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Abstract
Cyclic di-AMP (c-di-AMP) is an important signaling molecule for pneumococci, and as a uniquely prokaryotic product it can be recognized by mammalian cells as a danger signal that triggers innate immunity. Roles of c-di-AMP in directing host responses during pneumococcal infection are only beginning to be defined. We hypothesized that pneumococci with defective c-di-AMP catabolism due to phosphodiesterase deletions could illuminate roles of c-di-AMP in mediating host responses to pneumococcal infection. Pneumococci deficient in phosphodiesterase 2 (Pde2) stimulated a rapid induction of interferon β (IFNβ) expression that was exaggerated in comparison to that induced by wild type (WT) bacteria or bacteria deficient in phosphodiesterase 1. This IFNβ burst was elicited in mouse and human macrophage-like cell lines as well as in primary alveolar macrophages collected from mice with pneumococcal pneumonia. Macrophage hyperactivation by Pde2-deficient pneumococci led to rapid cell death. STING and cGAS were essential for the excessive IFNβ induction, which also required phagocytosis of bacteria and triggered the phosphorylation of IRF3 and IRF7 transcription factors. The select effects of Pde2 deletion were products of a unique role of this enzyme in c-di-AMP catabolism when pneumococci were grown on solid substrate conditions designed to enhance virulence. Because pneumococci with elevated c-di-AMP drive aberrant innate immune responses from macrophages involving hyperactivation of STING, excessive IFNβ expression, and rapid cytotoxicity, we surmise that c-di-AMP is pivotal for directing innate immunity and host-pathogen interactions during pneumococcal pneumonia.
Highlights
Pneumonia is a leading cause of morbidity and mortality worldwide [1]
TNFα was elevated in cell culture supernatants which included bacteria, with those containing pde2 or pde1 pde2 pneumococci reaching statistical significance
This study suggests that the pneumococcal phosphodiesterase 2 enzyme has distinct and prominent roles in dictating bacterial c-di-AMP content and macrophage innate immunity
Summary
Pneumonia is a leading cause of morbidity and mortality worldwide [1]. Children under 5 and adults over 60 years of age have the greatest risk of developing pneumonia [2]. The most common bacterial cause of community acquired pneumonia is the gram-positive extracellular bacterium, Streptococcus pneumoniae (pneumococcus). Pneumococcus can colonize the nasopharynx asymptomatically, or it can cause diseases such as otitis media, bacteremia, or meningitis, in addition to pneumonia [3]. Despite advances with pneumococcal vaccines, infections with non-vaccine serotypes remain important [4]. A better understanding of the pathogen and the host immune response may help develop novel prophylactics and therapeutics to lower the disease burden caused by S. pneumoniae
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