Impact of Type III Secretion Effectors and of Phenoxyacetamide Inhibitors of Type III Secretion on Abscess Formation in a Mouse Model of Pseudomonas aeruginosa Infection

Abstract

is a leading cause of intra-abdominal infections, wound infections, and community-acquired folliculitis, each of which may involve macro- or microabscess formation. The rising incidence of multidrug resistance among isolates has increased both the economic burden and the morbidity and mortality associated with disease and necessitates a search for novel therapeutics. Previous work from our group detailed novel phenoxyacetamide inhibitors that block type III secretion and injection into host cells In this study, we used a mouse model of abscess formation to test the efficacy of these compounds against the type III secretion system (T3SS). Bacteria used the T3SS to intoxicate infiltrating neutrophils to establish abscesses. Despite this antagonism, sufficient numbers of functioning neutrophils remained for proper containment of the abscesses, as neutrophil depletion resulted in an increased abscess size, the formation of dermonecrotic lesions on the skin, and the dissemination of to internal organs. Consistent with the specificity of the T3SS-neutrophil interaction, bacteria lacking a functional T3SS were fully capable of causing abscesses in a neutropenic host. Phenoxyacetamide inhibitors attenuated abscess formation and aided in the immune clearance of the bacteria. Finally, a strain resistant to the phenoxyacetamide compound was fully capable of causing abscess formation even in the presence of the T3SS inhibitors. Together, our results further define the role of type III secretion in murine abscess formation and demonstrate the efficacy of phenoxyacetamide inhibitors in infection.

Animal Models of Type III Secretion System-Mediated Pathogenesis

“…P. aeruginosa P. aeruginosa infection is characterized by subcutaneous abscess formation [26] or fluid accumulation in the lungs [135] P. aeruginosa is often studied in rodent species such as mice and rats, and these symptoms are used to determine the severity of disease. The Berube laboratory used abscess formation in mice as the primary indicator during their screen of potential T3SS inhibitors [26]. Following subcutaneous injection of P. aeruginosa, an abscess formed that protruded from the side of the mouse.…”

“…The T3SS is an attractive anti-virulence target, because many T3SS knockout strains have attenuated virulence [12,[22][23][24][25][26][27][28][29][30][31]. Efforts have gone into screening for T3SS inhibitors, and a common theme among them is a lack of toxicity to the pathogen [22,32,33].…”

Two Pseudomonas aeruginosa clonal groups belonging to the PA14 clade are indigenous to the Churince system in Cuatro Ciénegas Coahuila, México

“…aeruginosa QSR modulates the expression of several virulence factors such as pyocianin (PYO), elastase and rhamnolipids (RL) through the activity of two transcriptional regulators (LasR and RhlR) that interact with their cognate AIs 3-oxo-dodecanoyl-homoserine lactone (3O-C12-HSL) with LasR and butanoyl-homoserine lactone (C4-HSL) with RhlR. P. aeruginosa clades 1 and 2 share the secretion of toxins through the type III secretion system (T3SS), which is also an important virulence associated trait (Dacheaux et al, 1999;Berube et al, 2017). Strain PA14 and other members of clade 2 secrete ExoU and ExoT effectors through the T3SS (Miyata et al, 2003).…”

Tracking the genome of four Pseudomonas aeruginosa isolates that have a defective Las quorum-sensing system, but are still virulent

“…The virulence of P. aeruginosa is not only determined by the QS cascade, but other factors such as the type III secretion system are also involved [6, 7].…”