The lesson of SARS has taught us that coronaviruses can be the cause of emerging infectious diseases. Researchers all over the world are alerted to this possibility and doing a lot of animal and human sampling for coronaviruses as the cause of emerging infectious diseases. One year after the discovery of the SARS coronavirus, we were consulted to investigate another patient with acute community acquired pneumonia. He is an elderly patient with many underlying medical illnesses. An RT-PCR test for SARS was ordered because he was returning back from the Mainland recently. He has a marked deterioration with fever, cough and purulent sputum and most importantly bilateral lower zone pneumonic consolidation. He has multiple underlying illnesses and his respiratory tract is chronically infected by Pseudomonas. However all the microbiological workup are negative including the RT-PCR test for SARS coronavirus on his nasopharyngeal secretions. But our laboratory decided to walk one more mile, we do a consensus PCR targeting the pol gene, which can detect most coronaviruses. Here it showed a positive band of 440 base pair. DNA sequencing of this band showed that it has 91% amino acid identity and 84% nucleotide identity with the mouse hepatitis virus. We sequenced the whole genome of this novel human respiratory virus, you can see that the novel coronavirus is indeed a new human coronavirus and is distinct from other group 2 coronaviruses. We named this virus as human coronavirus HKU1 after the institution where it is discovered: The University of Hong Kong. Though we do not have an animal model to prove causation, by monitoring the viral load and antibody response against the recombinant nucleoprotein of human coronavirus, HKU1, we showed the viral load peaked before day 7, started to fall by day 10 with concomitant rise of the serum antibody titre. This is just a confirmation of the ELISA antibody testing by western blot analysis at the first, second and third week of illness which again showed that the amount of serum antibody of the patient increases markedly after the infection. Since our discovery of the human coronavirus HKU1, the virus has been found only in human specimens in Europe, United States, Asia, Australia. Most reported a winter seasonality. It varies from 0.3 to 2.7% in terms of detection in upper respiratory specimens. As for clinical diseases, it causes upper and lower respiratory tract illness, and may be associated with seizure, diarrhea, and hepatitis. In adult patients with acute community acquired pneumonia, the mortality can be around 10% in a limited case series. In 2005, we also first identified the bat coronavirus HKU4 in the lesser bamboo bat, which is found in Hong Kong and Southeast Asia. And we also found the bat coronavirus HKU5 in the Japanese pipistrelle bats in Hong Kong. To our surprise, in the first report of the Middle East respiratory syndrome coronavirus in New England Journal of Medicine in 2012, the authors specified that this new coronavirus is most closely related to our bat coronavirus HKU4 and HKU5. In summary, we have presented to you on how we investigate outbreaks caused by two novel coronaviruses. We start with the clinical investigation by history taking, physical examination and routine laboratory testing to determine if the disease is infectious or non-infectious in origin; If it is an infectious syndrome with negative tests for known microbes, we enhanced our laboratory investigation for novel viruses, bacteria, fungus, parasites. Once we find the novel microbe, we do phenotypic and genomic characterization of this novel microbe so that we can design more rapid and accurate laboratory tests to determine the association between the microbe and the disease using case control studies. But the final proof of causation depends on the satisfaction of the Koch’s postulates in animal models. Remember the ultimate control of an epidemic depends on the control at the source. 75% of emerging infectious diseases come from animals. Therefore, the control of emerging infectious disease outbreaks warrants detective work at hospitals, markets, farms and the wild. Thank you for your attention.