Linfa Wang CSIRO Australian Animal Health Laboratory (AAHL) 5740 papers. in 12 minutes?!

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1 SARS Linfa Wang CSIRO Australian Animal Health Laboratory (AAHL) 5740 papers. in 12 minutes?! 1

2 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 Organization and World Health Organization. 2

3 Discussion points (requested): Role and breadth of reservoir species and extent of infection in animal species Suspected modes of transmission to humans Pathogen-level characteristics (e.g. phylogeny/evolution/coevolution) 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 stopped it? Discussion points (to be presented): A brief review of the major events Suspected modes of transmission to humans Pathogen-level characteristics (e.g. phylogeny/evolution/coevolution) 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 stopped it? Role and breadth of reservoir species and extent of infection in animal species 3

4 1. A brief review of the major events : first case of atypical pneumonia (later named SARS) : Wide spread in Guangdong province : Spread to Hong Kong beginning of the global pandemic : WHO global travel alert : WHO established a 9-nation/11-instititute lab network : A coronavirus was isolated from SARS patients : full-length genome sequence of SARS-CoV determined : Causative status of SARS-CoV confirmed : SARS-CoV related viruses detected in market animals : WHO declared the end of the pandemic and reported a total of 8,096 cases with 774 deaths to : lab-based outbreaks in Singapore, Taiwan and Beijing to : 4 independent mild SARS cases in Guangdong : 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 : first case of atypical pneumonia (later named SARS) : Wide spread in Guangdong province : Spread to Hong Kong beginning of the global pandemic : WHO global travel alert : WHO established a 9-nation/11-instititute lab network : A coronavirus was isolated from SARS patients : full-length genome sequence of SARS-CoV determined : Causative status of SARS-CoV confirmed : SARS-CoV related viruses detected in market animals : WHO declared the end of the pandemic and reported a total of 8,096 cases with 774 deaths to : lab-based outbreaks in Singapore, Taiwan and Beijing to : 4 independent mild SARS cases in Guangdong : two independent groups reporting the detection of SARS-like-CoVs in horseshoe bats in mainland China and Hong Kong 4

5 2. Suspected modes of transmission to/among humans The primary mode of transmission appears to be 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 coronaviruses A hot spot for deletion: the signature 29-nt deletion in human isolates from the later stage of the outbreaks Rapid evolution of the spike protein: sequences from close to 100 human isolates identify 3 phases of human infections (key residues aa 479 and 487) Recombination: the virus is prone to genetic recombination in reservoir species 5

6 Major differences between bat and human/civet viruses Hot spot SARS-CoV is a novel coronavirus Science 2003, 300:1399 6

7 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 crossspecies transmission and one of the main determinants for virulence/pathogenesis Li et al., 2006, JVI 80: 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 in Close contact of human with infected animals in market or restaurant is believed to be responsible for the animal-to-human transmission 7

8 5. Emergence scenario Great genetic diversity in reservoir species (most likely bats) Certain 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? : first case of atypical pneumonia (later named SARS) : Wide spread in Guangdong province : 02 21: Spread to Hong Kong beginning of the global pandemic : WHO global travel alert : WHO established a 9-nation/11-instititute lab network : A coronavirus was isolated from SARS patients : full-length genome sequence of SARS-CoV determined : Causative status of SARS-CoV confirmed More efficient pathogen discovery/diagnosis through open and transparent collaboration at the beginning of the outbreak 8

9 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) 9

10 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. 10

11 N-terminal region of ACE2 is the key for SARS-CoV entry A. SARS-CoV Infection HuACE2 + RpACE2 ca ca1-356 ca ca1-205 ca1-148 ca ca B. pcdna HuACE2 RpACE2 ca ca1-356 CSIRO. ca ca1-205 ca1-148 ca ca aa change is sufficient for SARS-CoV entry using the horseshoe bat ACE2 A. Human Civet Cat Mouse Bat B. * * * * ** ** * MSSSSWLLLSLVAVTAAQSTIEEQAKTFLDKFNHEAEDLFYQSSLASWNYNTNITE..G.F...FA.L...T..L...ET..Y..QE.S...V...D..G.F...FA.L...T..L...E...E.S...D...T...LT..N...NN..Q...S.....G.F.F...T.DR...SHE...E...SD pcdna HuACE2 RpACE2 RpACE2-FYQ CSIRO. 11

12 Correlation of receptor assay and infection Species In vitro receptor assay In vivo infection Rhinolophus megaphyllus - - Pteropus alecto + + 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, 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 12

13 Challenges If 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 do better in response and control? Newly isolated/detected bat viruses Hendra Nipah ABLV Tioman Menangle Mapuera Porcine Rubulavirus Pulau Nelson Bay Melaka Kampar Bali-HK Broome SARS-like CoV Ebola Marburg Bat herpesvirus Bat adenovirus Bat astrovirus Hendra Nipah ABLV Tioman Menangle Mapuera Porcine Rubulavirus Pulau Nelson Bay Melaka Kampar Bali-HK Broome SARS-like CoV Ebola Marburg Bat herpesvirus Bat adenovirus Bat astrovirus Hendra Nipah ABLV Tioman Menangle Mapuera Porcine Rubulavirus Pulau Nelson Bay Melaka Kampar Bali-HK Broome SARS-like CoV Ebola Marburg Bat herpesvirus Bat adenovirus Bat astrovirus 13

14 Thanks to Virology Immunology Genomics/Bioinformatics Pathogenesis Animal studies CSIRO. Cell line Virus-host interaction Livestock Industries/AAHL Linfa Wang CEO Science Leader Phone: linfa.wang@csiro.au Web: Thank you Contact Us Phone: or enquiries@csiro.au Web: 14