The world of Coronaviruses

The world of
coronaviruses
John W. A. Rossen

Disclosure of speaker’s interests
(Potential) conflict of interest Employee of IDbyDNA
Potentially relevant company relationships in
connection with event
Employee of IDbyDNA
Sponsorship or research funding National and EU-grants (H2020, InterregVA)

Coronaviruses - history
Fields Virology 6th edition
• enveloped RNA viruses
• humans, other mammals, and birds
• first described early 1930s as causative
agent of infectious bronchitis in
chickens, transmissible gastroenteritis in
pigs and severe hepatitis and neurologic
diseases in mice
• the halo of spikes was described as
giving the viral particle the appearance
of the solar corona, which prompted
the name that was adopted for this new
virus group

Coronaviridae - taxonomy
• Over the next 40 years, coronaviruses were studied mainly because
• they cause economically significant respiratory and gastrointestinal diseases in domestic animals
• provide unique models for viral pathogenesis
• In humans, two coronaviruses were known to be responsible for a substantial fraction of common colds,
particularly those that circulate in winter months
• Expression of downstream genes via transcription of multiple 3’ nested subgenomic messenger RNAs
(mRNAs) Latin nido = “nest”

Coronaviruses -taxonomy
Coronaviruses have long been sorted
into three groups, originally on the
basis of serologic relationships and,
subsequently, on the basis of
phylogenetic clustering

Coronaviruses
• since the 2002 - 2004 SARS epidemic, molecular surveillance
and genomics efforts
• previously unknown coronaviruses à now constitute most
members of the Coronavirinae subfamily
• most identified in bats principally in Asia but also in Africa,
Europe, and North and South America
• these viruses include likely predecessors of SARS-CoV
• birds have also proven to be a rich source of new viruses
• bats and birds are ideally suited as reservoirs for the incubation
and evolution of coronaviruses, owing to their common ability to
fly and their propensity to roost and flock

• serologic studies demonstrated that SARS-CoV had not circulated to a significant extent in humans prior to
the outbreak in 2002–2003
• some persons working in wild animal wet markets in China had serologic evidence of a SARS-CoV–like
infection acquired before the 2003 outbreak but reported no SARS-like respiratory illness
• virus may have circulated in these wild animal markets for a few years, with the SARS outbreak occurring
only when a confluence of factors facilitated spread into larger populations
• although animals were the original source of SARS, its global spread occurred by human-to-human
transmission
SARS-CoV-1

“New” human coronaviruses
• HCoV-NL63 and HCoV-HKU1 were only discovered recently, in the post-SARS-CoV-1 era, each
has a worldwide prevalence and has been in circulation for a long time
• HCoV-NL63 displays homology with HCoV-229E
• Phylogenetic analyses suggest that HCoV-NL63 and HCoV-229E diverged approximately 1,000
years ago
• Unlike HCoV-229E, HCoV-NL63 does not use human aminopeptidase N as a receptor
• Infection of cells is mediated by ACE2, the same molecule that is used by SARS-CoV, an unrelated
betacoronavirus

IDbyDNA, Inc. Confidential. 2020
Microbiology of SARS-CoV-2
Zhou et al. Nature. 2020
Zhou et al. Nature. 2020
https://www.niaid.nih.gov/news-
events/novel-coronavirus-sarscov2-images
■+sense RNA virus: 29,811bp
■distinctive spike (S) protein
■SARS-CoV-2: beta-coronavirus
■related to known bat CoV

Coronaviruses - transmission
Trends in Immunology 2020 411100-1115DOI: (10.1016/j.it.2020.10.004)

SARS-CoV-1
Fields Virology 6th edition / WikiPedia

Why is SARS-CoV-2 more infectious than SARS-CoV-1?
• SARS-CoV-2 has a higher reproductive number (R0) than SARS-CoV-1, indicating much more
efficient spread
• R0 is defined as the average number of new cases of an infection caused by one typical infected
individual, in a population consisting of susceptibles only
• An R0 of less than 1 indicates the infection will die out “eventually.” An R0 of greater than 1
indicates the infection has the potential for sustained transmission

• SARS-CoV-2 has a higher reproductive
number (R0) than SARS-CoV-1, indicating
much more efficient spread
• R0 is defined as the average number of new
cases of an infection caused by one typical
infected individual, in a population consisting
of susceptibles only
• An R0 of less than 1 indicates the infection
will die out “eventually.” An R0 of greater
than 1 indicates the infection has the
potential for sustained transmission

• SARS-CoV-2 has a higher reproductive number (R0) than SARS-CoV-1, indicating much more
efficient spread
• R0 is defined as the average number of new cases of an infection caused by one typical infected
individual, in a population consisting of susceptibles only
• An R0 of less than 1 indicates the infection will die out “eventually.” An R0 of greater than 1
indicates the infection has the potential for sustained transmission
• SARS-CoV-2 has structural differences in its surface proteins enabling stronger binding to the
ACE 2 receptor
• SARS-CoV-2 has greater efficiency at invading host cells
• SARS-CoV-2 also has greater affinity (or bonding) for the upper respiratory tract and
conjunctiva, thus can infect the upper respiratory tract and can conduct airways more easily

R0 for other viruses
• Seasonal influenzavirus (R0 1 to 2), HIV (R0 2 to 5), measles virus (R0 12 to 16)
Lancet July, 2020 https://doi.org/10.1016/S1473-3099(20)30484-9

Coronaviruses – the S(pike) protein
In many beta- and gamma-coronaviruses the S protein is partially or completely cleaved by a furin-like host
cell protease into two polypeptides, denoted S1 and S2
The receptor S1 domain is extremely variable, exhibiting very low homology across the three genera and
often diverging extensively among different isolates of a single coronavirus
By contrast, the S2 domain is highly conserved à considered a potential antiviral target
The receptor for SARS-CoV and SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), structural
features of SARS-CoV-2 receptor binding domain increase its ACE2-binding affinity
The final jump of SARS-CoV from palm civets to human hosts was caused by mutation of only two (of four)
key RBD for civet SARS-CoV S protein to gain the ability to productively bind human ACE2
ACE2 is a cell-surface, zinc-binding carboxypeptidase involved in regulation of cardiac function and blood
pressure
ACE2 is expressed in epithelial cells of the lung and the small intestine, which are the primary targets of
SARS-CoV, as well as in heart, kidney, and other tissues

Host cells
BMJ2020;371:m3862, http://dx.doi.org/10.1136/bmj.m3862
1996

Disease
Human coronaviruses (HCoVs), the alphacoronaviruses HCoV-229E and HCoV-NL63,
and the betacoronaviruses HCoV-OC43, and HCoV-HKU1, typically cause common
colds
Can also cause lower respiratory tract infections and have more serious
consequences in the young, the elderly, and immunocompromised
HCoV-NL63 is strongly associated with childhood croup
Most severe HCoV-HKU1, -OC43, and -229E infections are manifest in patients with
other underlying illnesses

SARS-CoV-2 symptoms

• SARS-CoV 1º infects epithelial cells
• Mechanism of lung injury unknown
• Viral titers ↓ as severe disease ↑
• Rodent adapted SARS-CoV strains show similar clinical features to the human disease
• Increased levels proinflammatory cytokines and reduced T-cell responses
• Possible immunopathological mechanism of disease
Fehr Methods Mol Bio 2016; Hui Post Grad Med J 2004; Rodriguez-Morales AJ. Travel Med and Infect Dis. 2019
Pathogenesis SARS-CoV

SARS-CoV-2

Age-Associated COVID-19 Severity
Lancet July, 2020 https://doi.org/10.1016/S1473-3099(20)30484-9

Mechanisms underlying the diverse clinical outcomes
• host factors such as older age, male sex, and underlying
medical conditions
• virus-related (viral load kinetics)
• potential cross-reactive immune memory from previous
exposure to seasonal coronaviruses
• host-immune response
• sex-related differences in immune response
• men had higher plasma innate immune cytokines and
chemokines at baseline than women
• women had notably more robust T cell activation than men
• among male participants T cell activation declined with age
• adaptive immune response may be important in defining
the clinical outcome

Coronaviruses – immune response
• both the innate and adaptive arms of the immune response are required for successful virus
clearance
• must be appropriately controlled to minimize bystander immunopathologic damage
• one of the first steps in the host immune response to a coronavirus infection is the production
of type I IFN (IFN-a/b)
• once the initial IFN response is induced, virus clearance requires expression of pro-
inflammatory cytokines and chemokines and their receptors (such as CCL2, CXCL9, CXCL10,
CCL3, to mediate T-cell and macrophage trafficking to sites of infection
• like other coronaviruses, such as MHV and FIPV, SARSCoV infects macrophages and dendritic
cells; however, unlike these two animal coronaviruses, it causes an abortive infection in these
cells

Immune evasion
Coronaviruses use several approaches, both active and passive,
to evade the host IFN response and thereby establish a
productive infection

Recombination
• coronaviruses have the ability to cross species
• coronaviruses readily undergo recombination
• recombination events between canine (CCoV-I) and feline (FeCoV-I) coronaviruses and an
unknown coronavirus resulted in the appearance of two novel viruses (CCoV-II and FeCoV-II)
• this propensity for recombination has raised concerns about the use of live- attenuated coronavirus
vaccines
• in general, live attenuated vaccines are likely to be most effective in inducing protective immune
responses against coronaviruses

Antibody dependent enhancement
Nature Microbiology volume 5, pages1185–1191(2020)

Antibody dependent enhancement
• observed in SARS, MERS and other human respiratory virus infections including RSV and measles
• suggests a real risk of ADE for SARS-CoV-2 vaccines and antibody-based interventions
• clinical data has not yet fully established a role for ADE in human COVID-19 pathology
• steps to reduce the risks of ADE from immunotherapies include the induction or delivery of high doses
of potent neutralizing antibodies, rather than lower concentrations of non-neutralizing antibodies that
would be more likely to cause ADE

Coronavirus and vaccines before 2020
• development of live coronavirus vaccines is challenging
• often natural infection does not prevent either subsequent infection or disease
• an effective vaccine would need to be superior to immunity induced naturally
• genetic and antigenic variability of coronaviruses and their ability to readily recombine
hinder vaccine development
• no equal protection from all antigenic variants, and subsequent recombination with vaccine
strains could increase the number of different strains circulating in the wild
• recombinants of IBV vaccine strains with virulent wild-type strains have caused disease
outbreaks in chicken locks
• immunization with an S protein–expressing FIPV vaccine led to more severe disease after
subsequent natural infection
• concern that other coronavirus vaccines might also enhance, rather than protect, from
disease

Vaccines
https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html

Antivirals
6 Jan 2021https://doi.org/10.2217/fmb-2020-0120

https://www.nytimes.com/interactive/2020/science/coronavirus-drugs-treatments.html
• There is no cure yet for Covid-19
• Only one treatment, a drug called remdesivir, has been
approved by the F.D.A. for the disease, and research
suggests it may provide only a modest benefit to
patients.
• The F.D.A. has granted emergency use authorization to
some other treatments, but their effectiveness against
Covid-19 has yet to be demonstrated in large-scale,
randomized clinical trials.
• Scientists are also studying a wide range of other
potential treatments, but most are still in early stages of
research.
Antivirals

Why your GP advice aspirin against common cold

Coronaviruses variants
https://www.nytimes.com/interactive/2021/health/coronavirus-variant-tracker.html
• during replication errors are made during replication
• often results in ”less fit” virus
• sometimes beneficial (e.g., cross species barrier)
• coronaviruses have a proofreading RNA-dependent
RNA-polymerase
• mutation rates lower than for other RNA viruses
• not enough to prevent these mutations from
accumulating
• as the novel coronavirus ran amok around the world,
it was inevitable that a range of variants would arise
• for SARS-CoV-2, scientists estimate that one
mutation becomes established in the population
every 11 days or so

Variants

Do we get rid of SARS-CoV-2?
• HCoV-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1—are endemic in human populations
• HCoV-OC43 and HCoV-229E cause up to 30% of all upper respiratory tract infections
• In temperate climates, infections occur predominantly in the winter and early spring
• The high rate of HCoV infections early in life and the pattern of infections during outbreaks demonstrate that
HCoVs are efficiently transmitted in human populations
• Serologic studies suggest that infection with HCoV-229E and HCoVOC43 frequently occurs in young children
and then repeatedly throughout life
• Neutralizing antibodies against HCoV-OC43 or HCoV-229E have been detected in about 50% of school-age
children and up to 80% of adults
• The SARS-CoV-1 outbreak was partly controlled using quarantining, and the lack of efficient spread
contributed to the success of this approach

mRNA T-cell response

Virus neutralization
Antibody response

Killing infected cells

Adenovirus

Protein-based vaccine

The world of Coronaviruses

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