Necroptotic Cell Death Promotes Adaptive Immunity Against Colonizing Pneumococci

Front Immunol. 2019 Apr 4:10:615. doi: 10.3389/fimmu.2019.00615. eCollection 2019.

Abstract

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; colonization; innate and adaptive immune response; necroptosis; necrosis; pneumolysin (PLY); pore-forming toxin (PFT).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptive Immunity*
  • Animals
  • Antibody Formation / immunology
  • Apoptosis / immunology
  • Bacterial Proteins / immunology
  • Disease Models, Animal
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology
  • Female
  • Humans
  • Immunity, Innate
  • Male
  • Mice
  • Necroptosis / genetics
  • Necroptosis / immunology*
  • Pneumococcal Infections / genetics
  • Pneumococcal Infections / immunology*
  • Pneumococcal Infections / metabolism
  • Pneumococcal Infections / microbiology*
  • Streptococcus pneumoniae / immunology*
  • Streptolysins / immunology

Substances

  • Bacterial Proteins
  • Streptolysins
  • plY protein, Streptococcus pneumoniae