The nasal mucosa plays a key role in protecting against respiratory viruses. Scientists from leading research and medical centers in Boston and Cambridge, USA, have characterized its cellular composition in detail, tracked how it changes during infection, and shown that even nasal swabs can be used to assess the local immune response and identify signs of protection against severe disease.
These findings expand our understanding of the mechanisms underlying nasal mucosal defense. They may provide a basis for developing next-generation nasal vaccines capable of preventing infection, reducing disease severity, and limiting viral transmission.
Structure Of The Nasal Mucosa
The mammalian nasal cavity consists of respiratory and olfactory regions, which differ in their structure, functions, and cellular composition. The respiratory epithelium cleanses, humidifies, and warms inhaled air while trapping particles and microorganisms. The olfactory region contains sensory neurons that detect odors and transmit signals to the brain. The mucosa is supported by the sinuses and glands that produce mucus. Bowman’s glands, located beneath the mucosa near the olfactory epithelium, also contribute to local humidification. In humans, the nasopharynx contains nasal-associated lymphoid tissue (NALT), known as the adenoids. In mice, NALT is located above the hard palate.
Cellular Composition Of The Nasal Mucosa
Traditionally, nasal epithelial cells were classified as olfactory, squamous, transitional, or respiratory cells (ciliated and non-ciliated). However, the nasal mucosa has a much more complex cellular organization than previously thought:
- The respiratory epithelium contains several subpopulations of goblet, secretory, and basal cells that produce mucus and antimicrobial proteins;
- Ionocytes – spherical epithelial cells found in the mucosa of both humans and mice – are likely involved in regulating mucus viscosity and clearance;
- Ciliated cells transport mucus through the airways and are frequent targets of viral infection; they comprise several distinct types;
- Following infection, the number of deuterosomal cells – a transitional state between secretory and ciliated cells – increases. These cells are thought to contribute to the regeneration of the ciliated-cell population;
- Subpopulations of squamous epithelial cells may be relatively resistant to viral infection and capable of interacting with immune cells;
- Supporting cells in the olfactory epithelium are essential for olfaction and are targets of SARS-CoV-2;
- Bowman’s mucous glands are located beneath the olfactory epithelium and contain their own goblet and secretory cells;
- Olfactory/brush and chemosensory cells, which can trigger allergic inflammatory signals when barrier tissues are damaged, are distributed throughout the olfactory epithelium and are required in mice for stem-cell proliferation following allergic exposure.
Immune Cells Of The Nasal Mucosa
The nasal mucosa contains an extensive local immune defense system. It includes:
- Innate immune cells – neutrophils, eosinophils, macrophages, dendritic cells, mast cells, and NK cells.
- Adaptive immune cells – B cells, plasma cells, and CD4+ and CD8+ T cells.
- Secondary lymphoid tissues of the upper respiratory tract, including the adenoids and NALT, where B cells mature and form immunological memory. These tissues also contain follicular helper T cells (TFH) and regulatory T cells.
In adults, the adenoids often remain functionally active and continue to support B-cell maturation. Plasma cells generated in NALT from naive B cells in response to antigen exposure migrate to the nasal turbinates and glands and produce IgA antibodies essential for local mucosal protection. CD8+ T cells predominate in the epithelium, outnumbering CD4+ T cells by 5–10-fold.
Thus, the nasal mucosa provides continuous cellular and humoral immune surveillance that becomes enhanced and reorganized during infection.
Distinctive Features Of Nasal Mucosal Immunity
The nasal mucosa is a specialized immune environment that differs from other barrier tissues, including the lungs and intestine. Even adjacent regions of the upper respiratory tract have distinct cellular compositions and functional properties.
The diversity of epithelial cells is essential for maintaining the mucosal barrier: these cells regulate mucus production and transport as well as IgA production. Recently described epithelial subpopulations, including ionocytes and squamous epithelial cells, are likely involved in disease pathogenesis and recovery. Local immune cells contribute to the development of inflammatory diseases, while local lymphoid organs rapidly establish immunological memory.
Which Nasal Cells Are Targeted By Respiratory Viruses
The nasal mucosa serves as the first barrier against viruses. Cilia remove mucus containing trapped particles and microorganisms, while tight junctions between cells and the specialized organization of the epithelium make viral penetration and spread more difficult.
The susceptibility of the nasal mucosa to viruses depends on the type and state of epithelial cells, as well as the presence of receptors required for viral entry. Ciliated cells were found to be the primary targets of both SARS-CoV-2 and influenza A virus:
- In COVID-19, a small population of hyperinfected ciliated cells was identified: more than 80% of the RNA detected in these cells belonged to SARS-CoV-2. Such cells may support viral replication in the nose.
- During influenza infection, ciliated cells also contained the highest amounts of viral RNA.
In response to infection, ciliated cells produce type I and type III interferons (IFNs) and activate interferon-stimulated genes (ISGs).
Immune Response Of The Nasal Mucosa To Viral Infection
During viral infection, immune protection in the nasal mucosa is activated in several stages:
- During the first few days, neutrophils accumulate, and IFN responses are activated in epithelial and immune cells.
- Monocytes and macrophages then increase in number. They support antiviral defense and recruit lymphocytes, which can directly destroy infected cells and help maintain a local antiviral state, as well as support plasma-cell maturation in draining lymph nodes and NALT. Interestingly, during COVID-19, macrophages express more proinflammatory genes than during influenza A infection.
- After approximately one week, effector CD4+ Th1 cells and cytotoxic CD8+ T cells accumulate in the mucosa. In humans, the accumulation of T cells in the nasal cavity coincides with or occurs immediately after the peak viral load during COVID-19, indicating their key role in controlling infection. Interestingly, in mice, the appearance of effector T cells occurs at a similar post-infection stage despite the already declining viral load.
- Two to four weeks after influenza A infection, structures develop in nasal tissues where B cells mature and produce antibodies with enhanced binding to viral antigens. During SARS-CoV-2 infection, this process is influenced by the IFN response: depending on timing and conditions, IFNs can either promote memory B-cell formation or limit B-cell maturation.
- After recovery, both CD8+ and CD4+ tissue-resident memory cells (Trm) develop in the nasal turbinates and NALT. Following COVID-19, they persist for at least 12 months.
- Twelve months after COVID-19, memory B cells also remain in human adenoids, suggesting that non-antibody-secreting B cells may also persist in the nasal mucosa for extended periods.
Dynamics Of Viral Load In The Nasal Mucosa
The course of infection in the nasal mucosa depends on the type of virus, the route of infection, and the extent of tissue involvement. In humans, viral load during influenza A, COVID-19, and RSV typically peaks between days 5 and 8 and declines to undetectable levels by days 14–17.
The early immune response determines long-term protection: the activity of neutrophils and interferons influences the function of macrophages, dendritic cells, T cells, and B cells. As a result, long-lasting local immunological memory develops in the nasal mucosa.
The Interferon Response Influences The Severity Of Viral Infection
The outcome of respiratory viral infection depends in large part on the condition of the nasal mucosa before infection and the speed of the IFN response. Early activation of the IFN defense response is associated with milder COVID-19, and this response is stronger in children than in adults. Low baseline IFN activity before infection may enhance antiviral protection.
Conversely, chronic inflammation and disruption of the epithelial barrier may increase susceptibility to infection. For example, baseline neutrophilic inflammation in the nasal cavity is associated with the development of symptoms and increased cytokine production during RSV infection. Treatment with dupilumab, which blocks IL-4 signaling, reduces nasal polyps and symptom severity and is also associated with fewer respiratory infections, suggesting that chronic type 2 inflammation may weaken nasal mucosal protection.
Type III IFNs in the nasal mucosa are associated with mild COVID-19. Blocking epithelial IFN signaling during rhinovirus infection resulted in persistent viral replication, inflammation, and mucus hypersecretion. These findings confirm that a type III IFN response is required to limit both viral spread and inflammation.
Thus, an effective defense requires a balanced IFN response: it must rapidly restrict viral replication without causing prolonged inflammation or interfering with the development of immunological memory.
Immunological Memory In The Nasal Mucosa
After respiratory viral infection, IgA antibodies as well as memory B and T cells persist in the nasal mucosa, providing local protection against reinfection. High levels of nasal IgA are associated with better protection against infection, and following intranasal influenza vaccination, IgA can persist for at least one year.
Intramuscular vaccination alone induces weaker local immunity. In respiratory virus models, including influenza and SARS-CoV-2, primary vaccination followed by intranasal boosting enhanced IgA production in the mucosa, the formation of CD8+ and CD4+ Trm cells in the lungs, and protection against viral replication and transmission compared with injection-only vaccination. The strongest systemic and local immunological memory develops when infection and vaccination are combined – so-called hybrid immunity.
Prospects For Intranasal Vaccines
Intranasal vaccination can induce immunity directly in the nasal mucosa and reduce viral replication and shedding. In animal experiments, different vaccine platforms stimulated IgA production, activated T cells, and enhanced protection against influenza and SARS-CoV-2.
Vaccines that:
- activate reliable, temporally controlled IFN signaling in epithelial cells;
- prime and/or recruit innate immune cells from the circulation;
- maintain sustained antigen availability or presentation and subsequent antiviral signaling are particularly promising.
It is critical to recognize that interferons have a dual role: they rapidly suppress viruses, but an excessively strong and prolonged response may interfere with the development of long-term immunological memory. Therefore, the optimal strength and duration of the IFN response must be determined to provide both rapid and durable protection.
Reference
Nasal immunity in respiratory viral infection, transmission, and protection
