Mucosal immunity to severe acute respiratory syndrome coronavirus 2 infection

Despite its crucial role in protection against viral infections, mucosal immunity has been largely understudied in the context of coronavirus disease 2019 (COVID-19). This review outlines the current evidence about the role of mucosal immune responses in the clearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as potential mucosal mechanisms of protection against (re-)infection.

The angiotensin-converting enzyme 2 cellular entry receptor for SARS-CoV-2 is most highly expressed in the upper respiratory tract and most SARS-CoV-2 shedding occurs from the upper respiratory tract. Viral shedding peaks early during infection around the onset of symptoms, before dropping rapidly in most individuals within 7 days of symptom onset, suggesting mucosal inhibition of viral infection. Serum and mucosal immunoglobulin G and immunoglobulin M responses were found to be strongly correlated in infected patients, whereas correlations were much weaker for immunoglobulin A (IgA). Mucosal IgA responses have been detected in infected cases in the absence of serum antibody responses, with mucosal antibody levels correlating strongly with virus neutralization. Bulk and single-cell RNA sequencing analysis of nasopharyngeal swabs and bronchoalveolar lavage samples of COVID-19 patients revealed the induction of mucosal chemokine and cytokine genes, complement pathways, Janus Kinase/Signal Transducer and Activator of Transcription signaling and cytotoxic T cells.

Although most clinical studies focus on antibodies and cellular immunity in peripheral blood, mucosal immune responses in the respiratory tract play a key role in the early restriction of viral replication and the clearance of SARS-CoV-2. Identification of mucosal biomarkers associated with viral clearance will allow monitoring of infection-induced immunity. Further studies are needed to understand how the systemic immunological endpoints measured in vaccination studies translate to mucosal protection against SARS-CoV-2 infection.