Popularization of research advances on COVID-19

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A three-dimensional multicellular structure to study COVID-19

Numerous clinical trials are currently taking place to prevent or cure pneumonias caused by SARS-CoV-2. In parallel, pre-clinical research is essential in order to better understand the details of this illness, and also to identify new therapeutic targets.

In order to do this, models reproducing the cycle of infection and the complex physiopathology of COVID-19 are necessary. In vivo models use animals that are some way removed from humans (mice, hamsters, ferrets and cats) as well as those closer to humans, such as macaques. While the latter give the best indications of overall host-virus interaction, their use is limited, not only for ethical reasons but also because of their low levels of reproduction. Experiments on entire lungs, from deceased donors, are rare for obvious reasons of availability. In vitro models that use human cells from the respiratory epithelium expressing the ACE2 receptor (which allows the virus to enter cells) are more practical. But models of primary cells (from patients, and unmodified) reproduce slowly and in limited numbers, whereas modified lines, widely used in laboratories, are not suitable for studies of this infection.

However organoids are harvested cells which are then reworked in the laboratory. They are three-dimensional and composed of several cell types, reproducing the micro-anatomy of a human organ. They are capable of reproducing and so are the alternative model of choice for imitating physiological conditions.

As shown in the following diagram :

How are they obtained ?

The distal lung environment, principally targeted by SARS-CoV-2, is composed of terminal bronchioli and alveoli where gaseous interaction with the blood takes place. In certain patients, this infection brings about acute respiratory distress syndrome, though we are not sure how.

However, researchers at the University of Stanford have managed to create human pulmonary organoids by using primary stem cells derived from alveolar epithelial cells AT2 (pneumocytes) and basal KRT5+ (for maintenance of pseudostratified epithelium). The AT2 pneumocytes renew themselves efficiently and differentiate into AT1 cells to mimic the epithelium lining the alveoli. The basal cells differentiate into hair cells and bronchiole cells. The whole reorganises itself to form a complex polarised environment with microvilli and apical junctions which imitate the exterior lung surface. These organoids therefore provide a very satisfactory replica of the natural lung environment.

How do these organoids react to the virus?

Around 10% of the basal and  epithelial organoid cells are infected by SARS-CoV-2 due to the ACE2 receptor apical expression, just as in natural lungs. This system has also shown infection by the H1N1 flu virus to be inhibited by the nucleoside analogue Fdc.

However, and unexpectedly, the bronchiole cells could be a new target for the virus, damaging the production of the protective lining of lung tissues (glycosaminoglycans) and thereby stimulating the infection cycle.

These organoids are therefore suitable for use in research on antiviral compounds, even if their bronchiolotic compounds overreact. This new model, viable over the long term and simple to cultivate, could also allow study of other infectious lung diseases, interstitial or neoplastic, as well as finding application in precision medicine.

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