Coronavirus infection in the nose and lung - clues to COVID-19 variability
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects cells of the respiratory system resulting in coronavirus disease 2019 (COVID-19). The clinical presentation and severity of COVID-19 vary widely with the majority of patients exhibiting no or mild symptoms indicative of an infection in the upper airways (nose and throat). Some patients exhibit symptoms of infection in the lung, including potentially fatal pneumonia and respiratory distress. Severe COVID-19 outcomes are especially prevalent in the elderly and individuals with comorbidities such as diabetes and high blood pressure.
A lot is still unknown about SARS-CoV-2, including:
How SARS-CoV-2 enters the lung
Why there is such high variability in the severity and presentation of COVID-19 symptoms between patients
Why people with comorbidities are more likely to develop severe COVID-19 symptoms
Scientists at UNC-Chapel Hill sought to answer these questions by determining which cells SARS-CoV-2 preferentially infects along the respiratory tract.
Main Findings
To cause infection, SARS-CoV-2 enters a human cell by binding to a protein on the cell surface, called the ACE2 receptor. Hou et al first analyzed the expression patterns of ACE2 and hypothesized that the amount of ACE2 would correlate with the ability of SARS-CoV-2 to establish an infection. They found that in healthy individuals, ACE2 was more abundant in the nose compared to the lung, specifically in epithelial cells, which line the surfaces of the airway. This suggests that SARS-CoV-2 would be more likely to infect epithelial cells from the nasal passage compared to the lung.
The researchers next analyzed whether there was a relationship between the amount of ACE2 and the efficiency of SARS-CoV-2 infection. To visualize infection, SARS-CoV-2 was labeled with a fluorescent dye and incubated with cells isolated from different regions of the respiratory tract. Consistent with ACE2 levels, SARS-CoV-2 infectivity was higher in nasal epithelial cells compared to lung epithelial cells isolated from the bronchioles. Pneumocytes - cells that line the alveoli or air sacs deep within the lung - were also infected, although to a lesser extent than nasal and bronchial epithelial cells. Analysis of lungs isolated from COVID-19 deceased patients also demonstrated infection primarily in the epithelial cells and pneumocytes.
How does SARS-CoV-2 enter the lung?
As there was a relatively low amount of ACE2 receptor in the lung, as well as relatively poor SARS-CoV-2 infectivity, the researchers hypothesize that the virus is not breathed directly into the lung. Instead, they conclude that SARS-CoV-2 (1) first establishes infection in the nose. (2) Following this initial infection, the virus then enters nasal secretions, which can be swept into the lung via a process known as aspiration. Analysis of lungs from lethal COVID-19 patients demonstrated a patchy infection pattern that is consistent with delivery by aspiration and not direct inhalation of air.
Why are the severity and pathogenesis of COVID-19 so variable?
The incidence and severity of lower lung disease are highly variable among COVID-19 patients. Based on findings from the current study, some patients may be more prone to aspiration than others, allowing higher amounts of the virus to enter the lung and establish an infection. Additionally, the levels of ACE2 within the nose and lung varied between donors. Patients with higher levels of ACE2 may be more permissive for SARS-CoV-2 infection resulting in severe outcomes. In support of this hypothesis, the efficiency of SARS-CoV-2 infection also exhibited variability between cells isolated from different donors, especially in the lung. However, future studies are needed to analyze the distribution of the virus and ACE2 receptor within actual COVID-19 patients and how this correlates with disease severity.
Why are people with comorbidities more susceptible to severe COVID-19 outcomes?
Those at higher risk for severe COVID-19 outcomes - including the elderly, obese, and diabetics - are more prone to robust aspiration, which may transmit higher levels of the virus to the lung contributing to enhanced severity in these patients.
Patients with pre-existing lung disease, such as cystic fibrosis (CF), are also at increased risk for severe outcomes. Interestingly, this study found increased ACE2 levels in lung tissue from CF patients compared to healthy donors. This suggests that SARS-CoV-2 may have higher infectivity in the lungs of CF patients as the ACE2 receptor is higher, although this needs to be studied directly. Although it is unknown why ACE2 is higher in CF patients, this study found that inflammatory mediators that are found in CF secretions, including IL-1β, upregulated ACE2 on airway epithelial cells.
These findings have interesting implications for other comorbidities, such as diabetes and high blood pressure which are commonly treated with ACE inhibitors. ACE inhibitors increase ACE2, which may facilitate enhanced viral entry into the lung and more severe disease outcomes (Fang, 2020). Therefore, it may be important to reconsider the use of ACE inhibitors during the current pandemic. However, further studies are needed to test this hypothesis.
Big picture - wear a mask!
As the virus may initially infect the nose, it is important to keep your nasal cavity covered when in public. Additionally, treatments targeted specifically to the nose may be worth considering early in infection.
Reference:
Hou YJ, Okuda K, Edwards CE, et al. SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract. Cell. Published online 2020. doi:10.1016/j.cell.2020.05.042