In the post-SARS era, CoV research was brought back to the limelight and more effort was put into the search for novel HCoVs. The search was fruitful and two new HCoVs were identified in human samples positive for HCoV but not for SARS-CoV. NL63 and HKU1 were first isolated from a child suffering from bronchiolitis and a patient with pneumonia, respectively [14,15]. HKU1 is difficult to culture and can only be propagated in primary human airway epithelial cells cultured at the air–liquid interface. Similar to 229E and OC43, NL63 and HKU1 were found worldwide, causing mild respiratory diseases. Particularly, NL63 infection was associated with virus-induced croup in children [16]. All these four viruses are community-acquired HCoVs that are well adapted to humans. Only in rare cases, they might be accidentally mutated to cause more severe lower respiratory tract disease. For example, a subtype of NL63 was recently found to be associated with severe lower respiratory tract infection in China [17].