PROJECT SUMMARY Streptococcus pneumoniae (pneumococci) are Gram-positive cocci that usually exists as a commensal of the human nasopharyngeal mucosa but are often characterized as pathogens due to its ability to disseminate from the nasopharynx and into the inner ear and lower respiratory tract. High bacterial load during lower respiratory tract infection, such as bronchitis and pneumonia, restricts the efficacy of the mucociliary escalator, leading to inflammation and limited gas exchange. Mucus serves as a protective barrier between the lung epithelium and the environment and a nutritional source for the pneumococcus. We found that mucin serves as a key nutritional cue for S. pneumoniae, preventing autolysis and facilitating prolonged bacterial survival in stationary phase compared to traditional media. Since mucin is abundant in pneumococcal environmental niches, we wanted to assess the impact of mucin on various aspects pneumococcal biology. We found that mucin effectively blocked pneumococcal autolysis via inhibition of the primary autolysin, LytA. A fundamental aspect of pneumococcal biology is the capacity of the bacterium to rapidly undergo autolysis following entry into stationary phase during standard in vitro cultivation leading to a rapid loss in culture viability. We observed that mucin-mediated autolysis inhibition not only prevented this process but also promoted long-term stationary phase survival of the pneumococcus both planktonically and in biofilms. This phenotype was highly conserved amongst genetically diverse strain backgrounds and independent of capsular serotype. The mucin-mediated autolysis inhibition was found to be dependent upon the direct inhibitory activity of physiological concentrations mucin on LytA using peptidoglycan hydrolysis assays. Additionally, mice that over produce mucus were found to have enhanced pneumococcal nasal colonization. Based on these preliminary findings, we aim to determine 1) the specificity underlying mucin-mediated autolysis inhibition; 2) the impact of mucin-mediated autolysis inhibition on pneumococcal evolutionary tools such cytotoxicity; and 3) the genetic determinants that are required for prolonged stationary phase survival in mucin. Environmental context is critical to understanding the fundamental biology of pathogens. The primary host niche for the pneumococcus is the nasopharynx, which is replete with mucins. These data suggest that environmental niches harboring mucins may promote pneumococcal colonization over invasive infection by preventing host cell death and prolonged bacterial survival.