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.

 

[SNT Gatchaman]

Their introduction and refs are —

excessive NET formation contributes to coagulopathy, immunothrombosis, and tissue-damaging inflammation, particularly in severe cases of coronavirus disease 2019 (COVID-19) [2–4]. Recent studies have implicated NETs in sustaining chronic inflammation in patients with long COVID [5], but the mechanisms driving their overproduction and persistence remain poorly understood.

[2] Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome (2020, Blood)

Spoiler: Abstract

COVID-19 affects millions of patients worldwide, with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens, and they can trigger immunothrombosis.

We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n = 33) and age-and sex-matched controls (n = 17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), platelet factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-inhibitory factor (nNIF) to block NET formation induced by COVID-19 plasma.

Plasma MPO-DNA complexes increased in COVID-19, with intubation (P < .0001) and death (P < .0005) as outcome. Illness severity correlated directly with plasma MPO-DNA complexes (P = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19, and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline, and COVID-19 plasma triggered NET formation, which was blocked by nNIF.

Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19, and NETs may represent targets for therapeutic intervention.

KEY POINTS
NETs contribute to microthrombi through platelet-neutrophil interactions in COVID-19 ARDS.

nNIF blocks NETs induced by COVID-19 plasma and represents a potential therapeutic intervention in COVID-19.

[3] SARS-CoV-2–triggered neutrophil extracellular traps mediate COVID-19 pathology (2020, Journal of Experimental Medicine)

Spoiler: Abstract

Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology.

A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2–activated neutrophils promote lung epithelial cell death in vitro.

These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.

[4] Neutrophil extracellular traps in COVID-19 (2020, JCI Insight)

Spoiler: Abstract

In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have the potential to propagate inflammation and microvascular thrombosis — including in the lungs of patients with acute respiratory distress syndrome.

We now report that sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase-DNA (MPO-DNA), and citrullinated histone H3 (Cit-H3); the latter 2 are specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute-phase reactants, including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels.

Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro.

Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19.

[5] Neutrophil extracellular traps and long COVID (2023, Frontiers in Immunology)

Spoiler: Abstract

Post-acute COVID-19 sequelae, commonly known as long COVID, encompasses a range of systemic symptoms experienced by a significant number of COVID-19 survivors. The underlying pathophysiology of long COVID has become a topic of intense research discussion. While chronic inflammation in long COVID has received considerable attention, the role of neutrophils, which are the most abundant of all immune cells and primary responders to inflammation, has been unfortunately overlooked, perhaps due to their short lifespan.

In this review, we discuss the emerging role of neutrophil extracellular traps (NETs) in the persistent inflammatory response observed in long COVID patients. We present early evidence linking the persistence of NETs to pulmonary fibrosis, cardiovascular abnormalities, and neurological dysfunction in long COVID. Several uncertainties require investigation in future studies. These include the mechanisms by which SARS-CoV-2 brings about sustained neutrophil activation phenotypes after infection resolution; whether the heterogeneity of neutrophils seen in acute SARS-CoV-2 infection persists into the chronic phase; whether the presence of autoantibodies in long COVID can induce NETs and protect them from degradation; whether NETs exert differential, organ-specific effects; specifically which NET components contribute to organ-specific pathologies, such as pulmonary fibrosis; and whether senescent cells can escape clearance and drive NET formation in long COVID.

Answering these questions may pave the way for the development of clinically applicable strategies targeting NETs, providing relief for this emerging health crisis.

With Fluge and Mella commenting re ME/CFS in Charting the Circulating Proteome in ME/CFS: Cross System Profiling and Mechanistic insights (2025) —

Many of the granulocyte-related proteins found to be decreased in the patients are associated with neutrophil granules, stimulated secretion, and NETs, suggesting that changes in neutrophil maturation and/or activation states occur in ME/CFS