Human Streptococcal Necrotizing Fasciitis Histopathology Mirrored in a Murine Model

Keller, Nadia; Andreoni, Federica; Reiber, Claudine; Luethi-Schaller, Helga; Schuepbach, Reto A.; Moch, Holger; Maggio, Ewerton Marques

doi:10.1016/j.ajpath.2018.03.009

Cited by 15 publications

(14 citation statements)

References 20 publications

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“…We used a previously described mouse necrotizing fasciitis model, with minor modifications (23). At 24 and 48 h after infection, the mouse model was found to be histologically similar to human necrotizing fasciitis in terms of tissue necrosis, infection spread along fascial planes, inflammatory cell infiltration, hemorrhaging, and ulceration (24, 25) (Fig. 1A and B).…”

Section: Resultsmentioning

confidence: 83%

Streptococcus pyogenes Transcriptome Changes in the Inflammatory Environment of Necrotizing Fasciitis

Hirose

Yamaguchi

Okuzaki

et al. 2019

Appl Environ Microbiol

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Necrotizing fasciitis, a life-threatening subcutaneous soft-tissue infection, is principally caused by S. pyogenes. The inflammatory environment at the site of infection causes global gene expression changes for survival of the bacterium and pathogenesis. However, no known study regarding transcriptomic profiling of S. pyogenes in cases of necrotizing fasciitis has been presented. We identified 483 bacterial genes whose expression was consistently altered during infection. Our results showed that S. pyogenes infection induces drastic upregulation of the expression of virulence-associated genes and shifts metabolic pathway usage. In particular, high-level expression of toxins, such as cytolysins, proteases, and nucleases, was observed at infection sites. In addition, genes identified as consistently enriched included those related to metabolism of arginine and histidine as well as carbohydrate uptake and utilization. Conversely, genes associated with the oxidative stress response and cell division were consistently downregulated during infection. The present findings provide useful information for establishing novel treatment strategies.

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Section: Resultsmentioning

confidence: 83%

Streptococcus pyogenes Transcriptome Changes in the Inflammatory Environment of Necrotizing Fasciitis

Hirose

Yamaguchi

Okuzaki

et al. 2019

Appl Environ Microbiol

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“…Next, we aimed to corroborate these findings in a murine NF model that mimics key features of the pathophysiology of NF in patients (Keller et al, 2018). pDC infiltration into the epidermis of wild-type (WT) mice infected subcutaneously with a GAS WT strain peaked 24 hours after infection, as quantified by FACS and visualized by microscopy ( Figure 1c).…”

Section: Increased Pdc Numbers and Ifn-1 Levels At The Site Of Gas Inmentioning

confidence: 83%

Group A Streptococcal DNase Sda1 Impairs Plasmacytoid Dendritic Cells’ Type 1 Interferon Response

Keller

Woytschak

Heeb

et al. 2019

Journal of Investigative Dermatology

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Group A Streptococcus causes severe invasive infections, including necrotizing fasciitis. The expression of an array of virulence factors targeting specific host immune functions impedes successful bacterial clearance. The virulence factor streptococcal DNase Sda1 was previously shown to interfere with the entrapment of bacteria through neutrophil extracellular traps and TLR9 signaling. In this study, we showed that plasmacytoid dendritic cells are recruited to the infected tissue during group A streptococcal necrotizing fasciitis. We found that the streptococcal DNase Sda1 impairs plasmacytoid dendritic cell recruitment by reducing IFN-1 levels at the site of infection. We found that streptococcal DNase Sda1 interferes with stabilization of the DNA by the host molecule HMGB1 protein, which may account for decreased IFN-1 levels at the site of infection.

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“…We used a mouse necrotizing fasciitis model as described previously, with minor modifications [23]. At 24 and 48 h after infection, the mouse model of necrotizing fasciitis was histologically similar to human necrotizing fasciitis in terms of tissue necrosis, the infection spread along the fascial planes, inflammatory-cell infiltration, hemorrhage and ulceration [24, 25] (Fig 1A and 1B). Extensive scab formation was detected at 48 h post-infection and elimination of pus from infected hindlimbs was observed at 96 h post-infection.…”

Section: Resultsmentioning

confidence: 99%

Transcriptomic profiling of Streptococcus pyogenes M1T1 strain in a mouse model of necrotizing fasciitis

Hirose

Yamaguchi

Okuzaki

et al. 2019

Preprint

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Streptococcus pyogenes is a major cause of necrotizing fasciitis, a life-threatening subcutaneous soft-tissue infection. At the host infection site, the local environment and interaction between host and bacteria affect bacterial gene-expression profiles, but the S. pyogenes gene-expression pattern in necrotizing fasciitis remains unknown. In this study, we used a mouse model of necrotizing fasciitis and performed RNA-sequencing (RNA-seq) analysis of S. pyogenes M1T1 strain 5448 by using infected hindlimbs obtained at 24, 48, and 96 h post-infection. The RNA-seq analysis identified 483 bacterial genes whose expression was consistently altered in the infected hindlimbs as compared to their expression under in vitro conditions. The consistently enriched genes during infection included 306 genes encoding molecules involved in virulence, carbohydrate utilization, amino acid metabolism, trace-metal transport and vacuolar ATPase transport system. Surprisingly, drastic upregulation of 3 genes, encoding streptolysin S precursor (sagA), cysteine protease (speB), and secreted DNase (spd), was noted in the mouse model of necrotizing fasciitis (log2 fold-change values: >6.0, >9.4, and >7.1, respectively). Conversely, the consistently downregulated genes included 177 genes, containing genes associated with oxidative-stress response and cell division. These results suggest that S. pyogenes in necrotizing fasciitis changes its metabolism, decreases cell proliferation, and upregulates the expression of major toxins. Our findings could provide critical information for developing novel treatment strategies and vaccines for necrotizing fasciitis.Author summaryNecrotizing fasciitis, a life-threatening subcutaneous soft-tissue infection, principally caused by a Streptococcus pyogenes. At infection sites in hosts, bacterial pathogens are exposed to drastically changing environmental conditions and alter global gene expression patterns for survival and pathogenesis. However, there is no previous report about transcriptomic profiling of S. pyogenes in the necrotizing fasciitis. Here, we conducted comprehensive gene-expression analyses of S. pyogenes in the mouse model of necrotizing fasciitis at three distinct time points during infection. Our results indicated that S. pyogenes drastically upregulates the expression of virulence-associated genes and shifts metabolic-pathway usage during infection. The high-level expressions in particular of toxins, such as cytolysins, proteases, and nucleases, were observed at infection sites. In addition, the consistently enriched genes identified here included genes for metabolism of arginine and histidine, and carbohydrate uptake and utilization. Conversely, the genes associated with oxidative-stress response and cell division were consistently downregulated in the mouse model of necrotizing fasciitis. These data will provide useful information necessary for establishing novel treatment strategies (166 words).

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Human Streptococcal Necrotizing Fasciitis Histopathology Mirrored in a Murine Model

Cited by 15 publications

References 20 publications

Streptococcus pyogenes Transcriptome Changes in the Inflammatory Environment of Necrotizing Fasciitis

Streptococcus pyogenes Transcriptome Changes in the Inflammatory Environment of Necrotizing Fasciitis

Group A Streptococcal DNase Sda1 Impairs Plasmacytoid Dendritic Cells’ Type 1 Interferon Response

Transcriptomic profiling of Streptococcus pyogenes M1T1 strain in a mouse model of necrotizing fasciitis

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