A Discussion of Biological factors contributing to LongCovid/PASC Amy Proal, PhD
LongCovid/Post Acute Sequelae of COVID-19 (PASC)
Data collected by Hannah Davis and team at the patient-led organization “The radiopaedia.org Body Politic”
Chronic conditions initiated or exacerbated by infection "Infection-associated chronic disease”
• LongCovid / Post Acute Sequelae of COVID-19 (PASC)
• Myalgic encephalomyelitis / Chronic fatigue syndrome (ME/CFS)
• Post-treatment Lyme disease syndrome / Chronic Lyme
• Post-Ebola Syndrome
• Post-Zika Syndrome
• Post-Dengue Fatigue Syndrome
• …..others
Central symptoms of LongCovid (and ME/CFS):
• Flu-like symptoms/malaise/sore throat • Post exertional malaise (inability to recover from exercise) • Autonomic dysfunction (dysautonomia) • Pain • Nausea • Cognitive dysfunction
• Sleep problems
• Headache
• Muscle/joint pain
Scenarios for LongCovid/PASC Development 1. Organ injur 2. Pathogen persistenc 3. Reactivation of other persistent pathogen 4. Dysregulation of host microbiome/virome balance by facilitating pathobiont virulenc 5. Platelet hyperactivation/blood coagulatio 6. Extended “autoantibody” production, often via molecular mimicr
s
n
e
e
y
y
7. Disruption of vagus nerve and brainstem signaling
Positive SARS-CoV-2 nucleoprotein staining in scattered immune cells in haemorrhoid tissue and in sinusoidal liver Kupffer cells radiopaedia.org
Enteroviral capsid protein 1 in the stomach biopsy of an ME/CFS patient by immunoperoxidase staining (100x)
Identi cation of pathogen reservoir
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Fluids (blood, urine)
Tissue/nerves/CNS
Scenarios for LongCovid/PASC Development 1. Organ injur 2. Pathogen persistenc 3. Reactivation of other persistent pathogen 4. Dysregulation of host microbiome/virome balance by facilitating pathobiont virulenc 5. Platelet hyperactivation/blood coagulatio 6. Extended “autoantibody” production, often via molecular mimicr
s
n
e
e
y
y
7. Disruption of vagus nerve to brainstem signaling
Humans harbor persistent viruses
SARS-CoV-2 expresses at least 10 proteins that disable the host interferon signaling
Persistent pathogens create proteins and metabolites that: • Interfere with human gene expression (transcription/translation)
• Dysregulate the human immune response
• Interfere with human metabolism
The team demonstrated that EBV protein EBNA2 directly binds half of the locations on the human genome known to contribute to lupus risk.
radiopaedia.org
Autoantibody production (molecular mimicry)
Scenarios for LongCovid/PASC Development 1. Organ injur 2. Pathogen persistenc 3. Reactivation of other persistent pathogen 4. Dysregulation of host microbiome/virome balance by facilitating pathobiont virulenc 5. Platelet hyperactivation/blood coagulatio 6. Extended “autoantibody” production, often via molecular mimicr
s
n
e
e
y
y
7. Disruption of vagus nerve to brainstem signaling
Humans harbor trillions of interaction organisms: the microbiome/virome
radiopaedia.org
Modeling identi ed: 1) Signi cantly higher abundances of oral microbiome species that are known to promote in ammation via LPS production or other mechanism
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2) reduction of anti-in ammatory metabolic pathways
Healthy control subject
Scenarios for LongCovid/PASC Development 1. Organ injur 2. Pathogen persistenc 3. Reactivation of other persistent pathogen 4. Dysregulation of host microbiome/virome balance by facilitating pathobiont virulenc 5. Platelet hyperactivation/blood coagulatio 6. Extended “autoantibody” production, often via molecular mimicr
s
n
e
e
y
y
7. Disruption of vagus nerve and brainstem signaling
Central symptoms of LongCovid (and ME/CFS):
• Flu-like symptoms/malaise/sore throat • Post exertional malaise (inability to recover from exercise) • Autonomic dysfunction (dysautonomia) • Pain • Nausea • Cognitive dysfunction
• Sleep problems
• Headache
• Muscle/joint pain
The vagus nerve innervates every major trunk organ of the body
Nuclei in the dorsal brainstem control:
• Flu-like symptoms and nausea
• In
ammatory pain signaling
• Autonomic functions
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Proal & VanElzakker 2021
Microglia (resident macrophage)
Long COVID
“Multiple hits” can collectively activate/prime microglia
SARS-CoV-2
Epstein Barr Virus Gut microbiome dysbiosis
Oral microbiome dysbiosis
SARS-CoV-2
Enterovirus
Representative images of viral protein-positive cells (green arrows) in the medulla oblongata detected by anti-nucleocapsid protein antibody (A) or anti-spike protein antibody (B). (C) SARS-CoV-2 nucleoprotein (brown staining) could also be detected in subsets of cranial nerves originating from the lower brainstem.
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“PCR identi ed enteroviral RNA in the heart, muscles, hypothalamus, and brainstem of the patient”
SARS-CoV-2
Human herpesvirus 6 (HHV6)
We must collect tissue from patients with infection-associated disease!
A tissue biobank (image courtesy of BBMRI)