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Unique Roles for Streptococcus pneumoniae Phosphodiesterase 2 in Cyclic di-AMP Catabolism and Macrophage Responses

Alicia K Wooten1,2, Anukul T Shenoy1, Emad I Arafa1,2

  • 1Pulmonary Center, Boston University School of Medicine, Boston, MA, United States.

Frontiers in Immunology
|April 18, 2020
PubMed

Insights

Elevated cyclic di-AMP (c-di-AMP) in pneumococci triggers excessive innate immune responses, including interferon-beta (IFNβ) production and macrophage death. This highlights c-di-AMP

Area of Science:

  • Microbiology
  • Immunology
  • Molecular Biology

Background:

  • Cyclic di-AMP (c-di-AMP) is a prokaryotic signaling molecule recognized by mammalian cells as a danger signal, initiating innate immunity.
  • The precise roles of c-di-AMP in host responses during pneumococcal infections are not fully understood.
  • Phosphodiesterases (PDEs) are enzymes that degrade c-di-AMP, influencing its intracellular levels.

Purpose of the Study:

  • To investigate the role of c-di-AMP catabolism in pneumococci on host immune responses during infection.
  • To elucidate the mechanisms by which altered c-di-AMP levels modulate innate immunity, particularly interferon-beta (IFNβ) production.

Main Methods:

  • Generated pneumococcal strains deficient in phosphodiesterase 2 (Pde2) and phosphodiesterase 1 (Pde1).
  • Assessed IFNβ induction in macrophage cell lines and primary alveolar macrophages upon infection with wild-type and mutant pneumococci.
  • Utilized STING and cGAS knockout models to determine their role in the observed immune response.
  • Analyzed transcription factor phosphorylation (IRF3, IRF7) and bacterial phagocytosis.

Main Results:

  • Pneumococci lacking Pde2 exhibited significantly exaggerated IFNβ induction compared to wild-type or Pde1-deficient strains.
  • This heightened IFNβ response was dependent on STING and cGAS, bacterial phagocytosis, and IRF3/IRF7 activation.
  • Macrophage hyperactivation by Pde2-deficient pneumococci resulted in rapid cell death.
  • The unique effect of Pde2 deletion was observed under conditions promoting bacterial virulence.

Conclusions:

  • Elevated intracellular c-di-AMP in pneumococci, particularly due to Pde2 deficiency under virulence-associated conditions, drives aberrant innate immune responses.
  • These responses include STING pathway hyperactivation, excessive IFNβ production, and macrophage cytotoxicity.
  • c-di-AMP is a critical mediator of innate immunity and host-pathogen interactions during pneumococcal pneumonia.
Keywords:
STINGcyclic di-AMPinnate immunityinterferon-βmacrophagespneumococcuspneumonia

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