Distinct mutations and lineages of SARS-CoV-2 virus in the early phase of COVID-19 global pandemic and subsequent global expansion (preprint)

A novel coronavirus, SARS-CoV-2, has caused over 8538 million cases and over 1.8 1 million deaths worldwide since it occurred twelve months ago in Wuhan, China. Here we first analyzed 4,013 full-length SARS-CoV-2 genomes from different continents over a 14-week timespan since the outbreak in Wuhan, China. 2,954 unique nucleotide substitutions were identified with 31 of the 4,013 genomes remaining as ancestral type, and 952 (32.2%) mutations recurred in more than one genome. A viral genotype from the Seafood Market in Wuhan featured with two concurrent mutations was the dominant genotype (80.9%) of the pandemic. We also identified unique genotypic compositions from different geographic locations, and time-series viral genotypic dynamics in the early phase that reveal transmission routes and subsequent expansion. We also used the same approach to analyze 261,350 full-length SARS-CoV-2 genomes from the world over 12 months since the outbreak (i.e. all the available viral genomes in the GISAID database as of 25 December 2020). Our study indicates the viral genotypes can be utilized as molecular barcodes in combination with epidemiologic data to monitor the spreading routes of the pandemic and evaluate the effectiveness of control measures.

Self-organized stem cell-derived human lung buds with proximo-distal patterning and novel targets of SARS-CoV-2 (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the global COVID-19 pandemic and the lack of therapeutics hinders pandemic control1-2. Although lung disease is the primary clinical outcome in COVID-19 patients1-3, how SARS-CoV-2 induces tissue pathology in the lung remains elusive. Here we describe a high-throughput platform to generate tens of thousands of self-organizing, nearly identical, and genetically matched human lung buds derived from human pluripotent stem cells (hPSCs) cultured on micropatterned substrates. Strikingly, in vitro-derived human lung buds resemble fetal human lung tissue and display in vivo-like proximo-distal coordination of alveolar and airway tissue differentiation whose 3D epithelial self-organization is directed by the levels of KGF. Single-cell transcriptomics unveiled the cellular identities of airway and alveolar tissue and the differentiation of WNThi cycling alveolar stem cells, a human-specific lung cell type4. These synthetic human lung buds are susceptible to infection by SARS-CoV-2 and endemic coronaviruses and can be used to track cell type-dependent susceptibilities to infection, intercellular transmission and cytopathology in airway and alveolar tissue in individual lung buds. Interestingly, we detected an increased susceptibility to infection in alveolar cells and identified cycling alveolar stem cells as targets of SARS-CoV-2. We used this platform to test neutralizing antibodies isolated from convalescent plasma that efficiently blocked SARS-CoV-2 infection and intercellular transmission. Our platform offers unlimited, rapid and scalable access to disease-relevant lung tissue that recapitulate key hallmarks of human lung development and can be used to track SARS-CoV-2 infection and identify candidate therapeutics for COVID-19.