The body's antiviral response to initial infection may define the course of severe COVID-19, opening up new pathways for early pharmacological therapies that could prevent severe disease.
Researchers from the Massachusetts Institute of Technology (MIT) and Harvard University in the United States investigated if the path to severe sickness could begin much earlier than previously thought, possibly even during the initial response to the virus when it enters the nose.
They compared patients who developed moderate COVID-19 to those who proceeded to more severe disease and finally required respiratory support, using cells collected from nasal swabs taken at the time of their first COVID-19 diagnosis.
Patients who went on to develop severe COVID-19 had a substantially more muted antiviral response in cells obtained from early swabs than patients who had a moderate course of the disease, according to the findings, which were reported in the journal Cell.
"Our findings suggest that the course of severe COVID-19 may be determined by the body's intrinsic antiviral response to initial infection, opening up new avenues for early interventions that could prevent severe disease," said study co-senior author Jose Ordovas-Montanes, from Harvard Medical School.
To understand the early response to infection, the team collected nasal swabs from 58 people.
Thirty-five swabs came from COVID-19 patients, taken at the time of diagnosis, representing a variety of disease states from mild to severe.
Seventeen swabs came from healthy volunteers and six came from patients with respiratory failure due to other causes.
The team isolated individual cells from each sample and sequenced them, looking for RNA that would indicate what kind of proteins the cells were making -- a proxy for understanding what a given cell is doing at the moment of collection.
Cells use RNA as instructions to make proteins -- tools, machinery, and building blocks used within and by the cell to perform different functions and respond to its environment.
By studying the collection of RNA in a cell -- its transcriptome -- researchers understand how a cell is responding, at that particular moment in time, to environmental changes such as a viral infection.
Researchers can even use the transcriptome to see if individual cells are infected by an RNA virus-like SARS-CoV-2.
First, the team found that the antiviral response, driven by a family of proteins called interferons, was much more muted in patients who went on to develop severe COVID-19.
Second, patients with severe COVID-19 had higher amounts of highly inflammatory macrophages, immune cells that contribute to high amounts of inflammation, often found in severe or fatal COVID-19.
Since these samples were taken well before COVID-19 had reached its peak state of disease in the patients, both these findings indicate that the course of COVID-19 may be determined by the initial or very early response of the nasal epithelial and immune cells to the virus.
The lack of a strong initial antiviral response may allow the virus to spread more rapidly, increasing the chances that it can move from the upper to lower airways, while the recruitment of inflammatory immune cells could help drive the dangerous inflammation in severe disease.
The team also identified infected host cells and pathways associated with protection against infection -- cells and responses unique to patients that went on to develop mild disease.
These findings may allow researchers to discover new therapeutic strategies for COVID-19 and other respiratory viral infections.