Log in Register - scholar.harvard.edu · 14.03.2020 · and their usurpation of the cell death programmes. Important questions concerning the interaction between SARS-CoV-2 and host

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Review

A tug-of-war betweensevere acute respiratorysyndrome coronavirus 2and host antiviraldefence: lessons fromother pathogenic viruses

,Sin-Yee Fung ,Kit-San Yuen ,Zi-Wei Ye &Chi-Ping Chan Dong-Yan Jin #

Pages 558-570 | Received 19 Feb 2020, Accepted 25 Feb 2020,Published online: 14 Mar 2020

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''In this article

ABSTRACT

Discovery ofHCoVs

Animal hosts ofHCoVs

Bats as areservoir ofemerging viralpathogens ofhumans

Lessons fromHIVs

How similar anddifferent areSARS-CoV andSARS-CoV-2?

Asymptomaticcarriers: fact orfiction?

Evolving to beless pathogenic:is there a trend?

ABSTRACT

World Health Organization has declared the

ongoing outbreak of coronavirus disease

2019 (COVID-19) a Public Health Emergency

of International Concern. The virus was

named severe acute respiratory syndrome

coronavirus 2 (SARS-CoV-2) by the

International Committee on Taxonomy of

Viruses. Human infection with SARS-CoV-2

leads to a wide range of clinical

manifestations ranging from asymptomatic,

mild, moderate to severe. The severe cases

present with pneumonia, which can

progress to acute respiratory distress

syndrome. The outbreak provides an

opportunity for real-time tracking of an

animal coronavirus that has just crossed

species barrier to infect humans. The

( Figures & data ) References

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outcome of SARS-CoV-2 infection is largely

determined by virus-host interaction. Here,

we review the discovery, zoonotic origin,

animal hosts, transmissibility and

pathogenicity of SARS-CoV-2 in relation to

its interplay with host antiviral defense. A

comparison with SARS-CoV, Middle East

respiratory syndrome coronavirus,

community-acquired human coronaviruses

and other pathogenic viruses including

human immunodeficiency viruses is made.

We summarize current understanding of

the induction of a proinflammatory cytokine

storm by other highly pathogenic human

coronaviruses, their adaptation to humans

and their usurpation of the cell death

programmes. Important questions

concerning the interaction between SARS-

CoV-2 and host antiviral defence, including

asymptomatic and presymptomatic virus

shedding, are also discussed.

KEYWORDS: Coronavirus, SARS-CoV, SARS-CoV-

2, COVID-19, 2019 novel coronavirus, host antiviral

response, type I interferon

https://www.tandfonline.com/keyword/Coronavirus

https://www.tandfonline.com/keyword/Sars-cov

https://www.tandfonline.com/keyword/Sars-cov-2

https://www.tandfonline.com/keyword/COVID-19

https://www.tandfonline.com/keyword/2019+Novel+Coronavirus

https://www.tandfonline.com/keyword/Host+Antiviral+Response

https://www.tandfonline.com/keyword/Type+I+Interferon



Coronaviruses (CoVs) are found in various

animals including aves and mammals. They

can be divided into four genera named

Alphacoronavirus, Betacoronavirus,

Gammacoronavirus, and Deltacoronavirus

[1]. The 2019 novel CoV (SARS-CoV-2) is the

newest addition to human CoVs (HCoVs)

that also include 229E, OC43, HKU1, NL63,

severe acute respiratory syndrome (SARS)

CoV, and Middle East respiratory syndrome

(MERS) CoV. Whereas 229E and NL63

belong to Alphacoronavirus, others are

members in the genus of Betacoronavirus.

All of them are positive-stranded RNA

viruses containing a polycistronic genome

of ∼30 kb in size, coding for multiple non-

structural proteins (ORF1a and ORF1b,

processed into multiple nsp proteins) at the

5′-end plus multiple structural (S, E, M, and

N) and lineage-specific accessory proteins

(such as ORF3a, ORF3b, ORF6, ORF7a,

ORF7b, ORF8a, ORF8b, and ORF9b in SARS-

CoV) at the 3′-end (Figure 1). SARS-CoV and

MERS-CoV are highly pathogenic and can

cause severe diseases presented as acute

respiratory distress syndrome (ARDS).




Although the other four community-

acquired HCoVs are a common cause of

common cold only, they are thought to

cause pandemics and major outbreaks of

probably more severe respiratory diseases

when they initially crossed species barriers

to infect humans decades and centuries

ago. All seven HCoVs have a zoonotic origin

from bats, rodents, or domestic animals.

Their reservoir hosts are selected through

evolution. As a result of this selection and

mutual adaptation for a long period of time,

they usually become non-pathogenic or

cause very mild diseases in their native

reservoir hosts. However, when an animal

CoV such as SARS-CoV-2 enters a new host

such as humans, the severity of the disease

is significantly increased at the start of a

new round of adaptation. The outcome of

infection is governed largely by the

interplay between virus and host antiviral

defence. Through years of co-evolution, this

tug-of-war ultimately reaches a tie or a

balance under which virus and host co-exist

peacefully or even in mutual benefit.

Understanding the host restriction factors



and the viral countermeasures will shed

significant new light on viral pathogenesis

and antiviral development. Although it

remains to be elucidated how SARS-CoV-2

interacts with host antiviral immunity,

lessons can be learned from other HCoVs

and human pathogenic viruses in other

families including the human

immunodeficiency viruses (HIVs). In this

review, we focus on some of the key

questions surrounding SARS-CoV-2 and its

interplay with the host.

Figure 1. Genome organization of HCoVs.

Schematic diagram of seven known HCoVs

is shown (not in scale). The genes encoding

structural proteins spike (S), envelope (E),

membrane (M), and nucleocapsid (N) are in

green. The gene encoding haemagglutinin-

esterase (HE) in lineage A of

betacoronaviruses is in orange. The genes

encoding accessory proteins are in blue.

Display full size




Discovery of HCoVs

Avian infectious bronchitis virus was the

first CoV isolated in 1930. Different CoVs

were subsequently isolated in infected

rodents and domestic animals, including

mouse, pig, cow, turkey, cats, and dogs.

CoVs were once believed not to cause

human disease, but this was changed after

the successful isolation of HCoV strain B814

from the clinical specimen of patients with

common cold by serial passage of inoculum

in tracheal organ culture in 1962 [2]. In the

1960s, several novel HCoVs were described

but no further characterization was

performed in most cases [3,4]. 229E and

OC43 were known as causative agents of

the common cold and upper respiratory

tract infection, accounting for up to 30% of

cases with common cold [4]. 229E is a

prototype strain isolated using tracheal

organ culture. OC43 was isolated from

organ culture and subsequent serial

passage in the brain of suckling mice. The

clinical features of 229E and OC43 infection

were characterized in human volunteer







study [4]. In most cases, natural infection

with HCoVs results in mild common cold-

like symptoms. Severe lower respiratory

tract infection develops only in

immunocompromised patients [5]. Apart

from a respiratory infection, 229E and OC43

were suspected to infect the central

nervous system (CNS) as mRNA and CoV-

like particles were detected in CNS samples

of patients with multiple sclerosis. This

claim was further supported by the

susceptibility of human neural primary

culture to 229E and OC43 [6]. However, the

influence of 229E and OC43 on the

development and progression of multiple

sclerosis awaits further investigations.

In the pre-SARS era, it was generally

accepted that HCoVs cause mild respiratory

disease only. This concept was changed

after the emergence of SARS-CoV. The first

reported case of SARS-CoV infection was

retrospectively dated back to November

2002 in Guangdong Province of China. In

the subsequent seven months, the SARS

epidemic resulted in over 8000 reported

cases in 37 countries with a case fatality of






9.6% [7]. The superspreading events in

SARS-CoV transmission caused fears in the

society. Although the exact cause of

superspreading remains to be understood,

the host but not the virus only is thought to

play a key role in the release of large

amounts of virions in superspreading. In

this regard, the use of immunosuppressive

agents such as high-dose steroid in an early

phase of viral infection as a treatment

modality might boost viral replication

leading to the shedding of large amounts of

virus. Likewise, the immunocompromised

status of the superspreader could have the

same effect. In addition, mutation of virus

susceptibility genes encoding restriction

factors implicated in host antiviral defence

would also result in the shedding of

extraordinarily large quantities of the virus

[8]. In other words, compromising host

antiviral defence or decoupling host

antiviral immune response from viral

replication might allow or facilitate

superspreading.

SARS-CoV was isolated and identified as the

causative agent of SARS [9]. Unlike 229E






and OC43, SARS-CoV infection causes lower

respiratory tract infection, accompanied by

a cytokine storm in patients with poor

outcome. Life-threatening ARDS was

developed in some critically ill patients.

Apart from a respiratory infection,

gastrointestinal and CNS infection was also

found in some patients with SARS [10,11].

FRHK4 and Vero-E6 cells played an

important role in the discovery of SARS-CoV

[9]. The same as chicken embryos in which

other CoVs including avian infectious

bronchitis virus were isolated and cultured,

these cells are highly susceptible to SARS-

CoV infection because they are type I

interferon-defective [12]. Consistent with

this, infection of STAT1 mice with SARS-

CoV resulted in a lethal outcome with a

profibrotic phenotype in the lung [13].

These mice cannot clear the virus. All these

highlight the importance of host antiviral

response in the control of SARS-CoV

infection at the cellular and organismal

level.

In the post-SARS era, CoV research was

brought back to the limelight and more

−/−








effort was put into the search for novel

HCoVs. The search was fruitful and two new

HCoVs were identified in human samples

positive for HCoV but not for SARS-CoV.

NL63 and HKU1 were first isolated from a

child suffering from bronchiolitis and a

patient with pneumonia, respectively

[14,15]. HKU1 is difficult to culture and can

only be propagated in primary human

airway epithelial cells cultured at the air–

liquid interface. Similar to 229E and OC43,

NL63 and HKU1 were found worldwide,

causing mild respiratory diseases.

Particularly, NL63 infection was associated

with virus-induced croup in children [16]. All

these four viruses are community-acquired

HCoVs that are well adapted to humans.

Only in rare cases, they might be

accidentally mutated to cause more severe

lower respiratory tract disease. For

example, a subtype of NL63 was recently

found to be associated with severe lower

respiratory tract infection in China [17].

Another highly pathogenic HCoV outbreak

emerged in 2012 from Saudi Arabia. A new

HCoV subsequently named MERS-CoV was







isolated from patients who developed acute

pneumonia and renal failure [18]. Exported

MERS cases were also reported outside

Arabian Peninsula occasionally. One

relatively big secondary outbreak with 186

confirmed cases occurred in South Korea in

2015. Up to January 2020, >2500 laboratory-

confirmed case were reported with a case

fatality of 34.4%. Clinical symptoms were

diverse in MERS patients, ranging from

asymptomatic to ARDS [19]. Acute renal

injury was unique in MERS patients, but it is

more commonly observed in the Middle

East than in South Korea. MERS-CoV

replicates well in many different types of

cells and extrapulmonary tissues including

the kidney and intestinal tract [20,21].

MERS-CoV is endemic in Arabian Peninsula

with sporadic, but recurrent outbreaks

occurring continuously since 2012.

Animal hosts of HCoVs

The animal origin of HCoVs is supported by

similarities in genome organization and







phylogenetic relatedness of animal CoVs

and HCoVs as well as the geographical

coincidence of these viruses and plausible

routes of cross-species transmission such

as petting, butchering and close contact.

Error-prone RNA-dependent RNA

polymerase creates diversity in the CoV

genome, enabling them to jump across the

species barrier. However, HCoVs encode a

proofreading exoribonuclease (ExoN) that

plays a crucial role in RNA synthesis and

replication fidelity [22]. This serves to

reduce errors in RNA replication. The

inactivation of ExoN causes a mutator

phenotype and the resultant virus is either

attenuated or inviable. In addition, other

structural and non-structural genes might

also contribute to the genomic diversity of

CoVs by modulating polymerase and ExoN

activity [23]. In addition to mutations,

recombination and deletion also play an

important role in host switching and

adaptation. Among SARS-CoV, SARS-CoV-2,

and MERS-CoV, a mutation rate as high as

0.80–2.38 × 10 nucleotide substation per

base per year has been documented for

−3





SARS-CoV [24]. This is comparable to those

of primate lentiviruses, including HIVs.

Compared to SARS-CoV, the variabilities in

SARS-CoV-2 and MERS-CoV genomes are

much less dramatic. It will be of interest to

clarify how this might relate to their host

adaptability. In this regard, adaptive

mutations in the S protein of SARS-CoV

have been found during the outbreak to

result in better binding with the ACE2

receptor. Cryo-EM analysis has provided

structural evidence that S protein of SARS-

CoV-2 binds with ACE2 with higher affinity.

It will be of interest to see whether SARS-

CoV-2 might be further adapted to ACE2 in

the near future. Since the receptor-binding

domain also contains predominant

neutralizing epitopes, variations in this

domain are only relevant to the

development of a vaccine against SARS-

CoV-2 [25].

All HCoVs have a zoonotic origin. Whereas

bats are the evolutionary reservoir host of

229E, NL63, SARS-CoV, MERS-CoV, and

SARS-CoV-2, parental viruses of OC43 and

HKU1 have been found in rodents.





Intermediate and amplifying hosts of HCoVs

were also found in domestic and wild

mammals. Ancestors of OC43 were

identified in domestic animals such as cattle

and swine. The switch of hosts from cattle

or pigs to humans might have occurred in

the context of a pandemic of respiratory

disease recorded around 1890 in human

history [26]. Similar to MERS-CoV, 229E

could be acquired by humans from

dromedary camels. However, the direction

of this cross-species transmission remains

to be determined and the possibility cannot

be excluded that both humans and camels

might have acquired 229E from an

unidentified host including bats [27].

In an effort to identify the direct animal

source of SARS-CoV, SARS-CoV-related CoVs

(SARS-rCoV), which share 99.8% sequence

homology at the nucleotide level with SARS-

CoV, were isolated in 2003 from workers

working in a live animal market where

animal meats were sold and from animals

in the same market [28], including

Himalayan palm civets and a raccoon dog.

Palm civets were once thought to be the






natural host of SARS-CoV as anti-SARS-CoV

antibody was detected in civets in the

market. In experimental infection, civets

were equally susceptible to SARS-CoV and

SARS-rCoV. Infected animals displayed

clinical symptoms. However, no anti-SARS-

CoV antibodies were detected in any wild or

farmed civets [29], raising the possibility

that they are not a natural host of SARS-CoV

and SARS-rCoVs. In 2005, horseshoe bats

were identified as a natural host of SARS-

rCoVs [30,31]. These bat SARS-rCoVs serve

as the gene pool and an evolutionary origin

of SARS-CoV. It is particularly noteworthy

that a SARS-rCoV using the same ACE2

receptor as SARS-CoV was also found in

bats [32]. Their genomes share 95%

nucleotide sequence homology.

Presumably, palm civets and other

mammals in the market were transiently

infected, and they transmitted the virus to

humans. It remains to be clarified whether

another stable and natural reservoir host of

SARS-CoV, exactly like dromedary camels

for MERS-CoV, might exist.

The genomic sequence of MERS-CoV was







closely related to bat CoVs HKU4 and HKU5

[18]. Bat CoVs that are evolutionarily closer

to MERS-CoV, sharing ∼75% nucleotide

sequence homology and using the same

DPP4 receptor, were also identified [32].

Although bats are the evolutionary

reservoir host and bat CoVs serve as the

gene pool of MERS-CoV, humans acquire

MERS-CoV from diseased dromedary

camels, but not directly from bats. These

camels are the natural reservoir host of

MERS-CoV. MERS-CoVs isolated from

dromedaries are identical to those found in

humans. Experimental infection of

dromedary camels with MERS-CoV results in

mild disease, shedding large quantities of

the virus from the upper respiratory tract

[33]. In addition, other non-camelid

domestic animals in close contact with

infected camels, including sheep, goats, a

cow, and donkeys, are also infected by

MERS-CoV [34]. These domestic animals

could also pose a risk to humans and

should, therefore, be included in the MERS-

CoV surveillance programme.

SARS-CoV-2 was found to share 96.2%







nucleotide homology with a bat CoV

RaTG13 found in Rhinolophus affinis bats

[35]. However, their receptor-binding

domains in the S proteins differ

significantly. Some of the earliest patients

infected with SARS-CoV-2 were linked to the

Huanan Seafood Wholesale Market and

other live animal markets in Wuhan, Hubei,

China [36]. SARS-CoV-2 was detected from

the working environment of the market,

supporting the existence of a live animal

source. Bamboo rats in the family of

Rhizomyidae and civets are the prime

suspects of an intermediate host of SARS-

CoV-2, although no concrete evidence is

available. Metagenomic analysis of CoV

sequences indicates that pangolins, which

are a group of endangered small mammals,

carry betacoronaviruses at a high rate [37],

including some sharing ∼90% nucleotide

homology with SARS-CoV-2. The pangolin

betacoronaviruses are phylogenetically

related to both SARS-CoV-2 and RaTG13.

Existing evidence suggests that neither

RaTG13 nor pangolin betacoronaviruses

might be the immediate ancestor of SARS-






CoV-2. Further investigations are required

to determine whether pangolins and other

animals might harbour parental viruses of

SARS-CoV-2 and serve as its intermediate

and amplifying host.

Bats as a reservoir of emergingviral pathogens of humans

As the only flying mammals, bats are known

as a natural reservoir of various human

pathogenic viruses including but not limited

to rabies virus, Nipah and Hendra viruses,

Ebola virus, and influenza viruses. They can

directly transmit rabies virus, Nipah and

Hendra viruses, and Ebola virus to humans.

Ebola virus might also be transmitted to

humans indirectly through fruits

contaminated by fruit bats in the African

forests. Due to large geographical

distribution and great diversity of bat

species, a large number of bat CoVs can be

created through inter-genus and inter-

species transmission and recombination

[38].



Page 20 of 79https://www.tandfonline.com/doi/full/10.1080/22221751.2020.1…R0QY3C6yTMwGVZl8NE1kQ17WhHWPrKgs30zC5QmympdaKjOEexqCZZnCc8&

CoV-infected bats are asymptomatic or

have mild symptoms suggesting that CoVs

and bats are mutually adapted to high

degrees [38]. Particularly, bats are well

adapted to CoVs anatomically and

physiologically. First, a high level of reactive

oxygen species (ROS) generated from the

high metabolic activity may suppress CoV

replication in bats to a manageable level.

Second, degeneration of inflammatory

sensors and NF-κB signalling pathway in

bats attenuates virus-induced pathology

[39]. Particularly, NLRP3 inflammasome

activation is defective in bats [40]. Third,

constitutively active type I and III interferon

production and innate immune response

suppress viral replication through the

persistent expression of interferon-

stimulated genes [41]. It has been

speculated that endogenous retroviruses in

bats help to sustain interferon stimulation

in bats. On the other hand, STING signalling

is defective in bats and this might lead to

selective repression of a subset of

interferon-stimulated genes [42]. Finally,

upregulation of inhibitory natural killer cell








receptor NKG2/CD94 and low expression

level of major histocompatibility complex

class I molecules in bats may hinder natural

killer cell activity [43]. All these unique

features empower bats to survive CoV

infection and to co-exist with a large

number of bat CoVs. Moreover, a high

metabolic rate in bats may provide the

selection pressure for the generation of

highly pathogenic virus strains. High ROS

level in bats is mutagenic by affecting

proofreading of CoV polymerase [38]. More

pathogenic CoV strains may be generated

by recombination, leading to the

acquirement of novel proteins or protein

features for host adaptation. Bats have an

average life span of >25 years [38]. The long

life span and the possible establishment of

persistent virus infection in bats increase

the chance for cross-species transmission

of bat CoVs [38].

Lessons from HIVs

HIVs are the most studied viruses in history







and the best model to understand the

interplay between virus and host antiviral

defence. Tracing the origins of HIVs would

provide a framework for us to understand

cross-species transmission and

pathogenicity of SARS-CoV-2. The

comparison of SARS-CoV-2 and HIVs would

reveal a common theme and the

requirements for their successful species

jumping. In particular, lessons learnt from

HIVs are highly relevant and instructive to

SARS-CoV-2 for the following reasons. First,

both HIVs and SARS-CoV-2 are of zoonotic

origin. Second, infection of their reservoir

hosts with parental viruses of HIVs and

SARS-CoV-2 results in no or mild symptoms.

However, when they infect humans, much

more severe symptoms are developed.

Third, the similarities and differences

between HIV-1 and HIV-2 resemble those

between SARS-CoV and SARS-CoV-2. Finally,

both HIVs and SARS-CoV-2 are plausibly

derived from discrete cross-species

transmission events from animals to

humans. Thus, we will briefly review our

current understanding of the origins of HIVs



and how host anti-HIV defence has shaped

the emergence of the pandemic HIV strains.

There is persuasive evidence that HIVs are

derived from multiple cross-species

transmissions of simian immunodeficiency

viruses (SIVs) that naturally infect African

non-human primates. The pandemic HIV-1

strain of group M originated from a single

transmission event from a chimpanzee that

harbours SIVcpz near Cameroon in Central

Africa. Multiple other transmission events

of SIVs from chimpanzees to humans were

also detected, but their resulting HIV-1

viruses in groups N, O and P spread in

humans only to a limited extent [44]. Group

O was found in a few tens of thousands of

people in West-Central Africa. Groups N and

P were identified in 13 and 2 individuals,

respectively. Likewise, appreciable

spreading of HIV-2 within humans is seen

only with groups A and B resulting from two

cross-species transmissions of SIVsmm

from sooty mangabeys in West Africa [44].

All other groups (C–H) were found only in

single individuals. Thus, both HIV-1 and HIV-

2 originated from one or two primate-to-





human transmission events. The other

transmission events were unproductive,

representing incidents in which secondary

and tertiary spreading was very limited.

SIVs are non-pathogenic in their natural

hosts, but their transmission to a new host,

such as humans for HIV-1 and HIV-2 as well

as macaques for SIVmac, enable them to

become highly pathogenic. HIV-1 and HIV-2

share 40–60% nucleotide sequence

homology. The transmission rate of HIV-2 is

lower because the viral load is generally

lower in infected individuals. The natural

history of HIV-2 infection is quite different

from that of HIV-1. Although clinical

symptoms of acquired immunodeficiency

syndrome (AIDS) caused by HIV-1 and HIV-2

are indistinguishable, most people infected

with HIV-2 do not progress to AIDS. One

strong predictor of disease progression that

distinguishes pathogenic HIV infection and

non-pathogenic SIV infection is the

activation of host antiviral defence including

a prominent stimulation of T cells in the

former but not the latter. Another

possibility is that the natural hosts of SIVs



might be the survivors of ancient SIV

pandemics. One prediction is that HIVs and

humans will eventually adapt to each other

just like SIVs and their natural hosts. In this

regard, AIDS might be considered an

accident in which HIVs fail to adapt to

humans or humans fail to adapt to HIVs. In

support of this view, species-specific

features in host restriction factors, such as

TRIM5α and tetherin, can prevent SIV

infection of humans. On the other hand,

adaptive mutations and accessory genes

such as Vpu, Nef, and Vif in HIVs have been

found to counteract host restriction factors,

which constitute the antiviral defence, in a

host-specific manner. For example, a five-

codon deletion in the cytoplasmic domain

of human restriction factor tetherin results

in the prevention of its interaction with

SIVcpz Nef in humans [45]. On the side of

the virus, some HIV-1 strains use their Vpu

protein to degrade tetherin [45].

The origins of another pair of human

retroviruses named human T lymphotropic

viruses 1 and 2 (HTLV-1 and HTLV-2) are

also very similar and relevant to HCoVs [46].






HTLV-1 and HTLV-2 share ∼70% nucleotide

sequence homology. Whereas HTLV-1

causes a highly lethal disease named adult

T-cell leukaemia and another immune-

mediated disorder of the spinal cord, the

related virus HTLV-2 is largely non-

pathogenic and non-oncogenic. Both

viruses have counterparts in non-human

primates and so are HTLV-3 and HTLV-4

newly discovered in Cameroonian hunters

of non-human primates [47]. At least four

cross-species transmission events of HTLVs

have been identified, each of which involves

a different species of primates. The

spreading of HTLV-3 and HTLV-4 is very

limited in humans, but HTLV-1 and HTLV-2

have infected millions of people. The

infection of T lymphocytes with HTLV-2

provides a good example of asymptomatic

infection in humans.

HIVs and SARS-CoVs bear many similarities

in terms of cross-species transmission. It is

difficult to predict how the ongoing

outbreak of SARS-CoV-2 might develop in

the coming weeks and months.

Unprecedented measures have now been




taken to isolate the sources of SARS-CoV-2

infection, to block human-to-human

transmission and to protect the susceptible

individuals. It remains to be seen whether

and to what extent secondary and tertiary

spreading will be weakened and prevented

by the control measures. Apparently, the

intrafamily transmission of SARS-CoV-2 has

not been stopped in the epicentre of

Wuhan after 23 January 2020, when the city

was locked down and human gathering was

prohibited. It also remains to be

determined what percentage of the general

population in Wuhan have been or are

being infected by SARS-CoV-2. These are

important research questions that should

be set as priority. However, as seen in HIV-

1, HIV-2, HTLV-3, and HTLV-4, not every

animal-to-human transmission event gives

rise to a virus that is highly and sustainably

transmissible within humans. The

transmission of SARS-CoV-2 might be

stopped due to the intrinsic characteristics

of the virus, the action of human restriction

factors, and human intervention measures.

Another possibility is that SARS-CoV-2



becomes highly transmissible within

humans just like the other four community-

acquired HCoVs. Some estimates of the

transmission rate expressed as

reproductive number (R ) of SARS-CoV-2 fall

within the range of 3–4, which is higher

than that of SARS-CoV (Table 1). If that can

be sustained, SARS-CoV-2 will be well

adapted to humans ultimately. It will be

fortunate if it also becomes less pathogenic,

resembling 229E, OC43, HKU1, and NL63.

Plausibly, when they initially crossed

species barriers to infect humans decades

or centuries ago, 229E, OC43, HKU1, and

NL63 might have also caused pandemics in

which humans were suffering from more

severe respiratory diseases. As mentioned

above, one such pandemic recorded at the

end of nineteenth century has now been

linked to the jumping of OC43 from cattle to

humans [26].

0

Table 1. Comparisonbetween SARS-CoV andSARS-CoV-2.

CSV Display Table

/


https://www.tandfonline.com/action/downloadTable?id=T0001&doi=10.1080%2F22221751.2020.1736644&downloadType=CSV




How similar and different areSARS-CoV and SARS-CoV-2?

As viruses in the same lineage, SARS-CoV

and SARS-CoV-2 are very similar (Table 1),

sharing 82% nucleotide sequence homology

[48]. Known interferon antagonists encoded

by SARS-CoV include nsp1, nsp3, nsp16,

ORF3b, ORF6, M and N proteins [49]. They,

respectively, share 84, 76, 93, 32, 69, 91,

and 94% amino acid sequence identity with

their counterparts in SARS-CoV-2. Known

activators of NLRP3 inflammasome

encoded by SARS-CoV include E, ORF3a, and

ORF8b [50]. They, respectively, share 95, 72,

and 40% amino acid identity with their

counterparts in SARS-CoV-2. It is

noteworthy that some accessory proteins

that modulate interferon response and

inflammasome activation in the two viruses

varied substantially. It will be of interest to

see whether the divergence might have

affected the virulence and pathogenicity of

SARS-CoV-2.






Comparison of the sequence and genome

organization of SARS-CoV and SARS-CoV-2

reveals more similarities than differences.

Overemphasizing the differences in the

initial stage of the outbreak has turned out

to be counterproductive and very costly in

disease control. The sequence similarities

predict that the patterns and modes of the

interaction between SARS-CoV-2 and host

antiviral defence would be similar. Indeed,

they share many features during the course

of infection. First, they share the same

cellular receptor ACE2 [35]. Second, their

transmission routes and patterns are very

similar. While both are transmitted through

droplets primarily, close contact is a major

risk factor. The attack rate of SARS-CoV-2

within the family context is even higher

than that of SARS-CoV [36,51]. The faecal–

oral route for transmission of SARS-CoV-2

has been reported as in the case of SARS-

CoV. More studies are required to elucidate

the exact role of faecal–oral transmission in

the spreading of SARS-CoV-2. Third,

superspreading events have been

documented for SARS-CoV [52] and are also







suspected to have occurred in the

transmission of SARS-CoV-2, which could

explain the rapid increase in confirmed

cases in many places including 691 on the

Diamond Princess cruise ship as of 23

February 2020. Fourth, clinical

presentations of SARS-CoV and SARS-CoV-2

infection are similar, although symptoms

associated with SARS-CoV-2 infection are

generally milder. Fifth, host antiviral

defence plays a critical role in the course of

both SARS-CoV and SARS-CoV-2 infection.

For severe cases, immunopathogenesis and

induction of a proinflammatory cytokine

storm are the culprit. Finally, drugs tested

effective for SARS-CoV have been shown to

exhibit an anti-SARS-CoV-2 effect; examples

include nucleotide analogue Remdesivir

[53], protease inhibitors Lopinavir and

Ritonavir, as well as interferon α2a.

Particularly, activation of innate antiviral

response by interferon α2a should have

beneficial effects at least in the initial stage

of infection. However, cautions should still

be observed and the possibility that

interferon α2a might exacerbate




inflammation during the late phase of SARS-

CoV-2 infection cannot be excluded. Other

innate immune stimulators should also be

tested for anti-SARS-CoV-2 effects in future

in vitro and in vivo experiments.

Asymptomatic carriers: fact orfiction?

An asymptomatic carrier of SARS-CoV-2 was

reported in the first study of a family cluster

[51]. Transmission of SARS-CoV-2 from an

asymptomatic carrier to close contacts was

later suggested, but this has subsequently

been challenged. However, even if family

members and close contacts could be

infected by the index patient in the

presymptomatic window period as claimed,

it is still worthy of a significant concern.

Presumed transmission of SARS-CoV-2 from

an asymptomatic carrier to family members

has recently been documented [54]. The

existence of many asymptomatic carriers,

presymptomatic patients, and patients with

very mild symptoms posts a huge challenge





to infection control, as the transmission of

SARS-CoV-2 from these people to

susceptible groups would be difficult to

prevent. The number of people infected

with SARS-CoV-2 could be underestimated.

However, existing evidence suggests that

the risk might probably be lower than

expected. First, asymptomatic carriers are

not common. In the first family cluster that

was carefully studied, only one of the six

family members was found to be

asymptomatic or present with non-specific

and mild symptoms with the typical ground-

glass opacities in only one but not both

lungs [51]. Second, the transmission of

SARS-CoV-2 from asymptomatic carriers

and presymptomatic patients could be even

less common, if their viral loads are low and

virus shedding is not substantial. The key

questions concern how often asymptomatic

and presymptomatic virus shedding might

occur as well as whether their viral loads

could be high.

Asymptomatic carriers of other HCoVs

including 229E, OC43, NL63, and HKU1 have

been well documented. Importantly, the




detection rate of the virus in this group was

lower and viral loads were much lower

compared to patients with upper

respiratory tract symptoms [55]. This is

generally consistent with the notion that

asymptomatic or presymptomatic shedding

of SARS-CoV-2 might be less common than

some estimates such as half to half. In this

regard, epidemiological studies to

determine the percentages of

asymptomatic carriers and in selected large

cohorts of subjects in Wuhan should help

clarify the role of asymptomatic virus

shedding in SARS-CoV-2 transmission. This

analysis will also rule in or rule out our

prediction that asymptomatic virus

shedding exists but is uncommon. Since

patients with non-specific and mild

symptoms as well as asymptomatic carriers

can go undetected easily, the chance that

SARS-CoV-2 will be established in humans is

increased. It will likely become either

endemic in some regions or pandemic.

Theoretically, asymptomatic carriers might

arise when host antiviral defence is either

strong or decoupled. When the immune




response effectively limits but could not

completely block SARS-CoV-2 replication,

asymptomatic shedding might occur. In this

scenario, the risk of transmitting to others

is relatively low because of a low viral load.

Alternatively, if the immune response

against SARS-CoV-2 is decoupled from viral

replication as in the infection of natural

primate hosts with SIVs, the viral load would

be higher, posing a higher risk for person-

to-person transmission. A careful

quantitative analysis of the replication

dynamics of SARS-CoV-2 in asymptomatic

carriers over time is required to clarify the

validity of the two models.

Evolving to be less pathogenic: isthere a trend?

CoVs are believed to have existed for >6000

years. Molecular clock analysis enables us

to deduce the time of emergence or cross-

species transmission of some HCoVs.

Surprisingly, the highly pathogenic SARS-

CoV and MERS-CoV are thought to emerge



in the last 30 years [56]. Although NL63 and

HKU1 of low pathogenicity were isolated in

the post-SARS era, their time of emergence

was earlier than the other two highly

pathogenic viruses. Whereas NL63 emerged

>500 years ago [57], the origin of HKU1

dated back to the 1950s. In other words,

SARS-CoV and MERS-CoV represent

newcomers that are striving to adapt to

humans, whereas other community-

acquired HCoVs including NL63 and HKU1

are better adapted. The results of molecular

dating of HCoVs suggest that attenuation

might be favoured during evolution when

host adaptation takes place.

To shed further light on this trend, a

comparative analysis of the innate

immunomodulatory activity of viral proteins

encoded by different HCoVs would be

helpful. In the first place, type I interferon

antagonism of these proteins might be

compared. The use of interferon to treat

HCoV-infected patients was tested as early

as the 1960s, when various volunteer

experiments were performed to investigate

how humans combat HCoV infection.





Administration of interferon ameliorated

the severity of symptoms in 229E-

challenged volunteers [58], suggesting that

interferon confers protection against 229E

infection. Indeed, 229E potently induces

type I interferon and its replication is

susceptible to inhibition by type I IFN [59],

suggesting that interferon serves as a key

component of host antiviral defence. Since

interferon effectively suppresses the early

phase of viral replication, the suppression

of interferon production and signalling by

highly pathogenic HCoVs can exacerbate

disease progression. Thus, highly

pathogenic HCoVs adopt various

countermeasures to suppress host

interferon production and signalling as

reviewed elsewhere [49].

Host innate immune response is the first-

line defence triggered by type I interferon.

Type I interferon production is activated

through the detection of replicating viral

RNA by cytoplasmic RNA sensors RIG-I and

MDA5. Oligomerization of adaptor protein

MAVS is induced by the activation of RNA

sensor, leading to the formation of TRAF3-






TANK-TBK1/IKKϵ complex, which

phosphorylates transcription factor IRF3

and drives type I IFN transcription [49].

Highly pathogenic HCoVs often encode viral

proteins with a higher capability to

antagonize RNA-induced type I interferon

production through perturbation of RNA

sensing. For one example, double-stranded

RNA (dsRNA)-binding domain of MERS-CoV

ORF4a is responsible for the suppression of

Sendai virus- or poly (I:C)-induced type I

interferon production [60]. The gain of

dsRNA-binding ability is observed in bat CoV

HKU5 but not HKU4, suggesting that the

functional gain of MERS-CoV ORF4a and

HKU5 ORF4a might be acquired at a later

stage in evolution [60]. For another

example, only M proteins from highly

pathogenic CoVs, SARS-CoV and MERS-CoV,

were reported to potently suppress type I

interferon production [61,62], suggesting

that the loss of this activity might have

taken place during viral evolution, leading

to attenuation.

Other than suppressing type I interferon

induction, both alphacoronaviruses and








betacoronaviruses can use nsp1 to degrade

host mRNA transcripts, resulting in the

suppression of host interferon response,

although sequence homology between

nsp1 proteins of the two genera remains

low. A conserved domain is present in nsp1

of alphacoronaviruses and it is responsible

for the shut-down of host gene expression.

The deletion of 91–95 amino acids in 229E

and NL63 nsp1 partially restores host gene

expression as shown by luciferase reporter

assay [63]. The interferon-modulating

activity of nsp1 shows some variations

within the genus of Betacoronavirus.

Whereas nsp1 proteins encoded by SARS-

CoV and bat CoV Rm1 potently suppress the

induction of type I interferon, counterparts

in bat CoV 133 and bat CoV HKU9-1 are

relatively weak interferon suppressors [64].

Again, some degree of conservation in

interferon antagonism of nsp1 is seen

among different CoVs.

Apart from preventing interferon

production, CoV proteins have also evolved

to suppress interferon effector signalling.

One of the best-characterized examples is





the oligoadenylate synthetase (OAS)-RNase

L pathway. Upon activation by interferon in

response to the sensing of dsRNA,

transcription and expression of OAS are

induced to catalyse 2′,5′-oligoadenylate

(2′-5′A) synthesis [65]. 2′-5′A serves as a

second messenger, which activates RNase L

and limits viral replication through the

cleavage of cellular and viral single-

stranded RNA [65]. The cleaved RNA

fragments, in turn, prime RNA sensors to

amplify interferon production in infected

cells. To counter RNase L activity, some

CoVs have evolved phosphodiesterases

which cleave 2′-5′A [66]. The first CoV

phosphodiesterase identified is NS2a in

mouse hepatitis virus. From protein

sequence alignment, multiple CoVs

including NS2a from OC43 and a bat CoV, as

well as ORF4b encoded by MERS-CoV, are

very similar to NS2a of mouse hepatitis

virus. All these viral proteins preserve a

phosphodiesterase activity [67]. This

suggests that some CoVs have developed

an important enzymatic activity through

convergence and divergence. Hence,







although most HCoVs retain one or another

strategy to counter host antiviral defence,

the highly pathogenic CoVs are particularly

powerful in the suppression of host

immunity. These capabilities might be

weakened or lost when they adapt to

humans.

Although the exact mechanisms by which

SARS-CoV-2 might counteract host antiviral

defence remain to be elucidated, this

emerging virus is thought to be less

pathogenic than SARS-CoV. Our prediction

is that the IFN antagonism of SARS-CoV-2

and its ability to suppress other pathways

of innate antiviral signalling might fall

between those of SARS-CoV and the

community-acquired HCoVs. Plausibly, the

weakened IFN antagonism of SARS-CoV-2

compared to that of SARS-CoV might lead to

more robust host antiviral defence,

attenuated viral replication, and lower

pathogenicity.

To kill or not to kill?



Apart from the potent suppression of

interferon-mediated antiviral response,

highly pathogenic HCoVs often induce

massive cell death and cytopathy. Cell

death is a double-edged sword that can

play both antiviral and proviral roles during

viral infection [68]. On the one hand, it is

part of the host antiviral defence that

provides a dead end to viral replication and

infection, often at the price of pathological

changes including inflammation [69]. On

the other hand, dying and dead cells

release a large number of virions,

facilitating viral dissemination [70].

One form of cell death known as pyroptosis

is one of the results of a proinflammatory

cytokine storm, which drives at least in part

the high pathogenicity of SARS-CoV and

MERS-CoV. Poor outcomes of patients with

SARS and MERS are often associated with

exceedingly high levels of proinflammatory

cytokines in the lower respiratory tract and

other tissues [71]. The upregulation of

inflammatory cytokines, including

interleukin (IL) 1β, was observed in SARS-

CoV-infected monocyte-derived human







dendritic cells and tissue models [72].

Maturation of IL-1β is generated through

proteolytic cleavage of pro-IL-1β by caspase

1, the activation of which requires the

formation of a multiprotein complex

termed inflammasome. When danger

signals are sensed in the cells, NLRP3 is

activated to recruit ASC and facilitate its

oligomerization. For full activation of

inflammasome activity, two signals that,

respectively, stimulate pro-IL-1β

transcription (signal 1) and cleave pro-IL-1β

(signal 2) are required. Recombinant SARS-

CoVs with either deletion of ORF3a or

defective ion channel activity of E protein

are compromised in the activation of IL-1β

maturation and secretion [73,74].

Mechanistically, both ORF3a and E can

activate both signals. Both stimulates NF-κB

activation, resulting in the activation of pro-

IL-1β transcription [73,75]. In particular,

ORF3a achieves this through TRAF3-

dependent ubiquitination of p105 [73]. For

the activation of the second signal, ion

channel activity of SARS-CoV E protein

promotes assembly of NLRP3









inflammasome [76]. Different mechanisms

have been suggested for SARS-CoV ORF3a-

mediated inflammasome activation. We

demonstrated that SARS-CoV ORF3a

promotes NLRP3 inflammasome assembly

through TRAF3-dependent K63

ubiquitination of ASC [73]. Alternatively,

SARS-CoV ORF3a might provide a potassium

flux through its ion channel domain to

activate NEK7-dependent NLRP3

inflammasome [77]. Further investigations

are required to resolve the discrepancies

(Figure 2). Nevertheless, enhanced

secretion of IL-1β mediated by SARS-CoV E

and ORF3a proteins might contribute to the

induction of proinflammatory cytokine

storm since IL-1β further promotes the

expression of other proinflammatory

cytokines such as tumour necrosis factor α

and IL-6 [74,75]. Thus, small-molecule

inhibitors of NLRP3 inflammasomes such as

MCC950 and INF58 might prove useful in

the treatment of COVID-19. This merits

further preclinical and clinical studies.

Figure 2. A working model of SARS-CoV-

induced inflammasome activation. SARS-








CoV can activate both signal 1 (priming) and

signal 2 (activation). Upregulation of pro-IL-

1β transcription is achieved by NF-κB

activation. Two mechanisms of IL-1β

maturation have been proposed. In the first

model, potassium ion efflux is promoted by

ORF3a and E proteins, leading to NLRP3

inflammasome assembly. Alternatively,

ORF3a promotes ASC ubiquitination and

consequent assembly of inflammasome.

ORG8b interacts with and activates NLRP3.

Activation of inflammasome leads to

proteolytic cleavage of pro-caspase 1 and

pro-IL-1β. ASC, apoptosis-associated speck-

like protein containing a CARD. CASP1,

caspase 1. IKK, IκB kinase. IL-1, interleukin-

1. LPS, lipopolysaccharides. NLRP3, NACHT,

LRR, and PYD domains-containing protein 3.

NEMO, NF-κB essential modulator. TNF-α,

tumour necrosis factor α.

Apart from cytokine storm and pyroptosis

observed in highly pathogenic HCoVs, other

cell death programmes such as apoptosis

Display full size




and necrosis might also contribute to

pathogenesis. Apoptosis was detected in

various HCoV-infected samples derived

from not only the respiratory tract, but also

extrapulmonary sites. Autopsy studies on

SARS casualties revealed massive apoptosis

in multiple organs including the liver and

thyroid gland [78]. MERS-CoV induces

apoptosis in the kidney, lung, and primary T

lymphocytes, plausibly through induction of

Smad7 and FGF2 [21]. To delineate how

CoVs might activate apoptosis, pathway

analysis was performed with CoV proteins.

ORF3a, ORF3b, ORF7a, ORF8a, ORF9b, and E

proteins of SARS-CoV are pro-apoptotic

[79]. SARS-CoV ORF7a protein activates the

intrinsic pathway of apoptosis through an

interaction with anti-apoptotic protein Bcl-

X in the endoplasmic reticulum, thereby

sequestering a key suppressor of apoptosis.

MERS-CoV infection activates both intrinsic

and extrinsic pathways of apoptosis,

exacerbating viral pathogenesis [21]. Other

than apoptosis, SARS-CoV induces RIP3-

mediated necrosis through induction of

ORF3a oligomerization [80]. Generally,

L








highly pathogenic HCoVs are capable of

activating different cell death programmes

more efficiently. In this regard, it will be of

great interest to see whether and how the

lower pathogenicity and higher human-to-

human transmissibility of SARS-CoV-2 might

be linked to its abilities to modulate

inflammasome activation and cell death

programmes selectively.

Concluding remarks and futureperspectives

The outbreak of SARS-CoV-2 provides an

unprecedented opportunity for us to keep

track of a zoonotic CoV that has just crossed

the species barrier to infect humans.

Whether the transmission of SARS-CoV-2

within humans will come to a dead end

depends primarily on whether the virus has

acquired the ability to transmit from

person-to-person efficiently and

sustainably. In the cases of MERS-CoV and

SARS-CoV, secondary and tertiary spreading

becomes weakened, giving the opportunity



for quarantine and other measures of

human intervention to take effect so that

human-to-human transmission cannot be

sustained. However, if transmissibility of

SARS-CoV-2 is comparable to that of the

other four community-acquired HCoVs and

influenza viruses, we should prepare well

for the arrival of another community-

acquired HCoV. In this regard, it is crucial to

determine the infection rate in the

epicentre of Wuhan by RT–PCR and

serology. The real ratios of asymptomatic

carriers and patients with mild symptoms

as well as the transmission rates in

secondary, tertiary, and quaternary

spreading are also pivotal. If the attack rate

is sufficiently high, it will be tremendously

challenging to contain the spreading before

herd immunity develops.

The virulence and pathogenicity of SARS-

CoV-2 seem to lie between those of SARS-

CoV and community-acquired HCoVs. If

SARS-CoV-2 becomes more attenuated as it

adapts well in humans and increases its

person-to-person transmissibility as

anticipated, similar strategies for



prevention and control of CoVs and

influenza viruses might be adopted. To

reduce morbidity and mortality caused by

SARS-CoV-2, vaccines could be developed. If

quarantine cannot contain the spreading

and if it is necessary, vaccination will

provide the second opportunity to eradicate

SARS-CoV-2 from humans.

The interplay between SARS-CoV-2 and host

antiviral defence is at the core of viral

pathogenesis. It also determines the

infection outcome and might explain the

existence and risk of asymptomatic carriers.

SARS-CoV-2 is very similar to SARS-CoV in

many aspects. Lessons from other human

pathogenic viruses including SARS-CoV,

community-acquired HCoVs, influenza

viruses, and HIVs are very enlightening and

helpful. However, SARS-CoV-2 is also a

novel human pathogen that may interact

with host antiviral defence in a unique

manner. Basic research in the field of SARS-

CoV-2-host interaction holds the key to

many important questions in disease

control and prevention. Many important

questions concerning the identity and



mechanisms of interferon antagonists

encoded by SARS-CoV-2 will be answered in

the months and years to come. Particularly,

comparative analyses of SARS-CoV-2 and

SARS-CoV will advance the understanding of

SARS-CoV-2 pathogenesis. The new

knowledge gained will guide the

development of vaccines and anti-SARS-

CoV-2 therapeutics.

Acknowledgements

We thank Pearl Chan, Hinson Cheung,

Terence Lee, Shan-Lu Liu, Kam-Leung Siu,

and Roy Wong for critical reading of the

manuscript.

Disclosure statement

No potential conflict of interest was

reported by the author(s).

ORCID



Kit-San Yuen http://orcid.org/0000-0002-

1394-7709

Chi-Ping Chan http://orcid.org/0000-0001-

6876-0864

Dong-Yan Jin http://orcid.org/0000-0002-

2778-3530

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Additional information

Funding

Coronavirus research in our laboratory was

funded by the Hong Kong Health and Medical

Research Fund [HKM-15-M01] and Hong Kong

Research Grants Council [T11-707/15-R].



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https://www.tandfonline.com/servlet/linkout?suffix=CIT0080&dbid=16&doi=10.1080%2F22221751.2020.1736644&key=10.1038%2Fs41419-018-0917-y


http://scholar.google.com/scholar_lookup?hl=en&publication_year=2018&pages=904&author=Y+Yue&author=NR+Nabar&author=CS+Shi&title=SARS-coronavirus+open+reading+frame-3a+drives+multimodal+necrotic+cell+death



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Log in Register - scholar.harvard.edu · 14.03.2020 · and their usurpation of the cell death programmes. Important questions concerning the interaction between SARS-CoV-2 and host