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“Three decades of emerging infections”

Dedicated to our predecessors who laid the foundationof excellence in the study of infectious diseases

by setting personal examples in clinical care, teaching,and research at HKU.

The Centre of Infection was founded in 1998. One of its goal is to disseminate the fruits of our research work on emerging infection to the scientific, medical and general community. The following powerpoint slides outlined the history on the service, research and education the Li Ka Shing Faculty of Medicine of the University of Hong Kong since its foundation in 1887. The content is part of the Distinguished Lecture delivered by Professor Kwok-Yung Yuen, the Henry Fok Professor of Infectious Disease, Chair and Head of the department of Microbiology and the Senior Advisor and Ex-President of the Centre of Infection. This lecture is dedicated to our predecessors who laid the foundation of excellence in the study of infectious diseases by setting personal examples in the clinical care, teaching and research at the University of Hong Kong.

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1844–1922, father of tropical medicine

1878: filariae in elephantiasis; through Culex mosquito

1894: deduced malaria passing through mosquito

1887: founded Hong Kong College of Medicine for Chinese (HKU)

Patrick Manson, Foundation Dean

Our Foundation Dean of the Li Ka Shing Faculty of Medicine, Professor Patrick Manson who set up the HK College of Medicine for Chinese, the precursor of our university. He is known as the father of tropical medicine for his contribution in finding the parasite that causes elephantiasis which is transmitted by mosquitoes.

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From: Special Programme for Research and Training in Tropical Diseases (TDR)

As a surgeon, he used his scalpel to cut away the disfiguring and socially stigmastising elephantoid tissue with a very low mortality, only 2 deaths out of 61operations done under very improvised conditions. But he did not stop with his excellent operative results, his academic curiosity drove him to find the micro-organism that causes elelphantiasis, a novel group of round worm circulating in blood which causes the disease filariasis.

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120 million people are infected and at least 40 million disabled both physically and psychosocially;1.2 billion people worldwide are believed to be at risk of infection. From: WHO website

Patrick Manson: a great surgeon, infectious disease physician, and microbiologist.

His Contribution: Disease: filariasis/elephantiasis. Animal vector: mosquitoes.Microbe: blood nematodes. Epidemic centre: mosquito breeding sites.

Year 2000

The contribution of Professor Patrick Manson in defining this disease, the microbe, the animal vector and the epidemic center has major public health implications even after 100 years. In year 2000, the WHO has launched the program for the global elimination of lymphatic filariasis. This will benefit at least 120 million people in different continents.

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Shibasaburo KitasatoAlexandre Yersin

1894 HK race to find the cause of black death in Southern China: Yersinia pestis

Pure culture from

lymph node

Mixed culture

with? pneumococcus

1894, Hollywood Road

Ann Inst Pasteur 1894;8:662-667 Lancet 1894;2:428-430

Source: Jerome J. Platt, Maurice E. Jones & Arleen Kay Platt. The Whitewash Brigade: The Hong Kong Plague 1894. London: Dix Noonan Webb Ltd., 1998.

Hong Kong and Southern China has always been the focus of outbreaks of new emerging infections. In 1894 , an outbreak of plague in HK had attracted scientists racing to find the bacteria causing the black death. Dr. Kitasatofrom Japan made the first announcement and publication in Lancet but his culture was said to be contaminated and finally the bacteria was named after Dr. Alexandre Yersin of the Institut Pasteur.

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1906 Pathological Institute for bacteriology and now Hong Kong Museum of Medical Sciences ®

Like the Centre of Health Protection established after SARS, the government of Hong Kong had established the pathological institute for bacteriology in 1906 after taking lessons from the plague.

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Foundation Chair of Pathology (1920-1930)

Source: University ArchivesSection, HKU

At our university, Professor Wang Chung-Yick was appointed the foundation chair of pathology in 1920. He had published extensively on tuberculosis and syphilis in Lancet. His selfless devotion to medicine and early death from tuberculosis in 1930 was summarised by the VC in a famous sentence “ you saved others, yourself you could not save.”

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Second World War: Unit 731 BW programme on Yersinia pestis

+ ++ +++ ++++Severity of organ damage on

live autopsy

Type strain of Y. pestis

Serial passage in Chinese civilians and POW

Fleas harvested to weaponizebombs / direct spraying from

aircrafts

Community outbreaks of plague

in China

During the second world war, forty years after the discovery of this bacteria, the Japanese army use the Yersiniapestis as a biological weapon in China. It is important to remember that research on emerging infectious disease is strategic in both public health against epidemics and national defence against bioterrorism.

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Disease Bile duct cancer

Microbe Clonorchis sinensis

Animal host Freshwater fish

Epidemic centre Fish ponds with latrines

Professor Gibson established the Department of Microbiology in 1968.

Post-War Chair of Pathology (1948-1960)

The Relationship between primary carcinoma of the liver and infestation with clonorchis

sinensis

By Prof. HOU Pao-Chang, Department of Pathology, The University of Hong Kong

Source: University Archives Section, HKU

Our first post-war chair in pathology, Professor Hou Pau Chang, discovered the relationship between bile duct cancer and the parasite, Clonorchis sinensis which is transmitted through the consumption of undercooked freshwater fish.He was succeeded by Professor Kirk, and then Professor Gibson who considered infections as vicious as the hand of war. Perhaps because of this conviction, he established the department of microbiology as a sister department in 1968.

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Consultations to the Department of Microbiology, QMH, HKU

HKU, J Infect 1992

HKU, Clin Infect Dis 1998

After graduation and some postgraduate training in Internal Medicine and Surgery, Professor Kwok-Yung Yuen joined the department of Microbiology at the University of Hong Kong. His first assignment is to systematise the clinical infectious disease consultation service at Queen Mary Hospital. He advises on clinical assessment, collection of clinical specimens, rapid diagnostic test, antibiotics, infection control and immunisation. The number of clinical consultation went up from 200 per year to the present level of 3000, a fifteen times increase. Thanks to support from our clinical departments including Surgery, Medicine, Orthopaedics, Obstetrics and Gynaecology, Paediatrics and radiation oncology. Slide 12

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1990 – BMT service established in QMH, HKU.Suspected outbreak of hospital-acquired bacteraemia

3 patients in 1 month developed fever (39-41°C) within a few hours after routine platelet transfusionBlood culture: coagulase-negative staphylococci.

The University of Hong Kong started the bone marrow transplant service at Queen Mary Hospital under the supervision of Professor TK Chan, Professor Raymond Liang and Dr. Edmond Chiu, who invited Professor Kwok-Yung Yuen to advise on the infectious disease aspect of transplant. There was a suspected outbreak of bacteraemiaafter platelet transfusion. A common skin flora, the coagulase negative staphylococci, was isolated from the blood of these patients..

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Diagnostic difficulty: Neutropenic or transfusion bacteraemia?

Retaining all platelet bags at 4°C after all transfusions

Post-transfusion fever:

• blood culture (patients)

• platelet bag remnants ×smear and culture

Because platelet cannot be refrigerated, they are prone to bacterial overgrowth by skin flora which is also a common cause of infection in these very immunosuppressed patients. Our advice is that all the platelet bags must be retained for 24 hours after transfusion. If the patient developed a fever during this period, the platelet remnant and the patients’ blood should be sent for culture.

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Preemptive ganciclovir

Another fatal disease in the bone marrow transplant recipients is the Cytomegalovirus infection. By doing weekly monitoring for viral DNA using PCR on the blood of these patients , we can give preemptive antiviral treatment to maximise the efficacy and minimise the side effect and the cost. Even today we are still using this sensitive and specific test for our marrow transplant patients.

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Disease Fever of unknownorigin, lymphadenopathy

Microbe Penicillium marneffei

Animal Chinese bamboo ratsreservoir (Rhizomys sinensis)

Expanding HIV+ / immunosuppressedpopulationof susceptiblehosts

Penicilliosis marneffei, an indicator disease of AIDS; affects 10% AIDS patients in SE Asia.

Besides bone marrow transplant recipients, AIDS patients belong to another group of very immunosuppressedpatients. We found that about 10% of our AIDS patients are suffering from an infection caused by a fungus called Penicillium marneffei. This was normally carried by Chinese Bamboo rats. These patients often presented with fever of undetermined origin, enlarged lymph nodes and skin lesions. Remember that if China has 10 million AIDS patients in 2010, one million of them may suffer from this fungal infection.

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An emerging fungal disease of Southeast Asia

Professor PY Chau

Because fungal culture is not sensitive or slow, we designed a very simple immunofluorescent antibody test using the germinating conidia of this fungus for making rapid diagnosis. This was our first Lancet paper while still under the supervision of the mentorship of Dr. PY Chau.

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HKU: 12 publications (Lancet, Infect Immun, J Clin Microbiol), 1 patent. (Appendix 1, 2)

Using molecular technique, we have successfully cloned and patented the first immunodominant protein of this fungus which was useful for serodiagnosis and perhaps animal vaccination.

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-227 -117 -62 -36 0 76 139 167 251 463 506 562 590 736 806 904 1003 1115

Ag (1:20)

Ab(1:100)

ELISA detection of Ag and Ab of P. marneffei in patients

Culture positive

Sensitivity 88%Specificity 100%

HKU. J Clin Microbiol 1995, 2001

This antigen and antibody test was sensitive and highly specific. A positive test can precede a positive culture by a few weeks. By 1995 we were a bit more confident in doing molecular diagnostic test for emerging infections.

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First sign of an emerging epidemic: increased deaths in animals

No. ofhumaninfluenzaAH5N1cases

We are then put to test at 1997. The first sign of an emerging epidemic is often the appearance of increased deaths in animals. The two waves of farm outbreaks were followed by human cases but there was a window of opportunity in between.

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Because we have prepared, we are able to launch diagnostic tests using RT-PCR and immunofluorescent antigen detection for the management of these patients. This had led to a publication in Lancet two months after the outbreak.

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The first postgraduate infectious disease diploma course in Hong Kong launched from the Centre of Infection

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100150200250300350400450

1998-2000 2000-2002 2002-2004

Number of participants for CME only

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1998-2000 2000-2002 2002-2004

Number of diploma students

HA / DH / universities(93%)

Non-HA/DH(7%)

Profile of participants

First external examiner: Prof Allan Ronald

Besides clinical service and research, we have not forgotten the importance of teaching. With the support of Professor Grace Tang and Professor MH Ng, the Center of Infection launched the first structured training course for infectious disease in HK. For the last two years, we have 63 diploma students and another 400 attending update course for continuous medical education. The course has the important function of updating frontline clinicians on the best practice in treating patients suffering from them. Most of these alumni are coming from the public sector of HK. They have helped us a lot during the SARS outbreak by informing us of suspected cases, giving us the necessary clinical information and the vital clinical specimens. I am particularly grateful to Professor Grace Tang who gave us the seed money to get Professor Allan Ronald as our first external examiner.

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First sign of an emerging epidemic: a clinical case with unusualcharacteristics, severity and transmissibility in the hospital

After years of preparation, we are now ready for the real challenge. The first sign of emerging epidemic is often an atypical patient.

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M/53, HK resident Relative of Guangzhou Professor

(index case of KWH)DOA: 25/2/03

Isolation of the filterable virus in pure culture (absence of other pathogens).Consistent positive isolation / RT-PCR of SARS-CoV from SARS patients and subsequent seroconversion.First generation diagnostic test: RT-PCR for viral genes, immunofluorescent test for specific antibodies.

Cell culture with CPE(FRHK-4)

HKU, Lancet 2003.

The real challenge: SARS, 2003.

We have the privilege of seeing the index case in Kwong Wah Hospital, a health care worker travelling from Guangzhou with a rapidly deteriorating pneumonia. He did not respond to standard treatment and has infected his brother in law. A novel virus was cultured from the lung biopsy of his brother in law. The first generation diagnostic tests were then designed to identify new cases.

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Clinical and radiological progression of SARS

HKU, Lancet 2003.

Using the first generation tests, we were able to describe in detail the clinical features and radiological progression of SARS patients. You can see the shifting lung shadows and the pneumomediatinum here which is typical of SARS.

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With the recombinant viral protein, we can produce good monoclonal antibodies for SARS antigen detection. This is the antigen detection kit developed in collaboration with the First Military University of Zhuchiang Hospital in Guangzhou.

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HKU / Guangzhou Zhujian Hospital Emerg Infect Dis 2004.

Profile of circulating N antigen and antibody for SARS-CoV in 317 SARS cases

Using the serum of 317 SARS patients, the circulating viral antigen was positive in over 70% of cases before day 10 but the sensitivity decreases once the antibody is rising after day 10.

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Correlation of viral load in nasopharyngeal specimens between day 10 to 15, and respiratory failure & death

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Death (-) Death (+)

Median: 0

Median: 4.5

Median: 0

Median: 6.5

(Respiratory failure: defined as SaO2 < 90% at room air)

N = 154 patients

p < 0.01 p < 0.01

HKU Emerg Infect Dis 2004

As expected, a high viral load in the nasopharyngeal specimen is associated with respiratory failure and death from SARS. This finding suggested that decreasing viral load by drugs or antibody may improve the outcome of SARS patients.

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Implications:

1. Window of opportunity for antiviral treatment.

2. Success of isolation and quarantine.

3. ? Immunopathologicaldamage (continued deterioration after D10 in 20%).

HKU Lancet 2003

But do we have the window of opportunity to give a useful duration of treatment for SARS? Longitudinal viral load study showed that the viral load only peaked at around day 10 which should allows enough time for treatment to be effective and that good isolation in hospitals should control the outbreak.

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leukocytic

Protease inhibitors / interferons and ribavirin for SARS

HKU, J Clin Virol 2004

leukocytic

Time from symptom onset (days)

3020100

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porti

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ithou

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Treatment arm

Historical arm

Number at risk

Treatment arm 41 41 41 41 41

Historical arm 111 111 103 91 85

PI + ribavirin

Ribavirin

HKU, Thorax 2004

PI + ribavirin(Treatment arm)

Ribavirin(Historical arm)

72 hr

Interferon alpha/1000

0 5000 2500 1250 625 312.5 156 78 39 19.5 0Ribaviri n

200 + + + + + + + + + + -100 + + + + + + + + + + -50 + + + + + + + + + - -25 + + + + + + + + - - -

12.5 + + + + + - - - - - -0 + + + + - - - - - - -

96 hr

Interferon alpha/1000

0 5000 2500 1250 625 312.5 156 78 39 19.5 0Ribaviri n

200 + + + + + + + + + - -100 + + + + + + + + - - -50 + + + + + + + + - - -25 + + + + + + + + - - -

12.5 + + + + + - - - - - -0 - - - - - - - - - - -

+ = 50% inhibition CPE

In terms of the choice of antiviral treatment for SARS, ribavirin has synergistic activity when combined with some interferons in vitro. In clinical trials using historical control, protease inhibitor combined with ribavirin has decreased the mortality and the need for intensive care.

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SARS-coronavirus-infected human cell line

mRNA extraction

Labelled cDNA

Hybridization on microarray

Common cold-coronavirus-infected human cell line

mRNA extraction

Labelled cDNA

Hybridization on microarray

Genome Research Centre

Comparative transcriptomics

So much for the clinical research, we do not really understand how the SARS coronavirus produces damage at the cellular level. Using the microarray technology from the genome research centre, we define the cellular gene expression pattern after infection by a less virulent common cold coronavirus and that after infection by the more virulent SARS coronavirus.

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Common cold Common cold

Gene expression study clearly showed that the SARS coronavirus excites more inflammation and even clotting by activation of the coagulation genes.

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HKU Lancet 2003 Ding Y et al., J Pathol 2003

These findings are in keeping with the pathological findings which provide the rationale behind our treatment regimen: that SARS patients should receive respiratory support for the lung damage, immunomodulators for those with severe inflammation in the lung, antivirals to reduce the amount of virus and perhaps anti-coagulation for those with clotting up of the blood vessels.

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UrbaniTOR2

HKU 39849HKU 66078HKU 65806

CUHK-W1HKU36871GZ50

GZ01GZ43GZ60

SZ3SZ1

SZ16SZ13

HU-GZ-04-1HC-GZ-1

HC-SZ-9HC-SZ-1

HC-GZ-2CFB-SZ-40.001

Human - 2003

Animal - 2003 (May)

Human - 2003/04

Animal - 2003 (Dec.)

HKU, Guangdong / Shenzhen CDC

Phylogeneticanalysis of S gene

Finding the source of SARS coronavirus in Civet cats and other wild game food animals will prevent the return of SARS. The high degree of genetic relatedness between the human and animal SARS coronavirus had finally convinced the Mainland government about the importance of controlling the animal source.

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11.11.2004

Our work is recognised by the Central government who gives us the title of the State Key Laboratory of emerging infectious diseases.

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One year after SARSBiochem Biophys Res Commun 2004 Mar 19;315(4):1134-9.

Clin Chem 2003 Jun;49(6 Pt 1):953-5.

Clin Chem 2004 Jan;50(1):67-72.

Clin Chem 2004 Mar 30.

Clin Exp Immunol 2004 Mar;135(3):467-73.

Clin Infect Dis 2004 Feb 15;38(4):467-75.

Clin Infect Dis 2004 Jan 15;38(2):297-9.

Emerg Infect Dis 2004 Feb;10(2):176-8.

Emerg Infect Dis 2004 Feb;10(2):294-9.

Emerg Infect Dis 2004 Feb;10(2):342-4.

Exp Biol Med (Maywood) 2003 Jul;228(7):866-73.

Gastroenterology. 2003 Oct;125(4):1011-7.

J Biol Chem 2003 Oct 10;278(41):39578-82.

J Clin Microbiol 2003 Oct;41(10):4521-4.

J Clin Virol 2003 Dec;28(3):233-8.

J Clin Virol 2003 Dec;28(3):245-7.

JAMA 2003 Nov 26;290(20):2665-6.

Lancet 2003 Apr 19;361(9366):1319-25.

Lancet 2003 Jul 26;362(9380):263-70.

Lancet 2003 May 10;361(9369):1615-7.

Lancet 2003 May 24;361(9371):1767-72.

Lancet 2003 May 24;361(9371):1773-8.

Lancet 2003 May 3;361(9368):1519-20.

Lancet 2003 Nov 29;362(9398):1807-8.

Lancet 2003 Oct 25;362(9393):1353-8.

Lancet 2004 Jan 10;363(9403):99-104.

Lancet 2004 Mar 13;363(9412):841-5.

N Engl J Med 2003 Dec 18;349(25):2431-41.

N Engl J Med 2003 May 15;348(20):1977-85.

Nature 2003 May 15;423(6937):240.

Nature 2003 Oct 30;425(6961):915.

Respirology 2003 Nov;8 Suppl:S6-8.

Science 2003 Oct 10;302(5643):276-8.

Thorax 2004 Mar;59(3):252-6.

One year after the last case of SARS, we had 33 publications in leading medical and scientific journals including Lancet, NEJM, Nature, Science and many top specialist journals.

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Prof. KY YUEN

Prof. JSM PEIRIS

Dr. PL HODr. PCY WOO

Dr. Y GUAN

Dr. SSY WONG Dr. BJ ZHENG

Dr. RYT KAODr. LLM POON

Dr. SKP LAU

Research Team,Department of Microbiology,

Faculty of Medicine, The University of Hong Kong

Dr. WC YAMDr. HL CHEN

Department of Microbiology (12 academic staffs)

939.34174.11Total

Impact Factor

15711032Total Citations

21775Publications (PubMed)

1999 to 20031994 to 1998

All these work would not be possible without the painstaking effort of our DREAM TEAM. Let me introduce them one by one. Malik Peris, chair of virology. Guan Yi, zoonotic virologist, Patrick Woo and Susanna Lau, stamp collectors of novel virus and bacteria, PL Ho, expert in antimicrobial resistance, Samson Wong, expert in mycology, parasitology and tropical diseases. Zheng BJ, viral immunologist, Leo Poon and Dr. Chen HL molecular virologist,. Richard Kao, chemical geneticist and Yam WC, expert in laboratory diagnostics. The collaborative effort of our team has almost increased our number of publications three times, the total impact factor 5 times and citations by one and half times in the last 4 years.

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But the day to day actions cannot be met without the tireless effort of our postdoctoral fellows, postgraduate students, research technicians and research assistants.

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Our daily arrangement, research data and communications with others cannot be kept smooth and accurate without the support from our secretariat.

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In his reply to a toast to the first licentiates during the dinner given by Dean Cantlie, Dr Sun Yat Sen advocated the College to “thrive not only for ourselves but for everyone in Hong Kong”.

Hong Kong Med J 2003

Dr Tse Yuen Man

CUHK 1992

DrLau Tai Kwan(Paediatric

Surgery)

HKU 1969

Dr Cheung Sik Hin(ENT Surgery)

HKU 1970

Dr Cheng Ha Yan

HKU 1997

I salute to all the health care workers who have stood firm in the trench during the battle against SARS. Of the 4 doctors who were killed in action, three of them are our alumni. Their selfless devotion has exemplified what Dr. Sun Yat Sun had said, “thrive not only for ourselves but for everyone in Hong Kong.”

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Professor Kwok-Yung Yuen was particularly impressed by the kindness of this young patient, a primary two student, who empathised with the suffering of SARS patients and gave his Chinese new year red packet money and that of his younger brother for our SARS research. But I do not really know whether his younger brother agreed with his decision.

Support from friends and donorsI want to acknowledge all the friends of our centre and the benevolent donors for their spiritual and financial support without which all these work would not be possible.

Contributions of HKU alumni to support our SARS researchMany alumni, consultants and executives from the hospital authority, dept of health, other government departments, and many of our teachers have supported or facilitated our work in many different ways.

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First sign of an emerging epidemic: an unidentified microbe in the laboratory

Though an atypical patient is often the first sign of an emerging epidemic, it can also be an un-identified microbe in the laboratory

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Laribacter hongkongensis, gen. nov., sp. nov.

Blood culture of a cirrhotic patient

Stool culture of a diarrhealpatient

From an un-identified spiral bacteria found in the blood culture of a patient with liver cirrhosis, we trace the bacteria to the stool of diarrheal patients and finally the fresh water fish.

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Disease DiarrhoeaMicrobe Laribacter hongkongensisAnimal host Freshwater fishEpidemic centre ? Fish ponds/tanks

Again we associate infectious diarrhea with this novel bacteria and the animal host: fresh water fish. You can see that the DNA finger print is identical between the bacteria from one patient and that from the minced fish meat.

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1894 plague

1963-64 cholera

1968 influenza H3N2

1997 influenza H5N1

2003 SARS

Thailand, Xinhuanet 2004

Will research on emerging infectious disease research continue to benefit HK and the world? If you look at the history of infectious disease outbreaks in HK and its geographic position, you will agree that HK as the traffic hub of Southern China will be an important sentinel post guarding the whole world from emerging infections.

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Wild game animals

LaboratorySewage systemHospitalWet marketFarms

Convergence

DisseminationSA

RS

-CoV

SARS-CoVAnimal handler General population

Genetic changes

General population (expanding susceptible population)

Aggregationand cross infection

Importance of epidemic centres in the amplification of emerging infections

Animal to human

Human to human

Experience from SARS and bird flu teaches us about the importance of epidemic centres in the amplification of any new emerging infections. These epidemic centres such as farms and markets rapidly expand the microbial burden by cross infection Genetic exchange or mutations enables the microbe to spread from animal to human and from human to human. The success in the control of emerging infections depends on a rapid response research team which can provide the scientific information for the design of a control strategy.

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Clinical microbiologist(MD,MRCPath) Infected Patient

Clinician(MD)

Ward consult

Phone consult

Lab report

Infection control,Hospital Authority

Community infection control (epidemiology), Dept of Health

ID Problems

Basicscientists(PhD)

Microbe

Rapid Response Research team for emerging infections

A rapid research response would not be possible without a dedicated team consisting of clinicians, clinical microbiologist and basic scientists who closely collaborate with the hospital and public health epidemiologist.

46

Outbreaks:

• Public panic

• Media pressure

Answer:

Rapid Response Research Team

Hospital shuts wards as mystery

fever hits 28

Caritas tightens infection controls and isolates patients after four more fall ill

The recent outbreak of fever and respiratory diseases in Caritas Medical Centre of 2004 has again demonstrated the power of public panic and the media pressure on the government. The answer lies in a rapid response research team.

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PIV4B1

PIV4B2

88058_phospho_combine

1000

145389_PHOSPHO

CMC case

PIV4A1

PIV4A2

1000

1000

1000

1000

PIV2

1000

PIV1

PIV3

1000

0.05

Phylogenetic analysis of the parainfluenza virus phosphoprotein

32 out of 35 specimens tested positive for PIF4 by RT-PCR at two gene regions.

Within 48 hours, members of the Centre of Infection of the University of Hong Kong in collaboration with the Centre of Health Protection has identified the cause of the outbreak as Parainfluenza virus 4a using RT-PCR and gene sequencing. This has immediately stopped the issue from getting any front page coverage.

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Focus of HKU on emerging infections

Disease Microbe Animal sources Amplification premiseSyndrome Epidemic Centre

Pneumonia VirusesInfluenza H5N1 Waterfowls, poultry Wet market

Human/Civet/bat SARS CoV Game food mammals/Bat

Coronavirus HKU1

Diarrhoea BacteriaLaribacter hongkongensis Freshwater fish Fish tank / water

Other novel bacteria

Fever of Fungusunknown Penicillium marneffei Bamboo rats ? Soil and dustorigin (bioterrorist letters)

Therapeutic Antimicrobial resistancedifficulties Quinolones Food animals Farms,wet market and

Extended-spectrum fresh food premisesbeta lactamases

This is how we follow the foot steps of our predecessors into the unknowns. We start at the bedside with atypical disease syndrome. We identify the novel microbe in the laboratory. We find the animal reservoir in the field. And finally we control the epidemic centre.

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Circular maps of inferred Laribacter hongkongensis genome (5X coverage, genome size 3 Mb)

Department of Microbiology / Genome Research Centre, HKU.

Since the genome is the blue print of any life forms. Characterization of a novel microbe is not complete without a complete genome sequence. Here is the assembly of 15 million base of genetic information which is about 5X the coverage of the Laribacter hongkongensis genome. This would not have been possible without our Genome Research Centre

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Analysis of enormous amount of genomic information will generate useful knowledge for the discovery of new antibiotics, diagnostics, and vaccination.

Information↓

Knowledge↓

Wisdom (?)

Some people say that information is power but we believe information is also a responsibility. The enormous amount of genomic information are rapidly turned into knowledge that accelerated the discovery of new antibiotics, diagnostic tests and vaccines. But do we have more wisdom after getting more information and knowledge.

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Otaru, Hokkaido, Japan

June 2004

A clinician is most often judged by his clinical acumen, that is, “ are you alert of something going wrong at the very early stage.” When we visited Otaru in the summer of 2004 at this tourist spot, we found the writing of a Japanese child in a memorial album. The time of this writing was at the peak of SARS when nothing was going wrong in Japan. But the child was still very concerned whether SARS will come to Japan like the E coli O157 that attacked Japan 7 years ago(1996). He had the acumen and intuition of a good scientist and clinician.

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0

1000000

2000000

3000000

4000000

5000000

6000000

7000000

18411931

19411945

19471951

19611971

19761981

19861991

19982002

2003

Population of Hong Kong

1894, estimated 30-50% loss of population due to plague

World War II

What can shut down Hong Kong?War / political changes Infectious disease outbreaksWater / food shortage Mass poisoning / pollution

We will change only when we realize that our existence is being threatened. Top on the list is war and infection outbreaks as evident by a marked decrease of population and economic growth during 1894 and the second world war

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List of virus and bacteria named after HK/China discovered at HKU

Viruses:Human SARS coronavirusCivet SARS coronavriusBat SARS coronavirusCoronavirus HKU1Bat coronavirus HKU2 to 9Hokovirus

BacteriaLaribacter hongkongensisStreptococcus sinensisCatabacter hongkongensisEggerthella hongkongensisEggerthella sinensisActinomyces hongkongensisAlkanindiges hongkongensisPaenibacillus hongkongensisSedimentibacterhongkongensisAnaerospora hongkongensis

Through out the years, we tried to name every newly discovered virus and bacteria after HK and China.

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Sequential quantitative RT-PCR for CoV-HKU1 in NPAs and serum IgG titers against N protein of CoV-HKU1

Western blot analysis of purified recombinant CoV-HKU1 N protein

We have discovered another coronavirus in a patient suffering from pneumonia. Again the viral load in the nasopharynx decreases when the antibody goes up. We named it Coronavirus HKU1

Acknowledgement:JIDhttp://www.journals.uchicago.edu/doi/abs/10.1086/497151

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Genome organization of human coronavirus HKU1

J Virol 2004, in press

We have completed the whole genome sequence, cloned and expressed its immunogenic protein.

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Phylogenetic analysis of Coronavirus-HKU1 (CoV-HKU1)

Phylogenetic analysis of S protein of CoV-HKU1-associated pneumonia in 10 patients

Phylogenetic analysis of the Polymerase gene showed that it is another Group 2 coronavirus. We have found another 9 pneumonic patients having this virus with different genotypes. The story will continue. Please look at our publications if you want to know more about our work.

Acknowledgement JIDhttp://www.journals.uchicago.edu/doi/abs/10.1086/497151