Muc16 contributes to protection against invasive pneumococcal infection originating from nasal colonization

Streptococcus pneumoniae asymptomatically colonizes upper respiratory mucosa and invades into deeper tissue through mucosal membrane. Invasive pneumococcal disease has a significantly high rate of mortality, making its control an urgent concern. Mucin is a defensive system against respiratory infection. However, the role of transmembrane mucin against the development of invasive infection has been unclear. In this study, we demonstrate the roles of Muc16 on invasive pneumococcal disease. Muc16 knockout mice had significantly increased bacterial loads in the lungs and brain after nasal pneumococcal challenge, whereas bacterial loads in the nasal cavity had no difference. Under cigarette smoke extract (CSE)-pretreated conditions, they showed increased bacterial loads in the blood with the elevation of serum IL-6 level and a significant increase in the mortality rate. Infiltration of polymorphonuclear leukocytes was suppressed by deficiency of Muc16. The proportion of mucosal disruption in the olfactory epithelium was significantly increased by deficiency of Muc16, and the expression of tight junction molecule ZO-1 was inhibited in CSE-pretreated Muc16 knockout mice. Muc16 is, thus, considered to be essential for preserving the defensive system against pneumococcal translocation from nasal mucosa by regulating inflammatory cell infiltration and mucosal barrier integrity in the upper respiratory tract. MUC16 could be a new target in preventive strategy against pneumococcal infection.IMPORTANCEStreptococcus pneumoniae commonly colonizes the upper respiratory tract without causing symptoms but can sometimes invade deeper tissues and lead to life-threatening diseases, such as pneumonia, bacteremia, and meningitis. The mechanisms that prevent bacteria from spreading beyond the nasal mucosa are still incompletely understood. In this study, we demonstrate that the transmembrane mucin MUC16 plays an important role in protecting against invasive pneumococcal infection. Using a mouse model, we show that loss of Muc16 does not alter nasal colonization but increases bacterial dissemination to systemic organs and worsens survival, particularly under cigarette smoke exposure. Our findings suggest that MUC16 contributes to mucosal defense by maintaining epithelial barrier integrity and supporting neutrophil recruitment at the nasal surface. These results highlight the importance of transmembrane mucins in preventing bacterial invasion and provide new insight into how disruption of mucosal barriers may promote invasive pneumococcal disease.