When organoids meet coronaviruses
Assessing potential coronavirus drug targets in organoids

Date:
September 17, 2021
Source:
Hubrecht Institute
Summary:
Researchers established an organoid biobank to search for the genes
that are essential for the spreading of a SARS-CoV2 infection. Their
study highlights the usefulness of organoids for basic research
into coronaviruses, as well as highlighting potential drug targets.



FULL STORY ========================================================================== Researchers from the group of Hans Clevers in collaboration with the
group of Bart Haagmans (Erasmus MC) established an organoid biobank to
search for the genes that are essential for the spreading of a SARS-CoV2 infection. Their study was published in Nature Communications on 17
September and highlights the usefulness of organoids for basic research
into coronaviruses, as well as highlighting potential drug targets.


========================================================================== Organoids are tiny 3D structures grown from stem cells that mimic organ function. Researchers have previously succeeded in developing organoid
models for various organs, including the gut, lung, uterus and even
the snake venom gland. The organoids have proven useful for diagnostic purposes, predicting therapy responses in patients and unlocking secrets
about the development of tissues and rare cell types.

Host factors Researchers can add levels of complexity to the organoid
cultures for specific purposes. They can for example add immune cells
to tumor organoids to study the efficacy of therapy, or inject pathogens
into organoids to model their effect on the 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 appealing drug targets to influence
viral replication and -spreading.

Biobank of intestinal organoids To find out more about the host factors
that are specifically important for the replication and spreading of coronaviruses, the groups of Hans Clevers and Bart Haagmans developed a
biobank of mutant intestinal organoids. This means that the organoids,
that mimic the biology of the intestine, contained various mutations
in the host factors that were previously discovered to be relevant for coronaviruses. These mutations cause changes in the activity of the
host factors.

TMPRSS2 as therapeutic target Consequently, 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 spreading
of the virus. Among other things, they identified the gene TMPRSS2 to be involved in this process: organoids with non-functioning TMPRSS2 showed
reduced replication and spreading of the virus. This gene may therefore
be an attractive therapeutic target for this coronavirus. Specific
inhibitors for TMPRSS2 have recently been developed.

Relevance of human models Previously, studies used cell lines of animals
(most importantly, of the African green monkey) to identify therapeutic
targets for the coronavirus.

These cell lines are easy to work with, but do not fully recapitulate the biology of human cells that are targets of SARS-CoV-2. This is illustrated
by the anti-malaria drug Chloroquine, which was found to be effective
against SARS-CoV-2 infection in these cell lines, butturned out to be ineffective in clinical trials with patients. This indicates that the
cell lines cannot sufficiently predict the effectiveness of therapeutics
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 the results in clinical trials, suggesting that -- compared to animal cell lines --
the organoids could be better suited to predict the effectiveness of therapeutics in humans.

Future viruses With their study, published in Nature Communications,
the groups of Hans Clevers and Bart Haagmans underscore the relevance of organoids for research into coronaviruses. Furthermore, they identify
TMPSS2 as a potential therapeutic target for SARS-CoV2. Their newly
developed biobank could also aid in screening future emerging viruses
to rapidly identify therapeutic targets.

========================================================================== Story Source: Materials provided by Hubrecht_Institute. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Joep Beumer, Maarten H. Geurts, Mart M. Lamers, Jens Puschhof,
Jingshu
Zhang, Jelte van der Vaart, Anna Z. Mykytyn, Tim I. Breugem, Samra
Riesebosch, Debby Schipper, Petra B. van den Doel, Wim de Lau,
Cayetano Pleguezuelos-Manzano, Georg Busslinger, Bart L. Haagmans,
Hans Clevers. A CRISPR/Cas9 genetically engineered organoid
biobank reveals essential host factors for coronaviruses. Nature
Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-25729-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210917090428.htm

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