Distinct olfactory mucosal macrophage populations mediate neuronal maintenance and pathogen defense.

The olfactory mucosa is important for both the sense of smell and as a mucosal immune barrier to the upper airway and brain. However, little is known about how the immune system mediates the conflicting goals of neuronal maintenance and inflammation in this tissue. A number of immune cell populations reside within the olfactory mucosa and yet we have little understanding of how these resident olfactory immune cells functionally interact with the chemosensory environment. Identifying these interactions will allow therapeutic manipulations that treat disorders such as post-viral olfactory dysfunction. Macrophages are the most prevalent immune cell type in the uninflamed olfactory mucosa and here, we identify two distinct tissue macrophage populations in murine olfactory mucosa. P2ry12hi macrophages are transcriptionally specialized for neuron interactions, closely associated with olfactory neuron cell bodies, long-term tissue residents, and functionally specialized to phagocytose cells and debris, including olfactory neurons. Conversely, MHC Class IIhi macrophages are transcriptionally dedicated to cytokine production and antigen presentation, localized primarily within the olfactory lamina propria, more rapidly replaced by blood monocytes, and rapidly produce chemokines in response to viral infection. We further show that these macrophage signatures are present in human olfactory biopsies, and P2ry12-like olfactory macrophages are reduced in patients with long-term smell loss following COVID-19. Together, these data show that two olfactory macrophage populations regulate neurons and initiate the immune response, contributing to our understanding of both olfactory immunity and tissue-resident macrophage biology.

A protective and broadly binding antibody class engages the influenza virus hemagglutinin head at its stem interface.

Influenza infection and vaccination impart strain-specific immunity that protects against neither seasonal antigenic variants nor the next pandemic. However, antibodies directed to conserved sites can confer broad protection. Here we identify and characterize a class of human antibodies that engage a previously undescribed, conserved epitope on the influenza hemagglutinin (HA) protein. Prototype antibody S8V1-157 binds at the normally occluded interface between the HA head and stem. Antibodies to this HA head-stem interface epitope are non-neutralizing in vitro but protect against lethal influenza infection in mice. Antibody isotypes that direct clearance of infected cells enhance this protection. Head-stem interface antibodies bind to most influenza A serotypes and seasonal human variants, and are present at low frequencies in the memory B cell populations of multiple human donors. Vaccines designed to elicit these antibodies might contribute to "universal" influenza immunity.