Phagosomal granulocytic ROS in septic patients induce the bacterial SOS response.

Area of Science:

• Immunology
• Microbiology
• Molecular Biology

Background:

• Septic patients with poor prognosis exhibit increased circulating immature granulocytes (IG).
• These IG cells demonstrate diminished phagocytic capacity and reduced reactive oxygen species (ROS) production.
• The clinical implications of these functional deficits in sepsis remain incompletely understood.

Purpose of the Study:

• To investigate the functional capabilities of IG from septic patients.
• To determine the impact of sepsis-derived IG on bacterial responses, specifically antibiotic resistance.
• To elucidate the mechanisms underlying altered IG function in sepsis.

Main Methods:

• Development of an ex vivo model using human granulocytes from septic patients and healthy donors.
• Incubation of granulocytes with Escherichia coli.
• Assessment of reactive oxygen species (ROS) production and phagocytosis.
• Analysis of NADPH oxidase complex activation and protein expression.
• Evaluation of bacterial SOS response and quinolone resistance gene (qnrB2) expression.

Main Results:

• Granulocytes from septic patients (Sepsis-IG) exhibited significantly lower ROS production compared to healthy controls.
• Decreased activation and protein expression of the NADPH oxidase complex were observed in Sepsis-IG.
• Lower ROS production and phagocytosis by Sepsis-IG induced the bacterial SOS response.
• This bacterial response led to the upregulation of the qnrB2 gene, conferring quinolone resistance.

Conclusions:

• The impaired function of immature granulocytes in sepsis contributes to reduced bacterial clearance.
• Sepsis-induced immune dysfunction can inadvertently promote the emergence of antibiotic resistance.
• These findings highlight a novel mechanism linking sepsis pathophysiology to the development of antimicrobial resistance, independent of direct antibiotic pressure.