Streptolysin O Deficiency in Streptococcus pyogenes M1T1
 covR/S
 Mutant Strain Attenuates Virulence in
 In Vitro
 and
 In Vivo
 Infection Models

Langshaw, Emma; Reynolds, Simone; Ozberk, Victoria; Dooley, Jessica; Calcutt, Ainslie; Zaman, Mehfuz; Walker, Mark J.; Batzloff, Michael R.; Davies, Mark R.; Good, Michael F.; Pandey, Manisha

doi:10.1128/mbio.03488-22

Cited by 3 publications

(8 citation statements)

References 45 publications

(91 reference statements)

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“…SLO is a known inducer of apoptotic program in myeloid cells, which requires activation of caspase-8 [ 64 ]. Since SLO was previously shown to (i) impact maturation of murine DCs, (ii) to interfere with caspases [ 16 , 36 ], and (iii) its expression is under CovR/S control [ 60 ], we hypothesized that SLO might be responsible for impaired secretion of IL-18 by moDCs. First, hemolytic activity of stationary culture supernatants of 5448 and 5448AP was measured.…”

Section: Resultsmentioning

confidence: 99%

“…All strains were cultured in Todd-Hewitt broth (Carl Roth) supplemented with 1.5% (w/v) yeast extract (Carl Roth) at 37 °C. Hemolytic activity of GAS stationary culture supernatants was assessed as previously described [ 36 ]. To assess CovR/S functionality, SpeB secretion and activity were tested via casein digestion assay [ 54 ].…”

Section: Methodsmentioning

confidence: 99%

“…In murine models, it was shown that DCs are essential to limit GAS spread to the lymph nodes [ 40 ]. Furthermore, in vitro studies have demonstrated that GAS inhibit DC maturation in a capsule- and/or SLO-dependent manner and induce significant cell death [ 16 , 36 ]. In addition, the streptococcal DNase Sda1 was found to impair plasmacytoid dendritic cell recruitment by reducing IFN-1 levels at the tissue site of infection [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

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Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes

Tölken,

Paulikat,

Jachmann

et al. 2024

J Biomed Sci

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Background Streptococcus pyogenes (group A streptococcus, GAS) causes a variety of diseases ranging from mild superficial infections of the throat and skin to severe invasive infections, such as necrotizing soft tissue infections (NSTIs). Tissue passage of GAS often results in mutations within the genes encoding for control of virulence (Cov)R/S two component system leading to a hyper-virulent phenotype. Dendritic cells (DCs) are innate immune sentinels specialized in antigen uptake and subsequent T cell priming. This study aimed to analyze cytokine release by DCs and other cells of monocytic origin in response to wild-type and natural covR/S mutant infections. Methods Human primary monocyte-derived (mo)DCs were used. DC maturation and release of pro-inflammatory cytokines in response to infections with wild-type and covR/S mutants were assessed via flow cytometry. Global proteome changes were assessed via mass spectrometry. As a proof-of-principle, cytokine release by human primary monocytes and macrophages was determined. Results In vitro infections of moDCs and other monocytic cells with natural GAS covR/S mutants resulted in reduced secretion of IL-8 and IL-18 as compared to wild-type infections. In contrast, moDC maturation remained unaffected. Inhibition of caspase-8 restored secretion of both molecules. Knock-out of streptolysin O in GAS strain with unaffected CovR/S even further elevated the IL-18 secretion by moDCs. Of 67 fully sequenced NSTI GAS isolates, 28 harbored mutations resulting in dysfunctional CovR/S. However, analyses of plasma IL-8 and IL-18 levels did not correlate with presence or absence of such mutations. Conclusions Our data demonstrate that strains, which harbor covR/S mutations, interfere with IL-18 and IL-8 responses in monocytic cells by utilizing the caspase-8 axis. Future experiments aim to identify the underlying mechanism and consequences for NSTI patients.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes

Tölken,

Paulikat,

Jachmann

et al. 2024

J Biomed Sci

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show abstract

“…An increase in virulence of the GAS M1T1 clone can be attributed to the upregulation of its CDC streptolysin O (SLO). Recently, Langshaw et al investigated how SLO contributed to pathogenesis of covR/S mutant GAS disease [43 ▪▪ ]. Increased expression of SLO decreased dendritic cell viability and increased the production of TNF and monocyte chemoattractant-1.…”

Section: Streptococcus Pyogenes Streptolysin Omentioning

confidence: 99%

“…Increased expression of SLO decreased dendritic cell viability and increased the production of TNF and monocyte chemoattractant-1. Furthermore, GAS M1T1 deficient in SLO significantly reduces bacterial load and attenuates virulence [43 ▪▪ ,44,45].…”

Section: Streptococcus Pyogenes Streptolysin Omentioning

confidence: 99%

Bacterial cholesterol-dependent cytolysins and their interaction with the human immune response

Sanford,

Tweten,

Abrahamsen

2024

Current Opinion in Infectious Diseases

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Purpose of review Many cholesterol-dependent cytolysin (CDC)-producing pathogens pose a significant threat to human health. Herein, we review the pore-dependent and -independent properties CDCs possess to assist pathogens in evading the host immune response. Recent findings Within the last 5 years, exciting new research suggests CDCs can act to inhibit important immune functions, disrupt critical cell signaling pathways, and have tissue-specific effects. Additionally, recent studies have identified a key region of CDCs that generates robust immunity, providing resources for the development of CDC-based vaccines. Summary This review provides new information on how CDCs alter host immune responses to aid bacteria in pathogenesis. These studies can assist in the design of more efficient vaccines and therapeutics against CDCs that will enhance the immune response to CDC-producing pathogens while mitigating the dampening effects CDCs have on the host immune response.

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Dietary supplementation with Macleaya cordata extract alleviates intestinal injury in broiler chickens challenged with lipopolysaccharide by regulating gut microbiota and plasma metabolites

Wang,

Zhang,

et al. 2024

Front. Immunol.

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IntroductionThe prevention and mitigation of intestinal immune challenge is crucial for poultry production. This study investigated the effects of dietary Macleaya cordata extract (MCE) supplementation on the prevention of intestinal injury in broiler chickens challenged with lipopolysaccharide (LPS).MethodsA total of 256 one-day-old male Arbor Acres broilers were randomly divided into 4 treatment groups using a 2×2 factorial design with 2 MCE supplemental levels (0 and 400 mg/kg) and 2 LPS challenge levels (0 and 1 mg/kg body weight). The experiment lasted for 21 d.Results and discussionThe results showed that MCE supplementation increased the average daily feed intake during days 0-14. MCE supplementation and LPS challenge have an interaction on the average daily gain during days 15-21. MCE supplementation significantly alleviated the decreased average daily gain of broiler chickens induced by LPS. MCE supplementation increased the total antioxidant capacity and the activity of catalase and reduced the level of malondialdehyde in jejunal mucosa. MCE addition elevated the villus height and the ratio of villus height to crypt depth of the ileum. MCE supplementation decreased the mRNA expression of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 in the jejunum. MCE addition mitigated LPS-induced mRNA up-expression of pro-inflammatory factors IL-1β and IL-17 in the jejunum. MCE supplementation increased the abundance of probiotic bacteria (such as Lactobacillus and Blautia) and reduced the abundance of pathogenic bacteria (such as Actinobacteriota, Peptostretococcaceae, and Rhodococcus), leading to alterations in gut microbiota composition. MCE addition altered several metabolic pathways such as Amino acid metabolism, Nucleotide metabolism, Energy metabolism, Carbohydrate metabolism, and Lipid metabolism in broilers. In these pathways, MCE supplementation increased the levels of L-aspartic acid, L-Glutamate, L-serine, etc., and reduced the levels of phosphatidylcholine, phosphatidylethanolamine, thromboxane B2, 13-(S)-HODPE, etc. In conclusion, dietary supplementation of 400 mg/kg MCE effectively improved the growth performance and intestinal function in LPS-challenged broiler chickens, probably due to the modulation of gut microbiota and plasma metabolites.

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Streptolysin O Deficiency in Streptococcus pyogenes M1T1 covR/S Mutant Strain Attenuates Virulence in In Vitro and In Vivo Infection Models

Cited by 3 publications

References 45 publications

Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes

Reduced interleukin-18 secretion by human monocytic cells in response to infections with hyper-virulent Streptococcus pyogenes

Bacterial cholesterol-dependent cytolysins and their interaction with the human immune response

Dietary supplementation with Macleaya cordata extract alleviates intestinal injury in broiler chickens challenged with lipopolysaccharide by regulating gut microbiota and plasma metabolites

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