Chapter 1 14 SARS-CoV-1, with an interval between exposure to the virus and onset of symptoms of only 3-6 days. This hampered timely identification and isolation of an exponentially growing number of infected individuals, creating a major challenge for public health services. Owing to these unique features, SARS-CoV-2 was not successfully contained by case-finding and isolation measures rolled out during the first months of 2020. The outbreak was declared a pandemic on 11 March 2020[15]. SARS-CoV-2: origins, virology, and clinical presentation Most human coronaviruses (including HCoV-NL63, HCoV-229E and HCoV-OC43) result in mild disease, although complications can occur in infants, the elderly and immunocompromised individuals[16]. Understanding how these coronaviruses and their more virulent relatives, SARS-CoV-1 and MERS-CoV, spilled over into the human population provides important lessons about the zoonotic origin of SARS-CoV-2. For instance, ancestors of HCoV-NL63, HCoV-229E[17], SARS-CoV-1, and MERS-CoV[18] have been identified in bats, suggesting further evolution of these early strains produced viruses capable of infecting humans. Interestingly, evidence from molecular clock analyses and clinical case descriptions suggest that the so-called 1890 Russian influenza pandemic may actually have been caused by a bovine-to-human spill-over of HCoVOC43[19]. Specifically, central nervous system symptoms reported during this pandemic are more in keeping with neurotropism of HCoV-OC43 than the clinical features of influenza. Previous understanding of the spill-over from animals to humans of other human coronavirus has thus helped lay the foundation for research into the origins of SARS-CoV-2[4]. Subsequent in-depth analyses have suggested that individuals working in stalls selling live animals in the Huanan Seafood Market could have been infected through intense exposure to, or subsequent consumption of, infected intermediary hosts[20]. Investment in early molecular and clinical studies generated essential knowledge about SARS-CoV-2. Several studies demonstrated that SARS-CoV-2 binds to the same receptor as SARS-CoV-1 in the respiratory tract, ACE-2[21]. However, the SARS-CoV-2 receptor binding domain (RBD) has distinct structural features that explain the higher affinity of SARS-CoV-2 for ACE-2 compared to SARS-CoV-1[22]. After entering epithelial cells and replicating intracellularly, SARS-CoV-2 infection may present with a wide spectrum of clinical features. Respiratory symptoms may include anosmia/ageusia, rhinorrhoea and sore throat, with or without non-specific systemic features such as fatigue, myalgia and fever. Individuals who develop severe disease (initially estimated to be approximately one-fifth of infected non-immune adults[23, 24]; Figure 1.2) tend to deteriorate
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