Necroptotic Cell Death Promotes Adaptive Immunity Against Colonizing Pneumococci

Abstract

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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 Streptococcus pneumoniae (Spn) 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 Spn 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 Spn-associated submucosa. Colonized MLKL KO mice and wildtype mice colonized with Ply-deficient Spn produced less antibody against the bacterial surface protein PspA, were delayed in bacterial clearance, and were more susceptible to a lethal secondary Spn challenge. We conclude that PFT-induced necroptosis is instrumental in the natural development of protective immunity against opportunistic PFT-producing bacterial pathogens.

Keywords

• Streptococcus pneumoniae
• cell death
• necrosis
• necroptosis
• pore-forming toxin (PFT)
• pneumolysin (PLY)