Group B Streptococcus Adaptation Promotes Survival in a Hyperinflammatory Diabetic Wound Environment

Abstract

Diabetic wounds have poor healing outcomes due to the presence of numerous pathogens and a dysregulated immune response. Group B Streptococcus (GBS) is commonly isolated from diabetic wound infections, but the mechanisms of GBS virulence during these infections have not been investigated. Here, we develop a murine model of GBS diabetic wound infection, and using dual RNA-sequencing, demonstrate that GBS infection triggers an inflammatory response. GBS adapts to this hyperinflammatory environment by upregulating virulence factors including those known to be regulated by the the two-component system covRS, such as the surface protein pbsP, and the cyl operon which is responsible for hemolysin/pigmentation production. We recover hyper-pigmented/hemolytic GBS colonies from the murine diabetic wound which we determined encode mutations in covR. We further demonstrate that GBS mutants in cylE and pbsP are attenuated in the diabetic wound. This foundational study provides insight into the pathogenesis of GBS diabetic wound infections.

Heterogeneity of the group B streptococcal type VII secretion system and influence on colonization of the female genital tract

“…Given this striking subtype-specific phenotype, we sought to validate whether the T7SS subtype distribution observed in our GenBank GBS isolates is representative of recent clinical GBS isolates using collections of vaginal isolates from pregnant women and from diabetic foot ulcers that our laboratory has characterized previously (Burcham et al ., 2019, Keogh et al ., 2022). To determine GBS T7SS subtypes, we developed a multiplex PCR assay using primers against subtype specific transmembrane encoding genes, the amplicons of which could be distinguished by size ( Fig.…”

“…Vaginal isolates were obtained from Melody Neely from the Detroit Medical Center as described previously (Burcham et al ., 2019). Diabetic wound isolates were obtained from Elizabeth Grice (University of Pennsylvania) as well as the CU-Anschutz Medical center (Keogh et al ., 2022). GBS was grown statically in Todd Hewitt Broth (THB; Research Products International, RPI) at 37°C.…”

Group B Streptococcus and diabetes: Finding the sweet spot

“…However, metabolic respiration in GBS has been observed with supplementation of both heme and quinones, demonstrating that GBS may undergo respiration if it acquires these components from the environment [ 14 , 15 ]. Interestingly, GBS genes involved in heme homeostasis as well as electron transport and respiration were up-regulated during wound infection of diabetic mice compared to non-diabetic mice [ 11 ]. GBS may be able to acquire these enzymes from the diabetic environment or other pathogens as was shown recently between Staphylococcus aureus and Enterococcus faecalis that share metabolites during biofilm growth [ 16 ].…”

“…The ability of GBS to shift its metabolism has been hypothesized to assist the bacterium in surviving such diverse niches [ 14 ], which could be the case during diabetic infection. In addition, respiration metabolism leads to the accumulation of the major GBS nuclease NucA, which contributes to degradation of neutrophil extracellular traps (NETs) and virulence in the lung [ 17 ] and is speculated to promote GBS survival in the diabetic wound [ 11 ], although this has not yet been shown.…”

“…Multiple studies have used a murine model of streptozotocin-induced diabetes to demonstrate that diabetic mice are more susceptible to lethal GBS infection [ 8 ], as well as GBS sepsis, arthritis, and urinary tract infection [ 9 , 10 ]. Recent studies using lepr db mice to model diabetic infection showed that diabetic mice are more susceptible to GBS skin wound infection and that GBS triggers a hyper-inflammatory environment in the wound [ 11 ]. Here, we review current understanding of how GBS may thrive in the diabetic environment, highlighting the impact of glucose, GBS gene regulation, and immune disfunction in diabetic individuals.…”