COVID-19 is a transmissible respiratory disease, caused by a novel coronavirus SARS-CoV-2, and has become a global health emergency. There is an urgent need for robust and practical in vitro model systems to investigate viral pathogenesis. In this article, the authors generated human iPSCs-derived lung organoids (LORGs), cerebral organoids (CORGs), neural progenitor cells (NPCs), neurons and astrocytes. LORGs containing epithelial cells, alveolar type 1 and type 2, highly express ACE2 and TMPRSS2 and are permissive to SARS-CoV-2 infection. SARS-CoV-2 infection induces IFNs, cytokines and chemokines and activates critical inflammasome pathway genes. Spike protein inhibitor, EK1 peptide, and TMPRSS2 inhibitors (camostat/nafamostat) block viral entry in LORGs. Conversely, CORGs, NPCs, astrocytes, and neurons express low levels of ACE2 and TMPRSS2 and correspondingly are not highly permissive to SARS-CoV-2 infection. Infection in neuronal cells activates TLR3/7, OAS2, complement system and apoptotic genes. These findings will aid in understanding COVID-19 pathogenesis and facilitate drug discovery.