The World Health Organization reports that respiratory infections are responsible for the deaths of 15% of children under the age of five. Children are most frequently infected with human metapneumovirus. This virus accounts for approximately 16% of childhood acute respiratory infections worldwide, and by the age of five, almost all people have already been infected with it. However, humans do not develop long-lasting immunity to this virus, which leads to frequent reinfections. In adults, metapneumovirus infection causes lower respiratory tract complications in about 3% of cases and, in 1% of cases, results in death. The virus is especially dangerous for individuals with weakened immune systems.

Like other respiratory viruses, metapneumovirus primarily infects the body through the nasal epithelium. However, the mechanisms by which the antiviral defense of the nasal mucosa is activated remain insufficiently understood.

In 2025, American researchers examined how the nasal immune landscape changes during metapneumovirus infection. The study showed that nasal epithelial cells weakly activate their own antiviral defences even under high viral load, whereas nasal type I interferon (IFN-I) restores the nasal immune landscape 7–10 days after infection and accelerates viral clearance. These findings indicate that IFN-I on the mucosal surface is a key factor in maintaining antiviral defence in the nose.

Comparative Dynamics of Viral Replication in the Nose and Lungs

Researchers compared viral replication rates in different parts of the respiratory system. To do this, they infected mice with a highly contagious strain of metapneumovirus using two approaches:

  • One group of mice received infection directly into the trachea to model acute lower respiratory tract infection.
  • The other group was infected only through the nasal epithelium.

It was found that the number of viral particles in the nose increases continuously over the first 12 hours after infection. For comparison, the number of viral particles in the lungs reaches its peak after only 6 hours.

Further observation showed that, in the absence of treatment, the virus is completely cleared from the lungs by day 7, whereas in the nose it is removed only by day 10.

Based on these data, researchers hypothesized that the immune response of the nasal mucosa to metapneumovirus infection is significantly weaker than that in the lower respiratory tract. In subsequent experiments, they aimed to identify the causes of such a weak immune reaction.

Innate Antiviral Defense of the Nasal Mucosa Is Weakly Activated Even Under High Viral Load

Researchers monitored changes in the levels of protein markers of the inflammatory response during pathogen invasion. As in the previous experiment, the lower respiratory tract showed increased levels of signalling pro-inflammatory proteins after infection, whereas the nose maintained minimal levels despite a high viral load.

Next, the researchers assessed the relationship between this stable immune environment in the nose and the synthesis of type I interferon by epithelial cells. They focused specifically on IFN-I because previous studies had shown that this interferon is critical for activating the body’s antiviral defences and clearing the virus.

Researchers observed low or undetectable levels of IFN-I on the nasal mucosa. This remained true up to day 7 after infection. These findings were confirmed by genetic analysis of interferon-stimulated genes, which were also weakly activated despite high metapneumovirus concentrations. For comparison, lung tissue exhibited a significant increase in IFN-I levels as early as day 1.

To further clarify the nasal immune landscape, the researchers assessed changes in immune cell populations. They found that up to day 10 after infection, there were no changes in antigen-presenting cells, virus-specific T lymphocytes, NK cells, or macrophages.

Taken together, these data indicate a stable immune environment with low IFN-I and minimal immune cell presence during metapneumovirus infection.

Nasal Interferon Restores the Nasal Immune Landscape During Viral Infection

To alter the calm immune environment in the nose, which responds weakly to viral infection, researchers applied nasal IFN-I. They hypothesized that since nasal epithelial cells do not respond to increasing viral load and do not synthesize IFN-I, an exogenous interferon might change the situation. For this purpose, recombinant type I interferon was administered into the nasal sinuses of mice on the first day after infection.

As a result, nasal IFN-I significantly reduced viral load in the nose. By day 7 after infection, there were noticeably more both conventional T cells and virus-specific T lymphocytes in the nasal mucosa. The researchers emphasize that they intentionally performed the analysis on day 7 to capture the activation of adaptive immune responses stimulated by nasal IFN-I.

Continuing the experiment, the researchers treated mice with nasal IFN-I again on day 10 after infection to further amplify adaptive immunity. This procedure accelerated viral clearance in the upper respiratory tract.

Based on these findings, the researchers concluded that nasal interferon strengthens the immunity of the upper respiratory tract. As a result, a more effective antiviral response is formed, adaptive immunity is stimulated, and viral clearance is accelerated.

Conclusions

Respiratory infections account for 15% of deaths among children under the age of five. Children most frequently become infected with human metapneumovirus, yet long-lasting immunity does not develop. In adults, infection leads to death in approximately 1% of cases. The immune environment of the nose responds weakly to metapneumovirus infection – levels of signaling proteins, type I interferon, and immune cells change only minimally. Nasal IFN-I strengthens upper respiratory tract immunity, activates immune responses, and accelerates viral clearance.

Reference

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