Bitter taste receptors (T2Rs) in the human airway detect harmful compounds, including secreted bacterial products. Here, we show that activation of a subset of airway T2Rs expressed in human nasal solitary chemosensory cells activates a calcium wave that propagates through gaps junction to the surrounding respiratory epithelial cells. This stimulates robust secretion of antimicrobial peptides into the mucus capable of killing a variety of respiratory pathogens. Furthermore, sweet taste receptor (T1R2/3) activation suppresses T2R-mediated antimicrobial peptide secretion. We propose that T1R2/3-mediated inhibition of T2Rs exists to negatively modulate full antimicrobial peptide release during times of relative health. However, during acute bacterial infection, bacteria consume the airway surface liquid glucose, resulting in deactivation of T1R2/3 and removal of T2R inhibition, resulting in appropriate antimicrobial peptide secretion. Correlating these findings with clinical disease, we found that patients with chronic rhinosinusitis have elevated glucose concentrations in their nasal secretions. Previous studies have shown that hyperglycemic patients likewise have elevated nasal glucose levels. Taken together, these data suggest that increased glucose in respiratory secretions in pathologic states such as chronic rhinosinusitis or hyperglycemia could result in tonic activation of T1R2/3 and suppress T2R-mediated innate defense, representing a novel pathophysiological mechanism in upper respiratory tract infection.