Lecture 14 SARS-CoV-2 + COVID-19

COVID-19 spectrum of acute/persistent clinical manifestations

Respiratory, Vascular, Neurologic

COVID-19 is caused by… and is what type of virus?

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Betacoronavirus (like SARS-CoV)

SARS-CoV-2 infection initiation 

Spike (S) protein bind to Angiotensin-Converting Enzyme 2 (ACE2) on host cell surface

SARS-CoV-2 origin

UNCLEAR

Bat coronavirus mutation that infects human

SARS-CoV-2 LIKE virus in intermediary animal before human transfer

Consecutive mutation events from bat to intermediary animal host to humans

Lab accident of mutated bat coronavirus 

‘They intentiaonally made it’

Sequence Homology of SARS-CoV-2

75% with SARS

50% MERS

SARS-CoV-2 Mortality

1% Mortality Worldwide, 1.1% Mortality USA (compared to SARS 9.7%, MERS 36%)

Mortality rates highly correlated with age, elderly patients with comorbidities 50-75%
>Hypertension, diabetes, cardiovascular disease, asthma, smoking

SARS-CoV-2 Epidemiology 

Animals are considered to be the original source of SARS-CoV-2 → global spread has occurred via human-to-human transmission

Primary transmission for SARS-CoV-2 is contact of the mucous membranes with virus-infected respiratory droplets or aerosols

•Fecal-oral transmission has been considered as a potential route of human spread but remains unclear even though virus is detectable in feces

•It may be possible for a person to become infected through indirect contact by touching a contaminated surface (fomite)

•No evidence (currently) for virus spread via urine, tears, semen, vaginal fluid, breast milk, or blood transfusion although virus can be detected in these fluids

•Transmission of virus from mother to baby during pregnancy is “uncommon”, and the rate of infection is no greater when the baby is born vaginally, breastfed or allowed contact with the mother

SARS-CoV-2 Variants

ancestral → variants

Mutation in Spike protein → easier infection/spread

Mutation in virus → resistant to antibodies that fight SARS-CoV-2

SARS-CoV-2 Host Manipulation

•Coronaviruses exhibit “host shutoff” by causing cleavage of host cell mRNAs and thereby restrict host cell protein synthesis

•Coronaviruses dampen host antiviral responses by downregulation of Type 1 interferon synthesis (interferon a and interferon b) (antiviral interferons)

•Coronaviruses stimulate proinflammatory host responses that can lead to a “cytokine storm”

Coronaviruses activate programmed cell death pathways (necroptosis and pyroptosis) that contribute to overstimulation of an inflammatory response

Hypertension, Diabetes, ACE2

Expression of ACE2 is ↑↑ in patients with type 1/2 diabetes who are treated with angiotensin II type-1 receptor blockers

•Hypertension is also treated with angiotensin II type-1 receptor blockers

•ACE2 expression is increased by Ibuprofen

Diabetes and hypertension treatment with ACE2-stimulating drugs may increase the risk for developing severe and fatal COVID-19

SARS-CoV-2 Acute Disease

Most people have mild or asymptomatic disease

some develop
>acute respiratory distress syndrome (ARD)
>multiorgan failure
>septic shock
>vascular complications [blood clots]
>neurologic disease

SARS-CoV-2 Acute Disease Course

Incubate 1-14 days, av 5

81% of patients mild-to-moderate symptoms that include
>fever,
>dry cough
>fatigue
>diarrhea
>mild pneumonia

14% 
profound shortness of breath (dyspnea) w severe pneumonia

5% [16 days after onset of acute disease]
>Acute Respiratory Distress Syndrome (ARDS)
>Cardiovascular Disease (ischemic, hemorrhagic stroke, thrombotic complications)
>multi-organ failure (Cytokine Storm Syndrome)

Asymptomatic SARS-CoV-2 Infection

20-40% of SARS-CoV-2 infections are asymptomatic, but spread the virus efficiently

Diagnosed with RT-PCR-confirmed SARS-Cov-2 infections but without clinical symptoms

Virus shedding is ~19 days (range = 6 to 45 days), longer than the duration of virus shedding by virus-infected persons with minimal clinical symptoms (~14 days)

Virus-specific serum IgG levels in asymptomatic persons = lower than symptomatic persons

Asymptomatic persons = lower levels of 18 proinflammatory cytokines when compared with symptomatic persons

~40% of asymptomatic persons become seronegative versus 13% of symptomatic persons

Asymptomatic persons have a weaker immune response to SARS-CoV-2 infection

Cytokine Storm Syndrome

Critically ill patients with COVID-19 have t significant increases in amounts of proinflammatory cytokines → Cytokine Storm Syndrome

•A hyperimmune response induced by SARS-CoV-2 that results in an imbalance of cytokine levels

Immune system becomes hyperactive → acute respiratory distress syndrome (ARDS), septic shock, multiple organ failure, and possible death

Cytokine Storm Syndrome caused by SARS-CoV-2, SARS-CoV, and MERS-CoV are different with respect to the patterns of cytokines stimulated

Cardiovascular Disease Acute Clinical Disease

The cardiovascular system is affected broadly by SARS-CoV-2 infection

•Direct virus infection of myocardial tissue

•Lung injury → oxygen supply-demand imbalance to heart

•Hyperinflammation (Cytokine Storm Syndrome) → inflammation-related injury to heart tissue

•Microvascular dysfunction → microvascular thrombosis (blood clot)

Thrombotic Complications Acute Clinical Disease

COVID-19 predisposes patients to a hypercoagulable state

•Severe thrombotic complications → significant mortality

-ICU COVID-19 patients thrombosis rates 31-79%
-non-ICU COVID-19 patients thrombosis rates 9-15%

•SARS-CoV-2 directly infects endothelial cells through ACE2

•Vascular endothelial cell injury is an important observation in the lungs of patients with COVID-19 and primary blood clot formation occurs directly in the lungs

Neurologic symptoms Acute COVID-19

At least one “neurologic symptom” has been reported in over 90% of patients with acute COVID-19

Headache, Confusion, Dizziness

Who is more likely to develop neurologic abnormalities?

Severe acute COVID-19 infection 

Systemic hematogenous spread

>↑ expression of ACE2 receptor on blood-brain barrier endothelial cells = blood-borne virus (viremia) cause blood-brain barrier damage

>virus could enter CNS via infected circulating monocytes/macrophages using the “Trojan Horse” mechanism

>Cytokine Storm Syndrome → blood-brain barrier breakdown

Neuronal retrograde dissemination

Nasal cavity → olfactory route/nerve → brain

Can spread transneuronally from peripheral site of infection (lungs) to CNS (brain) via VAGUS NERVE→brainstem

Why is the brain susceptible to neurovirulence by COVID-19?

ACE2 receptor is widely expressed on neurons and glial cells

Is there a specific cell type in the CNS that is selectively susceptible to COVID?

NO, ACE2 found in neurons, astrocytes, microglial cells, oligodendrocytes, ependymal cells, endothelial cells

Taste and Smell Imparement

Gustatory and olfactory disorders are the most common sudden neurologic symptoms of SARS-CoV-2 infection

Loss of taste – 38.5%

Loss of smell – 35.8%

Recovery rate of both is ~25% throughout the two weeks after resolution of typical respiratory symptoms

SARS-CoV-2 Persistent Disease

Symptoms lasting longer than 3-4 weeks after initial mild diamild, moderate, or severe illness + lasting longer that 6 weeks following critical illness
[low grade fever, muscle weakness]
>Extreme fatigue   
>Difficulty concentrating (brain fog)  
>Lapses in memory  
>Muscle/body aches  
>Shortness of breath + chest pain 
>Partial/complete loss of taste/smell

SARS-CoV-2 Treatment

Monoclonal Antibodies

Antivirals

•Anti-inflammatory and immunosuppressive drugs

Monoclonal Antibodies

•Anti-SARS-CoV-2 monoclonal antibodies directed against the spike (S) protein have shown clinical benefits in treating SARS-CoV-2 infection

•The anticipated activity of different anti-SARS-CoV-2 monoclonal antibodies varies significantly depending on the circulating variant

•The Omicron variant and its subvariants have markedly reduced susceptibility to several anti-SARS-CoV-2 monoclonal antibodies

•Sotrovimab is a recombinant human IgG monoclonal antibody that binds to a conservative epitope on the spike protein

Antivirals

Remdesivir
Molnupiravir
Paxlovid

Remdesivir

Monophosphate derivative of an adenine nucleoside analogue, targets the RNA polymerase function of coronaviruses and therefore virus-specific RNA synthesis to shut down virus replication

•Initially developed to treat Ebola + Marburg virus infections

•Effective against SARS-CoV + MERS-CoV

•Cell culture studies showed antiviral activity against SARS-CoV-2 in human lung cells and human airway epithelium cells infected with the virus

•Superior to placebo in shortening the time to recovery in adults who were hospitalized with COVID-19, may prevent progression to more severe respiratory disease and possible death

•Administered intravenously over 30-120 min once daily for 5-10 days

Molnupiravir

Inhibits RNA polymerase function and promotes mutations(MOA)

•Metabolized into a ribonucleoside analog, resembles building blocks of RNA (cytidine and uridine) → incorporated into newly made virus RNA instead of authentic cytidine/uridine creating mutations and lethal mutagenesis

•Initially developed to treat influenza and other RNA viruses

•Similar to Tamiflu because it must be administered early in disease process

•Administered as a tablet twice daily for 5 days

Paxlovid

Inhibits virus protease function(MOA)

•Demonstrated antiviral activity against all coronaviruses

•Packaged with Ritonavir (HIV protease inhibitor), so a ritonavir-boosted antiviral drug

•Must be taken within the first five days of experiencing symptoms

•Administered as a tablet twice daily

•Presently being investigated for treatment of persistent COVID-19

Dexamethasone

Directed at the Cytokine Storm Syndrome responsible for Acute Respiratory Distress Syndrome (ARDS)

corticosteroid used in many conditions for its anti-inflammatory + immunosuppressive effects

•Corticosteroids have been used in the past to reduce pulmonary + systemic damage in patients with ARDS but without COVID-19

•COVID-19 patients treated with dexamethasone showed a significantly lower incidence of death when compared with standard care group receiving invasive mechanical ventilation (29% versus 41%)

•Dexamethasone has typical side effects associated with corticosteroids (glaucoma and psychological affects including confusion, irritation, mood swings)

Vaccines

OG
Moderna →mRNA

Pfizer→ mRNA

Johnson & Johnson→ Chimpanzee Adenovirus

NOW
Nuvaxovid→ Protein-based (Spike protein) vaccine formulated to target JN.1 variant(nanoparticle delivery)

Spikevax→ Moderna mRNA vaccine

Comirnaty→ Pfizer mRNA vaccine