Opinion on Professor Mark Krasnow’s Seminar
The lung has millions of gas exchange sites known as alveoli which branch out and interweave with a dense capillary network. Professor Mark Krasnow’s work in profiling human lungs using single cell technology is paving a new path in understanding how our body responds to respiratory diseases and viruses. His talk overviewed the details of the human gaseous exchange ecosystem and the delicate balance of cell types that are tipped by cancers and viral infections.
As Prof. Krasnow remarked, his friend was undergoing a procedure to remove cancerous lung tissue and asked if there was anything he can do with it. This serendipitous event initiated the human lung cell atlas project that identified 58 lung cell types and states including 14 novel cell types. The bulb shaped alveolus is bordered by alveolar type I cells (alv1) and kept intact by a coat of surfactant made by supporting alveolar type II cells (alv2). The space between the epithelial layer of the alv1 and the capillaries circling the alveolus is the essential space of the organ. The alv1 cells are the major site for pulmonary diseases such as bronchial pulmonary dysplasia and chronic obstructive pulmonary disease. A surprising and unrelated function of the alv2 cell discovered in mice is its ability to differentiate into both alveolar cell types to maintain the alveolus. A mutation in this pathway is oncogenic leading to unrestricted proliferation. Interestingly, they also found that the capillary cells lining the alveolus have a similar relationship. Similar to oncogenesis, capillary cells and alv2 cells battle between replenishing and dying due to viral infections.
Coronaviruses primarily target the lung and cause breaches in the alveolar space resulting in acute respiratory syndrome and pneumonia. At this stage the virus compromises the gCap and alv2 cells and causes systemic spread and immune cell invasion into the lung. Using human lung tissue slices maintained in cell culture, Prof. Krasnow developed a model to study early stages of lung tissue infection by introducing viruses into the culture medium followed by single cell transcriptome profiling in BSL3 conditions. Leveraging the data from the lung atlas project as a standard, they have successfully maintained gene expression and recovered all 58 lung cell types in this novel in-vitro model. They also found an interesting Jackpot effect where 1% of the cells contains between 10-10,000 viral RNA, while majority of the other cells are unaffected. Of these cells is the alveolar macrophage, which Prof. Krasnow suggested was used by the virus to invade and infect other lung cell types.
Prof. Krasnow’s seminar was a fascinating insight into the host epicentre of respiratory viruses. In my opinion, his work highlights the power of single cell technology in understanding the progression of viral infections and uncovering relationships between cell types. It paves the path towards finding novel biomarkers and early-stage drug targets in respiratory viruses. I personally like his in-vitro model because it has the potential to showcase the early stages in viral infection progression in human tissue. This model can be further expanded to study the effect of therapeutics and as a system to functionally validate research on other respiratory diseases and cancers. Overall, his seminar brought to light the significant contributions of single cell technology and the advantages of understanding cell type relationships in the context of cancers and viral infections progression.
References
Gillich, A., Zhang, F., Farmer, C.G. et al. Capillary cell-type specialization in the alveolus. Nature 586, 785–789 (2020). https://doi.org/10.1038/s41586-020-2822-7
Desai, T. J., Krasnow, M. A., Harbury, P. B., Brownfield, D. G., & Nabhan, A. N. (2018). Single-cell wnt signaling niches maintain stemness of alveolar type 2 cells. Science, 359(6380), 1118-1123. doi:10.1126/science.aam6603
