Experts at Newcastle University have found that all nasal cell types are vulnerable to infection and that some, such as ciliated and secretory cells, support even greater levels of infection.
Profiling the immune response of nasal cells, they found the way the nose lining reacts to the SARS-CoV-2 virus, which causes COVID-19, and the immune response it sets off in the body could determine disease and outcome.
The study, published today in Nature Communications, strengthens the government’s recent move to enforce the use of facemasks on public transport and in shops to try to limit the spread of the virus.
Scientific and clinical importance
Dr. Christopher Duncan, from Newcastle University’s Faculty of Medical Sciences and Honorary Consultant in Infectious Disease at The Newcastle upon Tyne Hospitals NHS Foundation Trust, who led the study, says the findings could help to inform the development of future treatments to prevent infection.
“It is possible that the outcome of the battle between the innate immune system and the virus in the nasal mucosa could be an important determinant of disease and if targeted quickly may help limit infection.”
Scientists used a model of the nasal lining grown from patient nasal biopsy material and used advanced techniques to profile infection and immune responses at the level of single cells.
The team of specialists in immunology, genomics, proteomics and airway biology then measured all the proteins produced in infected cell cultures. They found that nasal cells responded to infection by producing a robust immune response, dominated by antiviral substances known as ‘interferons.”
The study’s findings suggest that the interferon response initiates in the nasal mucosa in the early stages of infection.
Dr. Duncan said: “Interestingly, we saw that the interferon response took longer to get started than in nasal cells infected with other respiratory viruses, such as flu, suggesting that SARS-CoV-2 has ways of subverting this response in the early stages.
“However, once it was established, the interferon response began to hinder the replication of the virus. Consistent with this, when we added interferons before infection, we found that they potently blocked viral replication.
“This opens up the possibility that interferons, which are approved for treatment of other viral infections in patients, could be repurposed to develop interventions, such as a nasal spray, for preventing COVID-19 in certain clinical scenarios. These include helping to protect people who do not respond well to vaccines, or after specific high-risk exposures.”
Experts still do not fully understand what determines the outcome of infection and why some patients become extremely unwell with COVID-19, whereas others are infected without developing symptoms.
Further research will focus on the role of immune cells present in the nose in strengthening the interferon response.
Accumulating evidence indicates that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects not only the epithelial cells of the respiratory tract and lungs, but also epithelial and nonepithelial cells of other organs that express the angiotensin-converting enzyme 2 (ACE2) receptor (1–3).
Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection, has the potential to develop into life-threatening pneumonia. Most patients with COVID-19, however, have mild to moderate symptoms such as fever, cough, or olfactory and gustatory dysfunction because of the involvement of the upper respiratory tracts, including the nasal cavity (4).
Nevertheless, presymptomatic or mildly symptomatic patients with COVID-19 have a high viral load of SARS-CoV-2 in samples taken by nasal swab and show high transmissibility of the virus through respiratory droplets or aerosols (4–7). These findings imply that the human upper respiratory tract and the nasal cavity in particular could be the main site for viral replication and transmission of SARS-CoV-2.
The nasal cavity is lined mostly with pseudostratified ciliated epithelium, interspersed with mucus-secreting goblet cells (8, 9). Thus, the nasal cavity epithelium is covered with a thin layer of mucus with active ciliary movement (10) that ultimately traps and removes pathogens, including SARS-CoV-2, and particulate matter from inspired air. Although this epithelium serves as a front line in respiratory defense against lower airway infection, it also could be a target tissue for infection, multiplication, and propagation of pathogens (11–13). However, the specific cells that are the real targets of SARS-CoV-2 infection and replication in patients with COVID-19 have yet to be identified.
SARS-CoV-2 entry into host cells is mediated through interaction between the virus’s spike protein and the extracellular receptor binding domain of ACE2 (14, 15). Subsequent proteolytic processing by transmembrane serine protease 2 (TMPRSS2), FURIN, and other proteases (15) triggers the fusion of viral and cellular membranes.
Recent reports describe detection by single-cell RNA sequencing (scRNA-Seq) analyses of ACE2 and TMPRSS2 mRNA expression in human respiratory epithelium, including ciliated, goblet, club, alveolar type 1 (AT1), and AT2 cells. However, these expression levels not only are variable depending on cell type but also are relatively moderate or low (16–20). Thus, the specific cell types that coexpress the proteins related to SARS-CoV-2 entry into respiratory epithelium have yet to be clarified.
Although cellular tropism of SARS-CoV-2 has been described based on detection of mRNA using scRNA-Seq or in situ mapping (21, 22), transcript levels in an isolated single cell do not fully reflect the real-world expression and cellular localization of the protein of interest in a tissue (23).
Likewise, in host-virus interactions, the presence of some viral mRNA in a cell does not necessarily mean viral replication. When one or multiple viruses infect a host cell and hijack its machinery for viral RNA synthesis and translation, thousands of new virions can accumulate in the cell, which ultimately bursts, scattering its contents (24).
Thus, although we and others have studied SARS-CoV-2 pathogenesis using various model systems, including 2-dimensional and 3-dimensional organoid cultured bronchial or lung epithelial cells (24–28), direct and clear evidence of SARS-CoV-2 cellular tropism in the human respiratory tract is lacking.
In this study, by combining immunofluorescence staining (IFS) and scRNA-Seq, we delineated the localizations of SARS-CoV-2 entry–related host factors and their relative expression and level in the human nasal epithelium and in a nonhuman primate. In addition, in patients with COVID-19, we used the same methods to define the cellular tropism of SARS-CoV-2 in the human nasal respiratory epithelium.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245175/
More information: Catherine F. Hatton et al, Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2, Nature Communications (2021). DOI: 10.1038/s41467-021-27318-0