Researchers from Hans Clevers ‘group in collaboration with Bart Haagmans’ group (Erasmus MC) have set up an organoid biobank to search for genes essential for the spread of SARS-CoV2 infection. Their study was published in Nature Communications on September 17 and highlights the utility of organoids for basic coronavirus research, as well as highlighting potential drug targets.
Organoids are tiny 3D structures made from stem cells that mimic how organs work. Researchers have already succeeded in developing organoid models for various organs, including the intestine, lungs, uterus, and even the snake venom gland. Organoids have been shown to be useful for diagnostic purposes, predicting therapeutic responses in patients and revealing secrets about the development of rare tissue and cell types.
Researchers can add levels of complexity to organoid cultures for specific purposes. They can, for example, add immune cells to tumor organoids to study the effectiveness of therapy, or inject pathogens into organoids to model their effect on cells. The latter approach has recently been used to model coronavirus infections in human cells. One of the key questions about the coronavirus – and viruses in general – is what factors it uses to enter human cells and replicate. These so-called host factors could be attractive drug targets to influence viral replication and spread.
Intestinal organoid biobank
To learn more about host factors that are particularly important for the replication and spread of coronaviruses, the groups of Hans Clevers and Bart Haagmans have developed a biobank of mutant intestinal organoids. This means that organoids, which mimic the biology of the gut, contained various mutations in host factors that were previously found to be relevant to coronaviruses. These mutations cause changes in the activity of factors in the host.
TMPRSS2 as a therapeutic target
Therefore, the researchers injected the mutant organoids with SARS-CoV-2 – the virus responsible for COVID-19 – to study the effect of the mutations on the replication and spread of the virus. Among other things, they identified the TMPRSS2 gene to be involved in this process: organoids with non-functional TMPRSS2 showed reduced replication and spread of the virus. This gene could therefore be an attractive therapeutic target for this coronavirus. Specific inhibitors of TMPRSS2 have recently been developed.
Relevance of human models
Previously, studies used animal cell lines (especially the African green monkey) to identify therapeutic targets for the coronavirus. These cell lines are easy to use, but do not completely summarize the biology of human target cells for SARS-CoV-2. This is exemplified by the antimalarial drug Chloroquine, which has been shown to be effective against SARS-CoV-2 infection in these cell lines, but has been shown to be ineffective in clinical trials with patients. This indicates that cell lines cannot sufficiently predict the efficacy of therapy in humans. When repeating the chloroquine experiments using the mutant organoids instead of previously used cell lines, the research groups observed no therapeutic effect. In other words, the results in organoids were similar to results from clinical trials, suggesting that – compared to animal cell lines – organoids may be better suited to predict the efficacy of therapy in humans.
With their study, published in Nature Communications, the groups of Hans Clevers and Bart Haagmans highlight the relevance of organoids for research on coronaviruses. In addition, they identify TMPSS2 as a potential therapeutic target for SARS-CoV2. Their new biobank could also help screen for future emerging viruses to quickly identify therapeutic targets.
Beumer, J., et al. (2021) Genetically engineered CRISPR / Cas9 organoid biobank reveals essential host factors for coronaviruses. Natural communications. doi.org/10.1038/s41467-021-25729-7.