Bacterial ATP Release Modulates Local and Systemic Inflammation during Abdominal Sepsis

Core Concepts

Bacterial ATP release, mediated by ATP synthase and outer membrane integrity, suppresses local immune responses and is systemically distributed via outer membrane vesicles, exacerbating sepsis severity.

Abstract

The study investigates the mechanisms and roles of bacterial ATP release in the context of abdominal sepsis. Key findings:

Sepsis-associated bacteria, including E. coli, K. pneumoniae, E. faecalis, and S. aureus, release ATP in a growth-dependent and strain-specific manner.

ATP release is dependent on the inner bacterial membrane, particularly the ATP synthase complex, and correlates with bacterial growth and viability.

Impaired outer membrane integrity, leading to bacterial death, also contributes significantly to ATP release during bacterial growth.

In a mouse model of abdominal sepsis, bacterial ATP suppresses local immune responses, reducing neutrophil counts and impairing survival.

Bacterial ATP is transported systemically via outer membrane vesicles (OMVs), which are taken up by neutrophils and activate lysosomal pathways and degranulation processes, potentially exacerbating sepsis severity.

The study reveals the dual roles of bacterial ATP in modulating both local and systemic inflammatory responses during abdominal sepsis, highlighting the potential for targeting bacterial ATP release or signaling as a therapeutic strategy.

Stats

Sepsis causes an estimated 11 million deaths per year worldwide, accounting for 19.7% of all global deaths.
E. coli, one of the major pathogens in sepsis, released the highest cumulative amount of ATP compared to E. faecalis and S. aureus in a mouse model of abdominal sepsis.
Mutations in ATP synthase subunits had a greater impact on ATP release than mutations in cytochrome bo3 oxidase subunits.
The ΔompF porin mutant, which has impaired outer membrane integrity, showed the highest peak of ATP release during growth.
Abrogating bacterial ATP release in a mouse model of abdominal sepsis improved survival, despite no differences in local or systemic bacterial counts.

Quotes

"ATP release is directly dependent on ATP generation at the inner bacterial membrane."
"Destabilization of the outer bacterial membrane, as observed with the ΔompF mutant, results in bacterial death that is associated with ATP release."
"Delivery of ATP by OMV resulted in an upregulation of lysosomal activation and neutrophil degranulation."

Key Insights Distilled From

Released Bacterial ATP Shapes Local and Systemic Inflammation during Abdominal Sepsis

by Spari,D., Sc... at www.biorxiv.org 03-08-2024

https://www.biorxiv.org/content/10.1101/2024.03.07.583973v1

Deeper Inquiries

How do different bacterial species and strains regulate ATP release, and what are the underlying genetic and metabolic mechanisms?

Different bacterial species and strains regulate ATP release in a growth-dependent and strain-specific manner. In the study, sepsis-associated bacteria, including Escherichia coli (E. coli), Klebsiella pneumoniae, Enterococcus faecalis, and Staphylococcus aureus, were analyzed for ATP release. The amount of ATP released peaked during the exponential growth phase and was strain-specific. E. coli, a common pathogen in sepsis, released the highest amount of ATP. The release of ATP is dependent on the respiratory chain located at the inner bacterial membrane, particularly ATP synthase. Mutations in ATP synthase subunits significantly impacted ATP release, indicating the importance of ATP generation in this process. Additionally, impaired outer membrane integrity, as seen in the ΔompF mutant, led to bacterial death and subsequent ATP release. This highlights the role of bacterial death in ATP release during growth.

What are the specific signaling pathways and cellular responses triggered by bacterial ATP in host immune cells, and how can they be therapeutically targeted?

Bacterial ATP released into the extracellular space plays a crucial role in modulating inflammatory and immune responses in host immune cells. ATP activates ionotropic P2X and metabotropic P2Y receptors, leading to altered local and systemic cytokine secretion. In the study, bacterial ATP was shown to suppress local immune responses, reduce neutrophil counts, and impair survival in a mouse model of abdominal sepsis. Furthermore, ATP-loaded outer membrane vesicles (OMVs) distributed throughout the body and upregulated genes activating degranulation in neutrophils, exacerbating sepsis severity. Therapeutically targeting these pathways could involve inhibiting purinergic signaling receptors or developing strategies to prevent the release of ATP by bacteria, potentially reducing inflammation and improving sepsis outcomes.

Could bacterial ATP or ATP-loaded OMVs be used as diagnostic biomarkers to predict sepsis severity and guide treatment strategies?

Bacterial ATP or ATP-loaded OMVs have the potential to be used as diagnostic biomarkers to predict sepsis severity and guide treatment strategies. The presence of ATP in OMVs and its systemic effects on immune cells, particularly neutrophils, indicate their role in exacerbating sepsis severity. By measuring ATP levels in OMVs or bacterial cultures, healthcare providers could potentially predict the severity of sepsis and tailor treatment strategies accordingly. Additionally, the specific pathways activated by bacterial ATP in immune cells could serve as targets for therapeutic interventions to mitigate the detrimental effects of ATP release during sepsis. Further research and clinical studies are needed to validate the use of bacterial ATP or ATP-loaded OMVs as diagnostic biomarkers in sepsis management.