Type I IFN expression is stimulated by cytosolic MtDNA released from pneumolysin‐damaged mitochondria via the STING signaling pathway in macrophages

Abstract

Pneumolysin (Ply), a major virulence factor of Streptococcus pneumoniae (S. pn), affects the immunity of host cells during infection. It has been reported that Ply is involved in S. pn standard strain D39‐induced interferon‐β (IFN‐β) expression; however, other findings suggest that recombinant Ply protein is incapable of triggering IFN‐β expression. Here, we demonstrated that purified Ply was capable of initiating oxidative damage to mitochondria, resulting in the subsequent release of mitochondrial deoxyribonucleic acid (mtDNA), which mediated IFN‐β expression in macrophages. Importantly, we determined that IFN‐β expression was regulated by stimulator of interferon genes (STING) signaling in response to Ply. In conclusion, our study identified that IFN‐β production was triggered by Ply in macrophages and mtDNA released from Ply‐damaged mitochondria mediated this process, through the STING pathway. This is a novel mechanism by which S. pn modulates type I IFN response in macrophages.

An in vivo atlas of host–pathogen transcriptomes during Streptococcus pneumoniae colonization and disease

“…Second, however, leakage of mitochondrial DNA from damaged mitochondria in stressed or dying cells is also a potential ligand for STING/cGAS (49)(50)(51). Since Spn invasion causes cell stress and death, DNA from damaged mitochondria or dying cells would be another potential trigger of the IFN response during invasion.…”

The cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease

“…100 Interestingly, in the context of infection, there is an escape of mtDNA into the cytoplasm, where it activates cGAS-mediated type I interferon generation, conferring broad pathogen resistance. [101][102][103] However, these mtDNA-induced cGAS-mediated antiviral responses are suppressed by apoptotic caspases. 104,105 Apart from aforementioned mechanisms, cGAS is also regulated by the ionic environment.…”

“…101 An in vitro study showed that pneumolysin could initiate oxidative damage to mitochondria, resulting in the subsequent release of mtDNA, which mediates IFN-β expression in macrophages. 102 COVID-19 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread to produce a global pandemic. 147 In patients with COVID-19, levels of 14 cytokines are increased; among them, CXCL10, CCL7, and IL-1 receptor antagonists are significantly higher in severe cases and are associated with increased viral load, loss of lung function, lung injury and a fatal outcome.…”

The cGAS-STING Pathway in Hematopoiesis and Its Physiopathological Significance

“…The cGAS-STING pathway protects against infections with viruses, bacteria, and protozoan parasites by sensing pathogenic DNA, infection-induced mitochondrial damage, bacterial proteins, virulence factors and metabolites, and bacteria-derived cyclic dinucleotides (CDNs) (79)(80)(81)(82)(83)(84). Meanwhile, infected cells transactivate the cGAS-STING pathway in bystander cells via the cell-to-cell transmission of cGAMP or the release of extracellular vesicles (EVs) (85)(86)(87)(88)(89).…”

“…Activation of the cGAS-STING pathway may promote the myeloid-biased differentiation of HSPCs to enhance the anti-infection reservoir of the immune system. However, it should bear in mind that the activation of the cGAS-STING pathway may also increase the vulnerability to or severity of infections through dampening adaptive immunity, exacerbating inflammation or facilitating pathogen replication, survival, and infection (81,(108)(109)(110)(111)(112)(113).…”