Hyperglycemia and hyperfibrinogenemia alter Staphylococcus aureus abscess community morphology, antimicrobial susceptibility, and virulence in vitro.

Abstract

Staphylococcus aureus is a prevalent human pathogen responsible for an array of invasive infections, such as osteomyelitis and bacteremia, which may be life threatening, recurrent, and cause permanent tissue damage. S. aureus infections are exacerbated in patients with co-morbidities including obesity and type 2 diabetes (obesity/T2D) due to impaired immune function, which leads to chronic inflammation and poor healing. Immune dysfunction can be attributed to gut microbiome dysbiosis, characterized by altered community composition and abundance, with aberrant production of gut-immune axis metabolites. Alongside the heightened infection susceptibility exhibited by obese/T2D hosts, S. aureus adapts to the hyperglycemic and hyperfibrinogenemic host environment for robust colonization. S. aureus can persist in host tissues by forming staphylococcal abscess communities (SACs) encapsulated by a fibrin pseudocapsule that protect the bacteria from antimicrobials and immune cell killing. Our current work aims to investigate how S. aureus adapts to the hyperglycemic and hyperfibrinogenemic obese/T2D environment. Our data show that two S. aureus clinical isolates, USA300 FPR3757 and JAR06.01.31, utilize fibrinogen differently in obese/T2D-like conditions to form unique pseudocapsule structures. Furthermore, RNAseq data show that in obese/T2D-like conditions, S. aureus upregulates virulence and tissue invasion gene expression. Additionally, our data suggest that antibiotic susceptibility in obese/T2D-like conditions is affected by antibiotic size, charge and metabolic activity of S. aureus. Collectively, these investigations will elucidate the impact of hyperglycemia and hyperfibrinogenemia on S. aureus abscess formation in two clinically relevant strains and may inform future therapies for obese/T2D patients. ImportanceType 2 diabetes associated with obesity creates a unique host environment that promotes the severity and persistence of Staphylococcus aureus infections. Elevated blood glucose and fibrinogen disrupt the normal immune response and create conditions that favor bacterial persistence and dissemination. S. aureus is an opportunistic pathogen capable of causing a broad spectrum of diseases ranging from skin infection to life threatening blood and bone infection. A critical step in its pathogenesis is the formation of abscesses, which shield the bacteria from immune clearance and antibiotic treatment. In this study, we demonstrate that the altered metabolic and inflammatory state of the obese diabetic host reshapes the way Staphylococcus aureus constructs these protective abscesses. We show that S. aureus modifies its use of host fibrin and adjusts its gene expression in response to high blood glucose and fibrinogen, thereby enhancing its ability to persist in host tissues.