Whether Someone Gets Severe COVID-19 Could Be Determined By A Battle In the Nose and Throat


The Context: One of the major challenges we face in treating COVID-19 is that we still do not have effective ways of determining whether someone will develop a severe case or not. Gaining a better understanding of what influences disease severity early on in infection could inform preventative measures to protect those most vulnerable.

The Study: People who develop severe COVID-19 have blunted antiviral responses in the nasopharynx, finds a new study in Cell by NYSCF – Robertson Stem Cell Investigator José Ordovás-Montañés, PhD, of Boston Children’s Hospital.

Why it Matters: This study points to a possible reason why some people experience severe COVID-19 and could help to develop preventive treatments against it, like nasal sprays for patients to take early on in infection.

“Why some people get more sick than others has been one of the most puzzling aspects of this virus from the beginning,” said Dr. Ordovás-Montañés in a press release. “Many studies looking for risk predictors have looked for signatures in the blood, but blood may not really be the right place to look.”

A Deeper Dive into the Nose and Throat

The first place the SARS-CoV-2 virus infects the body is in the nose and throat (nasopharynx). The team of researchers – co-led by Bruce Horwitz, MD, PhD, of Boston Children’s, Alex K. Shalek, PhD, of MIT and Sarah Glover, DO, of the University of Mississippi – examined nasal swabs from 35 adults who were infected with COVID-19 between April and September of 2020, and who had experienced mildly symptomatic to critically ill disease. They also studied swabs from 17 healthy controls and six patients who were intubated but did not have COVID-19.

The scientists used a technique called single-cell RNA sequencing to examine RNA (genetic material that makes proteins) in cells on the nasal swabs, looking at which cell types were present, which appeared to be infected with the virus, and which genes had turned on or off in response to infection.

The team found that when cells lining the nose and throat – called epithelial cells – encounter the SARS-CoV-2 virus, the nasopharynx begins making more mucus-producing cells and losing its mature ciliated cells, which clean the airways. It seems that the nasopharynx then tries to compensate by making new ciliated cells, as the scientists found many immature ciliated cells in the swabs.

Importantly, many cell types were actively infected by SARS-CoV-2, and when they were, they turned on genes that help kickstart immune defense processes.

Blunted Immune Responses Lead to Severe COVID-19

The team then turned their attention to differences between patients who experienced mild or moderate COVID-19 and those who had severe disease.

The study revealed that in people with mild or moderate COVID-19, cells switched on genes designed to boost antiviral responses. They did this especially in response to type 1 interferon: a protein that signals cells that invaders are present.

In patients with severe COVID-19, however, antiviral responses were decreased. Even though the cells were carrying large amounts of the virus, the cells weren’t responding to the interferons in the same way as patients with mild or moderate COVID-19. Swabs from patients with severe COVID-19 also showed increased numbers of immune cells that boost inflammatory responses.

“Everyone with severe COVID-19 had a blunted interferon response early on in their epithelial cells, and were never able to ramp up a defense,” noted Dr. Ordovás-Montañés. “Having the right amount of interferon at the right time could be at the crux of dealing with SARS-CoV-2 and other viruses.”

Boosting Defenses in the Nasopharynx

“It’s likely that, regardless of the reason, people with a muted interferon response will be susceptible to future infections beyond COVID-19,” remarked Dr. Ordovás-Montañés. “The question is, ‘How do you make these cells more responsive?'”

The team plans to further investigate why these cells show decreased immune responses, expanding their studies to include newer variants of the virus as well. They will also explore whether treatments such as nasal sprays or drops could boost interferon responses, helping people with early COVID-19 avoid severe disease.

Journal article:

SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues

Carly G K Ziegler, Samuel J Allon, Sarah K Nyquist, Ian M Mbano, Vincent N Miao, Constantine N Tzouanas, Yuming Cao, Ashraf S Yousif, Julia Bals, Blake M Hauser, Jared Feldman, Christoph Muus, Marc H Wadsworth, Samuel W Kazer, Travis K Hughes, Benjamin Doran, G James Gatter, Marko Vukovic, Faith Taliaferro, Benjamin E Mead, Zhiru Guo, Jennifer P Wang, Delphine Gras, Magali Plaisant, Meshal Ansari, Ilias Angelidis, Heiko Adler, Jennifer M S Sucre, Chase J Taylor, Brian Lin, Avinash Waghray, Vanessa Mitsialis, Daniel F Dwyer, Kathleen M Buchheit, Joshua A Boyce, Nora A Barrett, Tanya M Laidlaw, Shaina L Carroll, Lucrezia Colonna, Victor Tkachev, Christopher W Peterson, Alison Yu, Hengqi Betty Zheng, Hannah P Gideon, Caylin G Winchell, Philana Ling Lin, Colin D Bingle, Scott B Snapper, Jonathan A Kropski, Fabian J Theis , Herbert B Schiller, Laure-Emmanuelle Zaragosi, Pascal Barbry, Alasdair Leslie, Hans-Peter Kiem, JoAnne L Flynn, Sarah M Fortune, Bonnie Berger, Robert W Finberg, Leslie S Kean, Manuel Garber, Aaron G Schmidt, Daniel Lingwood, Alex K Shalek, Jose Ordovas-Montanes. Cell. 2021. DOI: 10.1016/j.cell.2020.04.035

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