AAAS
March 4, 2023 1-2 pm
Room 147
Neuropathogenesis of COVID-19
Avi Nath
Chief, Section of Infections of the Nervous System National Institute of Neurological Diseases and Stroke, NIH Bethesda, Maryland, USA
PATTERNS OF LONG-COVID
Severity of symptoms
Severity of symptoms
new symptoms
Months
Months
Post-Intensive Care Syndrome
Balcom, et al., Brain 2021
Pathogenesis of Long-COVID
Persistent viral infection
Immune dysregulation
Antibodies
Macrophages
Can the virus enter the brain through the olfactory pathways?
Virus infects Sustentacular cells
Images: McQuaid et al., 2021 DOI: 10.1186/s12987-021-00267-y; Brann et al., 2020 DOI:10.1126/sciadv.abc5801
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Can the virus enter the brain through the olfactory pathways?
Virus infects Sustentacular cells
Images: McQuaid et al., 2021 DOI: 10.1186/s12987-021-00267-y; Brann et al., 2020 DOI:10.1126/sciadv.abc5801
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Images: Meinhardt et al., 2020 DOI:0.1038/s41593-020-00758-5
SARS-CoV-2 persistence in human body
At <2 wks post-infection: ~9,000 copies of virus/ngRNA in Respiratory tract
At > 1 month post-infection: <1 copy of virus/ng RNA in all organs
Chertow et al., Research Square 2021; Nature 2023
Detection of Spike protein in blood of patients with PASC (Long-COVID): Restricted viral replication
Swank et al., MedRxiv 2022
Autopsy cases (n=9) Cause of death:
Arrythmia (n=1)
Pulmonary embolism (n=1)
Sudden death (n=7) (non-hospitalized)
IHC CD61
Platelet-fibrin Thrombi
Anti-CD61 antibody recognizes platelet glycoprotein IIIa (GPIIIa)
Lee et al., NEJM 2021
200 μm
40x
50 μm
40x
50 μm
Complement and antibody deposition on endothelial cells
IA#1 Cerebellum
C1q and thrombosis
NY5 Basal ganglia
NY10 deep WM
IHC C1q
C1q in endothelial cells and brain parenchymal cells surrounding blood vessels Note the infarct area with a low density of cell population
Control
Antibody mediated injury to brain endothelial cells
COVID-19
Lee at al., Brain 2022
Activation of endothelial cells (PECAM-1) Deposition of complement
Deposition of IgG and IgM
Mina et al., In press
Increased plasma B cells in Long-COVID
Fibrinogen Leakage
BBB damage
Fibrinogen leakage links to neuroinflammation and neurodegeneration
The mechanisms linking fibrinogen, neurological diseases and cognitive impairment upon BBB breakage. Adapted from Petersen et al., Nat Rev Neurosci, 2018; and Merlini et al. Neuron, 2019
Fibrinogen leakage links to
microvascular dysfunction and
white matter pathology
IHC Fibrinogen: Non-covid-19 vs. Covid-19
IHC DAB
Control FCX- Multiple injuries Covid-19 IA#1 brainstem
IHC DAB
Control FCX – Abdominal injury
IHC RED
Control thalamus – Morphine intoxication
Covid-19 IA#1 brainstem
Fibrinogen leakage IA#1
NY4 midbrain
NY5 Basal ganglia
DualIHC CD61Fibrinogen
Non-Covid19, multiple injuries, 40/M Covid-19 NY5
Covid-19 NY1, 50/M, no known comorbidities
Inflammatory infiltrates
CD68: Macrophages GFAP: Astrocytes CD3 T cells
Correlation between leakage of fibrinogen and infiltration of macrophages
Lymphocytes in mainly perivascular (PV) regions
Lee et al., Brain 2022
BBB breakdown corelates with platelet aggregates and inflammatory infiltrates
Neuronal injury
Neuronal Injury in Brainstem
Post-mortem MRI (11.4T scanner)
100 micron sections
Vagus N
Nuc Ambiguus
XII Nucleus
Solitary N
CD68
Pre-Botzinger complex
Pre-Botzinger complex
Neuronophagia
Lee et al., NEJM 2021
Neuronal Injury: Loss of Purkinje cells in cerebellum
Control
COVID-19
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Stripes of neuronal loss
Lee et al., Brain 2022
Neuropathogenesis of LONG-COVID
Spudich and Nath Science 2022 Credit: Myounghwa Lee, NINDS
Can SARS-CoV-2 infection accelerate Neurodegenerative Diseases?
COVID cases: 401 Controls: 384
Douaud et al., 2022
MARKERS OF NEURONAL INJURY and ALZHEIMER’s DISEASE
control
COVID
Ziff et al., J Neurochem 2021
SARS-CoV-2 causes brain inflammation and induces Parkinson’s Disease pathology in macaques
Philippens et al.,
Peripheral neuropathies
Mina et al., In press
Questions that remain to be addressed
• Can SARS-CoV-2 accelerate the course of Neurodegenerative diseases?
• Are there common pathogenic mechanisms underlying each of the constellation of symptoms?
• Are there neuropathogeneic differences between the various strains of SARS-CoV-2?
• How to vaccinations modify the neuropathogenesis of the infections?
• What role does viral antigen persistence play?
• Can immunotherapy modify the course of the illness?
Acknowledgements
Marco Hefti (University of Iowa) Rebecca Folkerth (NY medical examiner) Daniel Perl (USUHS)
Eliezer Masliah (NIA)
Serena Spudich (Yale U)
NINDS, NIH
Myoughwa Lee, Wenxue Li, Dragan Marac (Neuropath)
Yair Mina, Farinaz Safavi, Bryan Smith, Brain Walitt, David Goldstein, Stave Jacobson, Amanda Weibold Ladifatou Fouanta Govind Nair, Alan Koretsky, Helen Murray (MRI)
Walter Koroshetz
deemagclinic
deemagclinic 