A new review pulls the whole picture together. SARS-CoV-2 doesn’t just infect. It disrupts immunity at multiple levels - from interferons to inflammasomes to deep T-cell exhaustion.
If you still think COVID is just a respiratory virus, this paper will change your mind🧵. @DavidJoffe64
If you still think COVID is just a respiratory virus, this paper will change your mind🧵. @DavidJoffe64
The study shows why severe COVID and Long COVID share the same roots - mis-timed immunity, destructive inflammation, and exhausted T cells that struggle to clear antigen or build lasting protection.
It’s now well-documented.
It’s now well-documented.
Current evidence - from interferon suppression to inflammasome activation to T-cell exhaustion - fits into one coherent biological picture.
Step One. The virus shuts down the interferon response.
SARS-CoV-2 is exceptionally effective at suppressing type I interferons.
This creates two immediate consequences
The virus replicates freely during the first days - very high viral load.
The immune system responds late and overreacts - foundation for severe disease.
SARS-CoV-2 is exceptionally effective at suppressing type I interferons.
This creates two immediate consequences
The virus replicates freely during the first days - very high viral load.
The immune system responds late and overreacts - foundation for severe disease.
This timing defect is one of the core reasons COVID-19 can escalate so quickly.
Step Two: Inflammasome activation and pyroptosis
Once interferons are blunted, a domino effect begins.
The virus strongly activates the NLRP3 inflammasome, producing IL-1β and IL-18 and triggering pyroptosis - a highly inflammatory form of programmed cell death.
Once interferons are blunted, a domino effect begins.
The virus strongly activates the NLRP3 inflammasome, producing IL-1β and IL-18 and triggering pyroptosis - a highly inflammatory form of programmed cell death.
The result.
Massive local and systemic inflammation,
lung and endothelial injury,
DAMP release that further amplifies immune activation.
This mechanistic cascade explains ARDS, vascular inflammation, even MIS-C.
Massive local and systemic inflammation,
lung and endothelial injury,
DAMP release that further amplifies immune activation.
This mechanistic cascade explains ARDS, vascular inflammation, even MIS-C.
Step 3. The immune system loses control - dysregulated circuits.
COVID-19 immunopathology is not caused by too strong immunity, but by mistimed immunity.
NK and T cells become dysfunctional and depleted,
regulatory feedback loops fail,
inflammatory pathways run unchecked while antiviral pathways collapse.
The biology resembles a system pressing the accelerator and the brake at the same time.
COVID-19 immunopathology is not caused by too strong immunity, but by mistimed immunity.
NK and T cells become dysfunctional and depleted,
regulatory feedback loops fail,
inflammatory pathways run unchecked while antiviral pathways collapse.
The biology resembles a system pressing the accelerator and the brake at the same time.
The major axis - T-cell exhaustion.
The newer literature adds a crucial and often overlooked dimension.
SARS-CoV-2 rapidly induces T-cell exhaustion, a profile typically associated with chronic infections like HIV, HBV, or HCV.
The newer literature adds a crucial and often overlooked dimension.
SARS-CoV-2 rapidly induces T-cell exhaustion, a profile typically associated with chronic infections like HIV, HBV, or HCV.
High expression of PD-1, TIM-3, LAG-3,
reduced IFN-γ, IL-2, TNF-α,
impaired proliferation and cytotoxicity,
transcriptional rewiring via TOX and NR4A,
metabolic stress (ROS, mitochondrial dysfunction),
epigenetic locking (H3K27me3, DNA hypermethylation).
This is remarkable - an acute virus induces exhaustion programs seen in chronic infections.
reduced IFN-γ, IL-2, TNF-α,
impaired proliferation and cytotoxicity,
transcriptional rewiring via TOX and NR4A,
metabolic stress (ROS, mitochondrial dysfunction),
epigenetic locking (H3K27me3, DNA hypermethylation).
This is remarkable - an acute virus induces exhaustion programs seen in chronic infections.
Clinical impact = worse acute outcomes and slower viral clearance
Exhausted T cells = reduced ability to eliminate infected cells.
This strongly correlates with
higher mortality,
prolonged illness,
delayed viral clearance,
greater tissue damage.
In mild disease, exhaustion can be transient - but in severe cases it becomes persistent.
Exhausted T cells = reduced ability to eliminate infected cells.
This strongly correlates with
higher mortality,
prolonged illness,
delayed viral clearance,
greater tissue damage.
In mild disease, exhaustion can be transient - but in severe cases it becomes persistent.
Long COVID as a state of persistent immunological dysregulation.
T-cell exhaustion leaves lasting scars
expanded PD-1 TOX CD8+ T cells for months,
reduced IL-2 and impaired proliferation,
weakened memory T-cell responses,
more frequent EBV/CMV reactivation,
increased vulnerability to opportunistic infections.
T-cell exhaustion leaves lasting scars
expanded PD-1 TOX CD8+ T cells for months,
reduced IL-2 and impaired proliferation,
weakened memory T-cell responses,
more frequent EBV/CMV reactivation,
increased vulnerability to opportunistic infections.
This forms a feed-forward loop.
Persistent antigen - exhausted T cells - impaired clearance - persistent symptoms.
Persistent antigen - exhausted T cells - impaired clearance - persistent symptoms.
This maps directly onto clinical features of Long COVID - fatigue, brain fog, dysautonomia, chronic inflammation, reduced vaccine response, impaired protection against reinfection.
The full picture = SARS-CoV-2 disrupts innate and adaptive immunity simultaneously.
The virus mounts a triple hit
Suppresses early antiviral defense (interferons),
Triggers destructive inflammasome pathways and pyroptosis,
Exhausts adaptive immunity and epigenetically rewires T-cell programs.
The virus mounts a triple hit
Suppresses early antiviral defense (interferons),
Triggers destructive inflammasome pathways and pyroptosis,
Exhausts adaptive immunity and epigenetically rewires T-cell programs.
By knocking out interferons, driving inflammasome injury, and exhausting T cells, SARS-CoV-2 creates an environment where acute disease is more severe, viral clearance is slower, and long-term sequelae are more likely.
Sum:
SARS-CoV-2 disrupts immunity on multiple fronts at once - it suppresses early defenses, triggers destructive inflammation, and epigenetically exhausts T cells. This combination explains the severe acute disease, the slow recovery, and the long-lasting post-infectious consequences observed in millions of people.
SARS-CoV-2 disrupts immunity on multiple fronts at once - it suppresses early defenses, triggers destructive inflammation, and epigenetically exhausts T cells. This combination explains the severe acute disease, the slow recovery, and the long-lasting post-infectious consequences observed in millions of people.
Roderick Chen‑Camaño et al., Frontiers in Immunology 2025. T‑cell exhaustion in COVID‑19: what do we know? @szupraha @ZdravkoOnline @adamvojtech86 frontiersin.org/journals/immun…
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