Pneumococcal phosphodiesterase 2 mutation elicits a unique type I interferon response in macrophages
Wooten, Alicia Kozue
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Streptococcus pneumoniae (pneumococcus) is a pathogenic organism and the leading cause of bacterial pneumonia. Host-pathogen interaction is poorly understood, and factors that drive a more severe phenotype are unknown. During pneumococcal pneumonia, the innate immune system is critical for detection of invading pathogens. Macrophages are among the first responders to initiate a cellular host defense. This response is heterogeneous and the mechanisms behind the variability is unknown. An essential bacterial second messenger, cyclic di-AMP, has been shown to be secreted into the host cytosol and acts as a pathogen associate molecular pattern (PAMP) to initiate a robust type I interferon response. This type I interferon response occurs through the activation of cGAS and Stimulator of Interferon Genes (STING) pathway. Type I interferons are crucial in combatting viruses and there has been an emerging role for extracellular bacteria. The gram-positive bacterium, Streptococcus pneumoniae synthesizes cyclic di-AMP, and degradation occurs through two enzymes, phosphodiesterase 1 (pde1) and phosphodiesterase 2 (pde2). Using bacterial strains with a deletion of one (Δpde1 or Δpde2) or both phosphodiesterase enzymes (Δpde1Δpde2), we investigated the impact pneumococcal phosphodiesterases would have on macrophage responses. Along with type I interferon expression, the STING pathway can also activate the canonical NF-κB pathway, and all phosphodiesterase mutant strains elicited an increase in macrophage NF-κB activation compared to those infected with the wildtype bacterial strain. In contrast, it was revealed that only the phosphodiesterase 2 deleted pneumococci were able to incite an IFNβ response in macrophages that was not seen in other phosphodiesterase mutant strains (Δpde1 or Δpde1Δpde2). This excessive IFNβ response associated with faster macrophage cell death and depended upon macrophage uptake and phagolysosomal fusion. Overall, we conclude that pneumococcal phosphodiesterases appear to have differing responses on macrophages. Pneumococcal phosphodiesterase 2 mutation skews macrophage responses towards type I interferon, suggesting that deletion of phosphodiesterase 2 enzyme (and not the phosphodiesterase 1 enzyme) can activate selective arms of innate immune response. An improved understanding of pneumococcal phosphodiesterase 2 influences on bacterial physiology and host response could provide better insight into the host-pathogen responses.