A Discussion of Biological factors contributing to LongCovid/PASC

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

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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)