Using existing data on the RNA found in different types of cells, the
researchers were able to search for cells that express the two proteins
that help the SARS-CoV-2 virus enter human cells. They found subsets of
cells in the lung, the nasal passages, and the intestine that express
RNA for both of these proteins much more than other cells.
The researchers hope that their findings will help guide scientists
who are working on developing new drug treatments or testing existing
drugs that could be repurposed for treating Covid-19.
"Our goal is to get information out to the community and to share
data as soon as is humanly possible, so that we can help accelerate
ongoing efforts in the scientific and medical communities," says Alex K.
Shalek, the Pfizer-Laubach Career Development Associate Professor of
Chemistry, a core member of MIT's Institute for Medical Engineering and
Science (IMES), an extramural member of the Koch Institute for
Integrative Cancer Research, an associate member of the Ragon Institute,
and an institute member at the Broad Institute.
Shalek and Jose Ordovas-Montanes, a former MIT postdoc who now runs
his own lab at Boston Children's Hospital, are the senior authors of the
study, which appears today in Cell. The paper's lead authors
are MIT graduate students Carly Ziegler, Samuel Allon, and Sarah
Nyquist; and Ian Mbano, a researcher at the Africa Health Research
Institute in Durban, South Africa.
Digging into data
Not long after the SARS-CoV-2 outbreak began, scientists discovered
that the viral "spike" protein binds to a receptor on human cells known
as angiotensin-converting enzyme 2 (ACE2). Another human protein, an
enzyme called TMPRSS2, helps to activate the coronavirus spike protein,
to allow for cell entry. The combined binding and activation allows the
virus to get into host cells.
"As soon as we realized that the role of these proteins had been
biochemically confirmed, we started looking to see where those genes
were in our existing datasets," Ordovas-Montanes says. "We were really
in a good position to start to investigate which are the cells that this
virus might actually target."
Shalek's lab, and many other labs around the world, have performed
large-scale studies of tens of thousands of human, nonhuman primate, and
mouse cells, in which they use single-cell RNA sequencing technology to
determine which genes are turned on in a given cell type. Since last
year, Nyquist has been building a database with partners at the Broad
Institute to store a huge collection of these datasets in one place,
allowing researchers to study potential roles for particular cells in a
variety of infectious diseases.
Much of the data came from labs that belong to the Human Cell Atlas
project, whose goal is to catalog the distinctive patterns of gene
activity for every cell type in the human body. The datasets that the
MIT team used for this study included hundreds of cell types from the
lungs, nasal passages, and intestine. The researchers chose those organs
for the Covid-19 study because previous evidence had indicated that the
virus can infect each of them. They then compared their results to cell
types from unaffected organs.
"Because we have this incredible repository of information, we were
able to begin to look at what would be likely target cells for
infection," Shalek says. "Even though these datasets weren't designed
specifically to study Covid, it's hopefully given us a jump start on
identifying some of the things that might be relevant there."
In the nasal passages, the researchers found that goblet secretory
cells, which produce mucus, express RNAs for both of the proteins that
SARS-CoV-2 uses to infect cells. In the lungs, they found the RNAs for
these proteins mainly in cells called type II pneumocytes. These cells
line the alveoli (air sacs) of the lungs and are responsible for keeping
them open.
In the intestine, they found that cells called absorptive
enterocytes, which are responsible for the absorption of some nutrients,
express the RNAs for these two proteins more than any other intestinal
cell type.
"This may not be the full story, but it definitely paints a much more
precise picture than where the field stood before," Ordovas-Montanes
says. "Now we can say with some level of confidence that these receptors
are expressed on these specific cells in these tissues."
Fighting infection
In their data, the researchers also saw a surprising phenomenon --
expression of the ACE2 gene appeared to be correlated with activation of
genes that are known to be turned on by interferon, a protein that the
body produces in response to viral infection. To explore this further,
the researchers performed new experiments in which they treated cells
that line the airway with interferon, and they discovered that the
treatment did indeed turn on the ACE2 gene.
Interferon helps to fight off infection by interfering with viral
replication and helping to activate immune cells. It also turns on a
distinctive set of genes that help cells fight off infection. Previous
studies have suggested that ACE2 plays a role in helping lung cells to
tolerate damage, but this is the first time that ACE2 has been connected
with the interferon response.
The finding suggests that coronaviruses may have evolved to take
advantage of host cells' natural defenses, hijacking some proteins for
their own use.
"This isn't the only example of that," Ordovas-Montanes says. "There
are other examples of coronaviruses and other viruses that actually
target interferon-stimulated genes as ways of getting into cells. In a
way, it's the most reliable response of the host."
Because interferon has so many beneficial effects against viral
infection, it is sometimes used to treat infections such as hepatitis B
and hepatitis C. The findings of the MIT team suggest that interferon's
potential role in fighting Covid-19 may be complex. On one hand, it can
stimulate genes that fight off infection or help cells survive damage,
but on the other hand, it may provide extra targets that help the virus
infect more cells.
"It's hard to make any broad conclusions about the role of interferon
against this virus. The only way we'll begin to understand that is
through carefully controlled clinical trials," Shalek says. "What we are
trying to do is put information out there, because there are so many
rapid clinical responses that people are making. We're trying to make
them aware of things that might be relevant."
Shalek now hopes to work with collaborators to profile tissue models
that incorporate the cells identified in this study. Such models could
be used to test existing antiviral drugs and predict how they might
affect SARS-CoV-2 infection.
The MIT team and their collaborators have made all the data they used
in this study available to other labs who want to use it. Much of the
data used in this study was generated in collaboration with researchers
around the world, who were very willing to share it, Shalek says.
"There's been an incredible outpouring of information from the
scientific community with a number of different parties interested in
contributing to the battle against Covid in any way possible," he says.
"It's been incredible to see a large number of labs from around the
world come together to try and collaboratively tackle this."
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