HMGB1 in severe soft tissue infections caused by Streptococcus pyogenes

Abstract

Extracellular High Mobility Group Box 1 (HMGB1) has been associated with acute and chronic inflammatory conditions. However, little is known about HMGB1 in necrotizing bacterial infections. We hypothesized that the local HMGB1 response is excessive in severe soft tissue infections (STIs), which are characterized by necrosis and hyperinflammation. To explore this, tissue biopsies were collected from patients with varying severity of Streptococcus pyogenes skin and STIs, including erysipelas, cellulitis, and necrotizing fasciitis. Tissue sections were immunostained for HMGB1, S. pyogenes, and inflammatory cell infiltrates and results quantified by acquired computerized image analysis (ACIA). HMGB1 expression increased in parallel to disease severity and was significantly higher in necrotizing fasciitis than in erysipelas (p = 0.0023). Confocal microscopy of sections co-stained for HMGB1 and cell markers revealed both extracellular and cytoplasmic HMGB1, the latter of which was found predominantly in macrophages. To further verify macrophages as main source of activation triggered HMGB1 release, human macrophages were infected with clinical S. pyogenes isolates. The results demonstrated infection triggered release of HMGB1. Dual staining's visualized HMGB1 in areas close to, but not overlapping, with neutrophils, indicating a potential chemotactic role. In vitro transmigration experiments showed a chemotactic effect of HMGB1 on neutrophils. The data furthermore provided in vivo support that HGMB1 may form immunostimulatory complexes with IL-1β. Taken together, the findings provide the first in vivo evidence that HMGB1 is abundant at the local site of severe bacterial STIs and its levels correlated to severity of infections; hence, indicating its potential value as a biomarker for tissue pathology.

Biofilm in group A streptococcal necrotizing soft tissue infections

“…The biopsies with biofilm were characterized by high bacterial load and a pronounced host response in terms of elevated levels of IL-8, resistin, and neutrophil influx. All these markers have previously been associated with increased severity of GAS tissue infections (13,20). However, in a subanalysis, no relation between biofilm findings and various clinical parameters of the 31 NSTI patients -including length of stay at the ICU and hospital, severity of infection as assessed by SAPSII or SOFA, number of surgical interventions, or presence of comorbidities -was identified (Supplemental Table 3).…”

“…Histological analysis and immunostaining of tissue biopsies. Cryosectioning, fixation, and staining were done as previously detailed (15,20). For cryosectioning, skin tissue models were treated with 2.0 M sucrose for 1 hour before being embedded in optimum cutting temperature compound (Sakura) and then frozen in liquid nitrogen and stored at -80°C.…”

Beyond microbial community composition: functional activities of the oral microbiome in health and disease

“…and Actinomyces spp [40]. However, there are disparities between microbial communities localized at acidic versus neutral pH strata.…”

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

“…This leads to a significant reduction in innate immune system responses, and protects GAS from autophagy (442) and lysosome acidification (443), and leads to a reduction in PARP activity. The reduction in PARP activity is believed to stimulate the release of high-mobility-group box protein 1 (HMGB1) from the nucleus to the cytosol, where it acts as an inflammatory mediator (444), is deposited in damaged tissues (445), and contributes to necrosis. Conversely, NADase-negative GAS is also able to activate PARP, by an unknown mechanism.…”