Increased nasal mucosal interferon and CCL13 response to a TLR7/8 agonist in asthma and allergic rhinitis

Abstract: Background Acute respiratory viral infections are a major cause of respiratory morbidity and mortality, especially in patients with pre-existing lung diseases such as asthma. Toll-like receptors (TLRs) are critical in the early detection of viruses and in activating innate immunity in the respiratory mucosa, but there is no reliable and convenient method by which respiratory mucosal innate immune responses can be measured. Objective To assess in vivo immune responses to an innate stimulus and compare responsiveness between healthy and allergic volunteers. Methods We administered the TLR7/8 agonist resiquimod (R848; a synthetic analogue of single-stranded RNA (ssRNA)) or saline by nasal spray to healthy non-allergic participants (n=12), those with allergic rhinitis (n=12), or allergic rhinitis with asthma (n=11). Immune mediators in blood and nasal fluid and mucosal gene expression were monitored over time. Results R848 was well tolerated and significantly induced interferon (IFN)-α2a, IFN-γ, pro-inflammatory cytokines (TNF-α, IL-2, IL-12p70) and chemokines (CXCL10, CCL2, CCL3, CCL4 and CCL13) in nasal mucosal fluid, without causing systemic immune activation. Participants with allergic rhinitis or allergic rhinitis with asthma had increased IFN-α2a, CCL3 and CCL13 responses relative to healthy participants; those with asthma had increased induction of interferon-stimulated genes DDX58, MX1 and IFIT3. Conclusion Responses to nasal delivery of R848 enables simple assessment of mucosal innate responsiveness, revealing that patients with allergic disorders have an increased nasal mucosal interferon and chemokine response to the viral RNA analogue resiquimod. This highlights that dysregulated innate immune responses of the nasal mucosa in allergic individuals may be important in determining the outcome of viral exposure.