Thread by @ZdenekVrozina

What a new Nature Immunology study shows about long COVID?
Long COVID is not post-infectious fatigue.
A new study shows that it is a clearly defined biological state =
chronic immune activation, T-cell exhaustion, and metabolic disruption🧵

https://twitter.com/yash25571056/status/1999453012126052683

The study analyzed 142 individuals, including 28 patients with long COVID.
Compared with recovered controls, people with long COVID showed persistent activation of inflammatory pathways lasting more than 180 days after infection.

These pathways include IL-6, IFN-γ, JAK–STAT signaling, complement activation, and coagulation pathways.
This pattern does not look like recovery.
It looks like an immune system that remains stuck in an activated state.

Importantly, this is not explained by ongoing viral replication.
Instead, it suggests a response to persistent immune triggers such as residual antigens, tissue damage, or immune dysregulation.

At the same time, the authors describe a breakdown in coordination between the innate and adaptive immune systems.
Inflammatory signals remain active, but the cytotoxic and regulatory functions of T cells progressively weaken!

In people with long COVID, cytotoxic T-cell signaling and granzyme B are reduced, while markers of immune exhaustion increase!
This points to dysregulated cross-talk between immune compartments:
the system is active, but inefficient.

A key finding involves interferon-γ.
Chronic upregulation of IFN-γ is associated with reduced T-cell activation and increased T-cell exhaustion, suggesting that prolonged immune stimulation leads to functional T-cell impairment!

The immune changes are accompanied by profound metabolic shifts.
In long COVID, the study found reduced amino acid metabolism and impaired energy related pathways, alongside increased stress - and hormone related signaling.

Specifically, corticotropin-releasing hormone signaling, leptin signaling, and lipid, bile acid, and beta-alanine metabolism are increased.
Together, these changes resemble a state of chronic metabolic stress and reduced energetic flexibility!

This helps explain common symptoms such as fatigue, poor exercise tolerance, and cognitive slowing.
Energy is redirected toward sustaining inflammation, leaving less available for muscle recovery and brain function.

Proteomic data add another important layer.
People with long COVID show reduced activity of pathways involved in DNA damage recognition and repair, telomere maintenance, chromatin regulation, and DNA methylation.

Impaired telomere maintenance may contribute to premature cellular senescence or apoptosis, limiting the body’s ability to repair and regenerate tissues!
In other words, the system is not only inflamed - it is also repairing itself less effectively.

Crucially, many of these immune differences are already detectable during the acute phase of infection in individuals who later develop long COVID.
This suggests that long COVID is not random, but a measurable immunological trajectory that begins early.

Long COVID is sometimes described as an anything-goes sequela.
This study shows the opposite.
A consistent, reproducible biological signature across independent cohorts.

Sum:
Long COVID is best understood as a systemic immunological condition characterized by persistent inflammation, T-cell exhaustion, metabolic disruption, impaired cellular repair
It is not a vague post-viral state, but an active pathology.

Aid at al., Long COVID involves activation of proinflammatory and immune exhaustion pathways.
Nature Immunology 2025. nature.com/articles/s4159…

From a public health perspective, this matters.@szupraha @ZdravkoOnline @adamvojtech86
Long COVID represents a persistent immune and metabolic state. Preventing infection is not only about avoiding hospitalization or death but about preventing long-term biological harm, across the lifespan.

This also matters for children.
These immune and metabolic pathways are not unique to adults. Increasing evidence shows that children can develop measurable biological changes after SARS-CoV-2 infection - even after mild or asymptomatic disease.

For children, the implications are particularly serious.
Persistent immune activation and impaired repair mechanisms occur during periods of active growth and development, raising concerns about long-term effects that may not be immediately visible.

SARS-CoV-2 infection has been shown to affect immune and inflammatory pathways even in infants and young children, whose immune systems and organs are still developing.

This suggests that long COVID is not a binary state.
Some degree of immune and metabolic disruption may occur in many infected individuals, even if only a subset develop symptoms severe enough to meet clinical definitions of long COVID.