The SARS-CoV-2 pandemic offered an unprecedented opportunity to study why the same virus provokes dramatically different responses, from severe disease to none at all. To uncover the causes of this variability, the COVID Human Genetic Effort (CHGE) was established in 2020. Its central goal is to identify rare inborn immune errors and autoimmune mechanisms predisposing individuals to severe COVID-19.
The CHGE consortium proposed a key hypothesis: the virus itself does not directly cause disease or determine its manifestation; rather, it acts as an external trigger in genetically predisposed individuals, revealing underlying immune and genetic mechanisms of susceptibility.
Scientists focused on the mechanisms of the following conditions linked to COVID-19:
- Hypoxemic critical pneumonia.
- Multisystem inflammatory syndrome in children (MIS-C).
- Neuro-COVID-viral encephalitis and acute inflammation of the central or peripheral nervous system.
- “COVID toes”-inflammatory frostbite-like lesions.
- Post-COVID syndrome.
- Resistance to infection in high-risk individuals.
- Post-vaccination myocarditis following mRNA immunization.
1. Hypoxemic Pneumonia in COVID-19
The first breakthrough identified inborn errors in TLR3-dependent type I IFN production and response in patients with critical hypoxemic pneumonia. Later, defects in 13 genes were found to underlie severe disease, including genes that control IFN-I responses (TLR3, TLR7, IRAK4, MYD88, UNC93B1, TBK1, TICAM1, IRF3, IRF7) or regulate IFN-I signalling (IFNAR1, IFNAR2, STAT2, TYK2). All represent rare inborn anomalies, except for IFNAR1 (p.Pro335del), which is common in southern China.
Moreover, 15% of patients with critical pneumonia and 20% of those who died from COVID-19 carried neutralizing autoantibodies against IFN-I, present long before infection. Their prevalence increases with age, reaching almost 7% among people over 80, confirming the central role of the IFN system in protecting the lungs against SARS–CoV–2.
Genomic analyses revealed additional DNA regions associated with severe COVID-19 risk, including a Neanderthal-derived haplotype and loci affecting IFN-I pathway genes such as IFNAR2, TYK2, JAK1, OAS1, IRF1, IFNA10, and DOCK2.
Similar defects and anti-IFN autoantibodies also occur in other viral diseases, such as herpes, tick-borne encephalitis, enteroviruses, and influenza.
Disease severity varies even among those with similar defects due to compensation by alternative antiviral pathways-MDA5 and RIG-I sensors, type III IFN signaling overlapping with IFN-I, and adaptive immune responses, including cross-reactive antibodies from prior infections or vaccines. These insights help select patients who will most benefit from interferon-based therapies.
2. Multisystem Inflammatory Syndrome in Children (MIS-C)
MIS-C typically appears about a month after viral infection, affecting 1-2 per 10,000 infected children. The syndrome manifests as fever, rash, abdominal pain, and myocarditis, clinically resembling Kawasaki disease. Blood tests reveal endothelial and epithelial injury markers, high inflammatory cytokine levels, and persistent monocyte activation with neutrophilia. Early stages feature enhanced type II IFN (IFN-γ) signaling. Roughly 75% of patients show strong CD4⁺ and CD8⁺ T-cell activation, suggesting a viral superantigen.
CHGE (2023) discovered that defects in OAS1, OAS2, or RNASEL disrupt the antiviral OAS-RNaseL pathway. Upon SARS-CoV-2 exposure, these defects cause excessive cytokine release by monocytes, leading to post-infectious hyperinflammation. Later studies identified rare BTNL8 variants that regulate intestinal γδ T cells, which are critical for gut barrier integrity; carriers exhibit a fourfold higher risk of MIS-C due to intestinal permeability and inflammation.
Thus, MIS-C involves two main processes: uncontrolled systemic inflammation caused by mononuclear phagocytes and intestinal inflammation. Epstein-Barr virus (EBV) reactivation may further elevate T-cell proliferation in affected children.
3. Neuro-COVID
Although SARS-CoV-2 primarily targets the respiratory system, some patients experience neurological complications. These include both central (meningoencephalitis, encephalopathy, acute demyelinating encephalomyelitis) and peripheral manifestations (Guillain-Barré syndrome, myopathies). Collectively, these are referred to as neuro-COVID.
SARS-CoV-2 is rarely detected in cerebrospinal fluid or brain tissues, suggesting limited replication in neural cells. Possible entry routes include the olfactory bulb, endothelial barriers, or infected monocytes. Experimental data show that SARS-CoV-2 can infect neural progenitor cells in vitro, yet autopsies mostly reveal meningeal inflammation, neuronal loss, and hypoxia/ischemia rather than direct viral presence.
A striking case study identified a rare DBR1 gene defect in a teenager with brainstem encephalitis caused by SARS-CoV-2. DBR1 encodes a protein that degrades circular RNA structures; its deficiency leads to RNA accumulation and increased neuronal susceptibility to infection. Restoring DBR1 expression corrected the defect, establishing the first known inborn immune error linked to neuro-COVID and showing how genetic variation can shape neurological vulnerability.
4. COVID Toes
During early pandemic waves, young healthy individuals presented frostbite-like lesions dubbed “COVID toes.” Most lacked detectable virus or IgG seroconversion (<10%) but displayed strong local and systemic IFN-I responses, often accompanied by IgA activity, indicating transient viral exposure and robust innate immunity. While IFN-I defends against viruses, excessive activation can damage tissues. Patients with COVID toes exhibit an exaggerated IFN-I response to SARS-CoV-2, leading to rapid viral clearance followed by inflammation. Their leukocytes produce abnormally high IFN-I levels upon SARS-CoV-2 stimulation but not upon DNA virus stimulation. Plasmacytoid dendritic cells (pDCs) exhibit hypersensitivity to TLR7 stimulation, opposite to TLR7-deficient patients, who are prone to severe pneumonia.
Hence, these frostbite-like lesions result from pDC infiltration and IFN-I-driven inflammation, aggravated by cold-induced vasoconstriction and endothelial injury.
5. Post-COVID Syndrome
Post-COVID syndrome develops in some people after recovering from COVID-19 and manifests as fatigue, cognitive impairment, vascular and autonomic dysfunction, and fever with minimal signs of systemic inflammation. The causes of post-COVID syndrome remain unclear.
Studies show that many patients retain viral antigens and exhibit elevated levels of SARS-CoV-2-specific antibodies and B cells, indicating prolonged viral persistence. Gender also plays a role: 75-80% of cases occur in women of reproductive age, which may reflect the influence of hormones on the immune response. Interestingly, women with post-COVID syndrome have autoantibodies to non-immune targets. For example, autoantibody reactivity to the sciatic nerves and meninges correlated with headaches and disorientation reported by patients. Recent work links long COVID to serotonin deficiency, potentially driven by sustained IFN-I activity through:
- Impaired tryptophan uptake due to intestinal inflammation.
- Platelet hyperactivation and serotonin depletion.
- Accelerated breakdown via monoamine oxidase.
This cascade reduces peripheral serotonin, weakening vagus nerve signalling, which is important for memory and cognition, while promoting chronic inflammation, coagulopathy, and autonomic imbalance.
More information is available in “The Post-COVID Syndrome: Symptoms, Causes, Treatment”.
6. Hidden Infections and Resistance to COVID-19
Many exposed individuals neither fall ill nor develop detectable antibodies, appearing naturally resistant yet showing persistent T-cell responses-evidence of “silent” or abortive infections halted before viral replication. A link has been proposed between the allele HLA-B*15:01 and such latent infections.
Protection likely arises from pre-existing cross-reactive T-cell immunity to common cold coronaviruses and rapid innate responses involving IFN-I/III and NK cells. Genetic variants that lower ACE2 expression or the O blood group allele may also contribute, though mechanisms remain uncertain.
7. Mild and Severe Reactions to mRNA Vaccines
While mRNA vaccines are safe for most, some people experience rare complications-myocarditis or thrombosis with thrombocytopenia (VITT). The HLA-A*03:01 allele correlates with fever, chills, and stronger side effects after the Pfizer-BioNTech vaccine. Carriers exhibit a greater rise in spike-reactive CD8⁺ T cells after the second dose, reflecting enhanced antigen presentation.
Vaccine-associated myocarditis occurs in about 1 per 100,000 recipients, more often in young men, and up to 35 per 100,000 after a second dose. The pathology stems from cytokine-mediated inflammation. The CHGE consortium continues to examine genetic and immunologic mechanisms underlying these events to determine which vaccine component-spike protein, lipid nanoparticle, or mRNA-triggers the aberrant immune reaction.
Reference
The seven enigmas of SARS-CoV-2: From the past to the future
