'Hotspots' of a coronavirus infection in the human body
Researchers identify new possible entry points for SARS-CoV-2 into human bodies

Date:
September 3, 2020
Source:
DZNE - German Center for Neurodegenerative Diseases
Summary:
An infection with the coronavirus SARS-CoV-2 can affect multiple
organs.

Researchers have investigated cellular factors that could be
significant for an infection. They analyzed the activity of 28
specific genes in a wide range of human tissues.



FULL STORY ==========================================================================
An infection with the coronavirus SARS-CoV-2 can affect multiple
organs. With this in mind, researchers of the German Center for Neurodegenerative Diseases (DZNE) and Cornell University in the US
have investigated cellular factors that could be significant for an
infection. To this end, they analysed the activity of 28 specific genes
in a wide range of human tissues. Their findings, which provide a map of potentially disease-relevant factors across the human body, are published
in the journal Cell Reports.


========================================================================== "SARS-CoV-2 not just infects the respiratory system, it has the potential
to affect many other organs in the body. Even if the virus infects the respiratory system first, it is essential to be able to predict where
it might go next.

This aids to develop therapies. Our goal was thus to learn more about what makes the different organs susceptible to infection," explained Dr. Vikas Bansal, a data scientist at the DZNE's Tuebingen site. "Therefore, we
looked at different tissues to see which components of the cellular
machinery might be relevant for infection and also which cell types
appear to be particularly susceptible." Bansal co-authored the current
paper with Manvendra Singh, a Cornell presidential fellow, and with
Cedric Feschotte, professor in the Department of Molecular Biology and
Genetics at the Cornell University.

Searching candidates In cooperation with his US colleagues, Bansal
started by identifying 28 human genes, respectively cellular factors,
that enable the virus to enter human cells or that might otherwise be
important for an infection. In addition to receptors on the cell surface,
these included, for example, proteins that the pathogen presumably needs
in order to multiply within a cell. Importantly, the list of studied
factors also contains enzymes that block the penetration of pathogens
into cells -- known as "restrictors factors." In summary, the 28 analysed cellular features are dubbed "SCARFs" for "SARS-CoV-2 and coronavirus associated receptors and factors." "The virus is known to misuse the
so-called ACE2 receptor, which occurs on the surface of human cells,
to dock and infiltrate them. A lot of attention is therefore paid to
this receptor and other factors associated with it. They are potential
starting points for therapies," said Bansal. However, related corona
viruses are known to use a broad range of possibilities to infect cells.

According to the researcher, evidence suggests that this also applies
to SARS- CoV-2. "Therefore, we have extended our analysis to cellular
factors that have been found to be relevant in other corona viruses
and may therefore also be important for SARS-CoV-2." Whether this is
actually the case, future experiments will have to show, explained
Bansal. For such investigations, he said, the aim was to identify
promising candidates. "Our study is only a snapshot, however. Research
is developing rapidly. We are constantly learning new facts about this
virus." Profiles of gene activity Using information from scientific
databases, the researchers analysed gene activity -- also known as
"expression patterns" -- in around 400,000 human cells from various
types of tissue. These included nasal mucosa, lungs, gut, kidneys,
heart, brain and reproductive organs. Analysis was done on a single-
cell level and using sophisticated bioinformatics methods. "This enabled
us to investigate in which cells the SCARFs are expressed and also what percentage of cells within a given tissue express these factors," said
Bansal. "Our results are certainly limited by the fact that expression
patterns can change in the course of an infection and that such activity profiles do not directly reflect the abundance of proteins such as
cell receptors. However, expression patterns are good indicators." Battlegrounds and hotspots In line with the known fact that SARS-CoV-2
attacks in particular the respiratory tract, the expression patterns
identify the nasal mucosa as a "battleground." Accordingly, cells of
the nasal mucosa contain both factors that facilitate infection like the
ACE2 receptor as well as factors that inhibit viral entry, like IFITM3
and LY6E. "IFITM3 is a protein known to prevent other coronaviruses from crossing the cell membrane. Same might also apply to SARS-CoV-2. LY6E also
acts as a defensive mechanism," said Bansal. "It thus seems that contact
of the virus with the nasal mucosa leads to a tug-of- war. The question therefore is, who will emerge as the winner. Interestingly, our data
suggest that the expression level of entry factors in the human nasal
tissue shift with age. This could be a reason why the elderly are more susceptible to infection by SARS-CoV-2." According to the current study,
the intestine, kidneys, testes and placenta are potential hotspots, that
is, these areas seem to be characterized by significant co-expression of
ACE2 with TMPRSS2, an enzyme involved in viral entry in combination with
ACE2. "We were also able to identify a number of cellular factors that, as alternatives to the ACE2 receptor, could contribute to SARS-CoV-2 entering
the lungs, heart and central nervous system," said Bansal. "SARS-CoV-2 is
by now known to be able to trigger neurological disorders. Although the
virus has not yet been detected in neurons, the nervous system includes
other cells such as astrocytes and pericytes that are for example
involved in the regulation of the blood-brain barrier, which is the
interface between the brain and the bloodstream. According to our study
these cells might well be susceptible to infection. This could possibly
involve a receptor called BSG. All in all, our study therefore provides a wealth of data and specific clues for future studies on the coronavirus."

========================================================================== Story Source: Materials provided by DZNE_-_German_Center_for_Neurodegenerative_Diseases.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Manvendra Singh, Vikas Bansal, Ce'dric Feschotte. A single-cell RNA
expression map of human coronavirus entry factors. Cell Reports,
2020; 108175 DOI: 10.1016/j.celrep.2020.108175 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200903105555.htm

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