Biology subjects

Spari, D.

Publications and source records attributed to Spari, D..

2 recordsLinked to original sources

bioRxiv2024

Released Bacterial ATP Shapes Local and Systemic Inflammation during Abdominal Sepsis

Sepsis causes millions of deaths per year worldwide and is a current global health priority declared by the WHO. Sepsis-related deaths are a result of dysregulated inflammatory immune responses indicating the need to develop strategies to target inflammation. An important mediator of inflammation is extracellular adenosine triphosphate (ATP) that is secreted by inflamed host cells and tissues, and also by bacteria in a strain-specific and growth phase-dependent manner. Here, we investigated the mechanisms by which bacteria release ATP. Using genetic mutant strains of Escherichia coli (E. coli), we demonstrate that ATP release is dependent on ATP synthase within the inner bacterial membrane. In addition, impaired integrity of the outer bacterial membrane and bacterial death notably contribute to ATP release. In a mouse model of abdominal sepsis, local effects of bacterial ATP were analysed using a transformed E. coli bearing an arabinose-inducible periplasmic apyrase hydrolyzing ATP to be released. Abrogating bacterial ATP release shows that bacterial ATP suppresses local immune responses, resulting in reduced neutrophil counts and impaired survival. In addition, bacterial ATP has systemic effects via its transport in outer membrane vesicles (OMV). ATP-loaded OMV are quickly distributed throughout the body and upregulated expression of genes activating degranulation in neutrophils, potentially contributing to the exacerbation of sepsis severity. This study reveals mechanisms of bacterial ATP release and its local and systemic roles in sepsis pathogenesis.

microbiology↗

bioRxiv2019

Compartmentalization of intestinal bacteria by hepatic ILC3s prevents infections after surgery

Infections after surgical interventions are assumed to be caused by contamination. We show by analyzing multicentric data of 6561 patients that surgical infections as well as sepsis had a predominantly enteric microbial signature irrespective of the type of surgery, suggesting failure of intestinal bacterial compartmentalization. In mice, we reveal that hepatic surgery induced dysregulation of intestinal and hepatic type 3 innate lymphoid cells (ILC3s) and intestinal leakage resulting in enteric bacterial translocation via lymphatic vessels. In the absence of hepatic ILC3s, inflammasome activation and the induction of antimicrobial peptide encoding genes, bacteria colonized remote systemic organs and impaired surgical outcomes. Conversely, mammalian-microbial commensalism is required for the education of host immunity to ensure optimal hepatic healing responses. In fact, microbial-derived products were sufficient for the induction of proliferative transcriptional networks in the mouse liver, as illustrated by serum transfer experiments, mass spectrometry and RNA expression analysis, indicating that the balanced exposure of the host to commensals is essential for recovery. This study reveals the intestinal origin of microbes causing complications after surgical interventions and highlights host protective mechanisms of controlled commensalism that prevent infections.\n\nOne Sentence SummaryIntestinal bacteria cause surgical infections

immunology↗