Necroptotic Cell Death Promotes Adaptive Immunity Against Colonizing Pneumococci

Pore-forming toxin (PFT) induced necroptosis exacerbates pulmonary injury during bacterial pneumonia. However, its role during asymptomatic nasopharyngeal colonization and toward the development of protective immunity was unknown. Using a mouse model of ( ) asymptomatic colonization, we determined that nasopharyngeal epithelial cells (nEC) died of pneumolysin (Ply)-dependent necroptosis. Mice deficient in MLKL, the necroptosis effector, or challenged with Ply-deficient showed less nEC sloughing, increased neutrophil infiltration, and altered IL-1α, IL-33, CXCL2, IL-17, and IL-6 levels in nasal lavage fluid (NALF). Activated MLKL correlated with increased presence of CD11c antigen presenting cells in -associated submucosa. Colonized MLKL KO mice and wildtype mice colonized with Ply-deficient produced less antibody against the bacterial surface protein PspA, were delayed in bacterial clearance, and were more susceptible to a lethal secondary challenge. We conclude that PFT-induced necroptosis is instrumental in the natural development of protective immunity against opportunistic PFT-producing bacterial pathogens.