US Pharm. 2020;45(5):31-34.
Researchers from the Massachusetts Institute of Technology (MIT) and Harvard, with assistance from colleagues from around the world, have identified specific cell types that appear to be targets of the coronavirus.
Employing existing data on the RNA found in different types of cells, the researchers searched for cells that express the two proteins that help the COVID-19 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 in other cells. The scientists 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,” explained Alex K. Shalek, the Pfizer-Laubach career development associate professor of chemistry at MIT. Dr. Shalek and Jose Ordovas-Montanes, a former MIT postdoc who now runs his own laboratory at Boston Children’s Hospital, are the senior authors of the study, which appeared 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.
Not long after the COVID-19 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 penetrate 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,” Dr. Ordovas-Montanes said. “We were really in a good position to start to investigate which are the cells that this virus might actually target.”
In the nasal passages, the researchers found that goblet secretory cells, which produce mucus, express RNAs for both of the proteins that COVID-19 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, the scientists 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.
The researchers also observed 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,” Dr. Ordovas-Montanes said. “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; on the other hand, it may provide extra targets that help the virus infect more cells.
Dr. Shalek 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 COVID-19 infection.
