AUTHOR=Riegler Ashleigh Nichole , Brissac Terry , Gonzalez-Juarbe Norberto , Orihuela Carlos J. 

TITLE=Necroptotic Cell Death Promotes Adaptive Immunity Against Colonizing Pneumococci

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00615

DOI=10.3389/fimmu.2019.00615

ISSN=1664-3224

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