RNA-based therapeutic target for COVID-19-associated hyperinflammation.

Web | DOI | PDF | Advanced Science | Open Access

 

[SNT Gatchaman]

Collectively, these results demonstrate a dual mechanism through which tRF-His-GTG-1 regulates neutrophil lipophagy and NET formation via TLR8–mTOR activation and RAB7A suppression. tRF-His-GTG-1 functions upstream to activate TLR8–mTOR while concurrently repressing RAB7A. The TLR8mTOR pathway drives LD biogenesis and NET formation, whereas RAB7A loss further impairs lipophagy.

RAB7A is a "small, RAS-related GTP-binding proteins that are important regulators of vesicular transport".

The DecodeME-highlighted RABGAP1L is a modulator of RAB7A. From RabGAP1L modulates Rab7A and Rab10 to orchestrate cell-autonomous immunity (2025) —

RabGAP1L regulates cell-autonomous immunity by inactivating Rab7A and Rab10

However, DecodeME said —

The allele that increases the risk of ME/CFS is associated with decreasing RABGAP1L gene expression.

Which would seem to be the opposite direction required if this mechanism of RAB7A suppression were at play in ME/CFS. Things might be more complicated and counter-intuitive though (or I'm summarising incorrectly).

 

[Jonathan Edwards]

Immunometabolism and neutrophil extracellular traps (NETs) play pivotal roles in the pathogenesis of coronavirus disease 2019 (COVID-19) and its postacute sequelae.

I don't know where this idea comes from but for postacute sequelae it seems to me totally implausible. It is just the fashion that comes up in almost all seminars on immunologically mediated disease these days.

As usual the abstract gives no actual data to support the conclusion the authors assumed before starting.