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SARSSARS

Linfa WangCSIRO Australian Animal Health Laboratory (AAHL)

5740 papers…. in 12 minutes?!

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Joint mission to China on Animal Reservoir of the SARS-CoV and potential transmission to humans (August 9 – 22, 2003)

Chinese Government, Food and Agriculture Organizationand World Health Organization.

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Discussion points (requested):

• Role and breadth of reservoir species and extent of infection in animal species

• Suspected modes of transmission to humansSuspected modes of transmission to humans • Pathogen-level characteristics (e.g. phylogeny/evolution/co-

evolution) linked to transmission within and among species• Interface aspects affecting evolution, exposure, or

transmission among species and to humans, including ecological aspects if relevant.

• What was the emergence scenario• When could we have stopped it earlier? How could we have• When could we have stopped it earlier? How could we have

stopped it?

Discussion points (to be presented):

• A brief review of the major events• Suspected modes of transmission to humans• Suspected modes of transmission to humans • Pathogen-level characteristics (e.g. phylogeny/evolution/co-

evolution) linked to transmission within and among species• Interface aspects affecting evolution, exposure, or

transmission among species and to humans, including ecological aspects if relevant.

• What was the emergence scenarioWh ld h t d it li ? H ld h• When could we have stopped it earlier? How could we have stopped it?

• Role and breadth of reservoir species and extent of infection in animal species

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1. A brief review of the major events• 2002-11-16: first case of atypical pneumonia (later named SARS)• 2003-01-22: Wide spread in Guangdong province• 2003-02-21: Spread to Hong Kong – beginning of the global pandemic• 2003-03-12: WHO global travel alert• 2003-03-17: WHO established a 9-nation/11-instititute lab network• 2003-03-24: A coronavirus was isolated from SARS patients• 2003-04-12: full-length genome sequence of SARS-CoV determined• 2003-04-17: Causative status of SARS-CoV confirmed• 2003-05-23: SARS-CoV related viruses detected in market animals• 2003-07-05: WHO declared the end of the pandemic and reported a total of

8 096 ith 774 d th8,096 cases with 774 deaths• 2003-09 to 2004-04: lab-based outbreaks in Singapore, Taiwan and Beijing• 2003-12 to 2004-01: 4 independent mild SARS cases in Guangdong • 2005-10: two independent groups reporting the detection of SARS-like-CoVs

in horseshoe bats in mainland China and Hong Kong

1. A brief review of the major events• 2002-11-16: first case of atypical pneumonia (later named SARS)• 2003-01-22: Wide spread in Guangdong province• 2003-02-21: Spread to Hong Kong – beginning of the global pandemic• 2003-03-12: WHO global travel alert• 2003-03-17: WHO established a 9-nation/11-instititute lab network• 2003-03-24: A coronavirus was isolated from SARS patients• 2003-04-12: full-length genome sequence of SARS-CoV determined• 2003-04-17: Causative status of SARS-CoV confirmed• 2003-05-23: SARS-CoV related viruses detected in market animals• 2003-07-05: WHO declared the end of the pandemic and reported a total of

8 096 ith 774 d th8,096 cases with 774 deaths• 2003-09 to 2004-04: lab-based outbreaks in Singapore, Taiwan and Beijing• 2003-12 to 2004-01: 4 independent mild SARS cases in Guangdong • 2005-10: two independent groups reporting the detection of SARS-like-CoVs

in horseshoe bats in mainland China and Hong Kong

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2. Suspected modes of transmission to/among humans

The primary mode of transmission appears to p y ppbe direct mucous membrane (eye, nose, and mouth) contact with infectious respiratory droplets and/or through exposure to formites.

Role of aerosol transmission in airplane by super spreader?!

3. Pathogen-level characteristics

•Overall genome structure: similar to other known coronavirusescoronaviruses

• A hot spot for deletion: the signature 29-nt deletion in human isolates from the later stage of the 2002-2003 outbreaks

• Rapid evolution of the spike protein: sequences from close to 100 human isolates identify 3 phases of y phuman infections (key residues aa 479 and 487)

• Recombination: the virus is prone to genetic recombination in reservoir species

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Major differences between bat and human/civet viruses

Hot spot

SARS-CoV is a novel coronavirus

Science 2003, 300:1399

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4. Role interface aspects(a. Pathogen-host interface)

•Identification of ACE2 as the functional receptor

• Identification of S – ACE2 fitness as the main barrier for cross-species transmission and one of the main determinants for virulence/pathogenesis

Li et al., 2006, JVI 80: 4211

4. Role interface aspects(b. Animal-human interface)

•Why did it start in Guangdong?

Live animal markets

• Why in 2003?

Dramatic increase in the consumption of wildlife meat after 20 years of rapid economic growth in the region

Close contact of human with infected animals inClose contact of human with infected animals in market or restaurant is believed to be responsible

for the animal-to-human transmission

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5. Emergence scenario

•Great genetic diversity in reservoir species (most likely bats)

•Certain subtypes have the right spike protein to infect non-reservoirCertain subtypes have the right spike protein to infect non reservoir species, but rate of contact to susceptible spillover host(s) is low

•The farming and increasing trading activities of civets (happens to be a highly susceptible host for SARS-CoV) in Guangdong resulted in the spillover into civet populations either directly from the reservoir species or through one or more intermediate animals

•Rapid evolution in civets made the virus(es) more suitable for human infection

•Virus underwent further evolution in humans during early phases of outbreaks

(Note: Neither the exact reservoir species nor the country origin of the SARS-CoV progenitor virus is certain at the present time!)

6. When could we have stopped it earlier? How could we have stopped it?

• 2002-11-16: first case of atypical pneumonia (later named SARS)• 2003-01-22: Wide spread in Guangdong province• 2003 02 21: Spread to Hong Kong beginning of the global pandemic• 2003-02-21: Spread to Hong Kong – beginning of the global pandemic• 2003-03-12: WHO global travel alert• 2003-03-17: WHO established a 9-nation/11-instititute lab network• 2003-03-24: A coronavirus was isolated from SARS patients• 2003-04-12: full-length genome sequence of SARS-CoV determined• 2003-04-17: Causative status of SARS-CoV confirmed

More efficient pathogen discovery/diagnosis through open and transparent collaboration at the beginning of the outbreak

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7. Role and breadth of (suspected) reservoir species and extent of infection in animal species

Multi-directional transmission:

•Animal to animal

•Animal to human

•Human to human

•Human to animal

Extent of infection in animal species

Fruit bat (P. alecto)

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Role of bats ?

Significant difference in the receptor binding domain

1) Can the bat SARS-like-CoV use human ACE2 as an entry receptor?

2) Can the human SARS CoV use bat ACE2 as an entry receptor ?

CSIRO.

2) Can the human SARS-CoV use bat ACE2 as an entry receptor ?

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RpACE2

HuACE2 +--cA357-805

SARS-CoV InfectionA.

N-terminal region of ACE2 is the key for SARS-CoV entry

cA357 805

cA1-356

cA206-356

cA1-205

cA1-148

cA57-206

cA1-56

+-++-+

B.

CSIRO.

HuACE2pcDNA RpACE2 cA357-805 cA1-356

cA206-356 cA1-205 cA1-148 cA57-206 cA1-56

A.* * * * ** ** *

3-aa change is sufficient for SARS-CoV entry using the horseshoe bat ACE2

B.

* * * * ** ** * Human MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITECivet ..G.F.....FA.L......T..L.....ET..Y..QE.S....V..........DCat ..G.F.....FA.L......T..L.....E.......E.S...............DMouse ...............T...LT..N.....NN..Q.....S................Bat ..G.F.F.............T.DR...............SHE......E.....SD

10 20 30 40 50

CSIRO.

pcDNA HuACE2 RpACE2 RpACE2-FYQ

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S i I it t I i i f ti

Correlation of receptor assay and infection

Species In vitro receptor assay In vivo infection

Rhinolophusmegaphyllus - -

Pteropusalecto + +

Conclusion

• Surveillance of bats in different parts of the world has revealed a great genetic diversity of bat coronaviruses

• SARS-like-CoV has been detected in horseshoe bats in Asia• SARS-like-CoV has been detected in horseshoe bats in Asia, Africa and Europe

• Our receptor study, coupled with in vivo infection, has identified the following species susceptible to SARS-CoV infection:

• Rhinolophus sinicus• Myotis daubentonii• Pteropus alecto• Rousettus leschenaultii

• Preliminary data from Vietnam indicated the presence of neutralising antibodies in Rousettus bat against SARS-CoV

• International collaboration is required to widen the surveillance to identify the true reservoir species for SARS-CoV or its progenitor virus

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Challenges

If we are not ready to predict the unknownIf we are not ready to predict the unknown, can we at least predict the partially known?

If we are unable to stop the spillover, can we p p ,do better in response and control?

Newly isolated/detected bat viruses

• Hendra• Nipah• ABLV• Tioman

• Hendra• Nipah• ABLV• Tioman

• Hendra• Nipah• ABLV• TiomanTioman

• Menangle• Mapuera• Porcine Rubulavirus• Pulau• Nelson Bay• Melaka • Kampar• Bali-HK

B

Tioman• Menangle• Mapuera• Porcine Rubulavirus• Pulau• Nelson Bay• Melaka • Kampar• Bali-HK

• Tioman• Menangle• Mapuera• Porcine Rubulavirus• Pulau• Nelson Bay• Melaka • Kampar• Bali-HK

• Broome• SARS-like CoV• Ebola• Marburg• Bat herpesvirus• Bat adenovirus• Bat astrovirus

• Broome• SARS-like CoV• Ebola• Marburg• Bat herpesvirus• Bat adenovirus• Bat astrovirus

• Broome• SARS-like CoV• Ebola• Marburg• Bat herpesvirus• Bat adenovirus• Bat astrovirus

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Thanks to …

Virology Immunology Genomics/Bioinformatics

CSIRO.

Pathogenesis Animal studies

Cell line Virus-host interaction

Livestock Industries/AAHLLinfa WangCEO Science Leader

Phone: +61 3 5227 5121Email: linfa.wang@csiro.auWeb: www.csiro.au/group

Contact UsPhone: 1300 363 400 or +61 3 9545 2176

Email: enquiries@csiro.au Web: www.csiro.au

Thank you