Tissue Tropism in Streptococcal Infection: Wild-Type M1T1 Group A<i>Streptococcus</i>Is Efficiently Cleared by Neutrophils Using an NADPH Oxidase-Dependent Mechanism in the Lung but Not in the Skin

Lei, Benfang; Minor, Dylan; Feng, Wenchao; Jerome, Maria; Quinn, Mark T.; Jutila, Mark A.; Liu, Mengyao

doi:10.1128/iai.00527-19

Cited by 5 publications

(3 citation statements)

References 54 publications

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“…Here, when mice were depleted of neutrophils, the bacterial burden of the SLSdeficient S. pyogenes nasopharyngeal infection was unaffected (Fig 4). We also noted that neutrophil-deplete mice infected with the wildtype bacteria was also unaffected yet had increased amounts of bacteria present in their lungs (S3 Fig) , which concurs with a study highlighting the role of neutrophils in preventing streptococcal pneumonia in mice [47]. Although neutrophil depletion did not restore bacterial burden in the nasopharynx, bacterial burden was recovered in a streptococcal skin infection (Fig 4E), which was expected given that the lack of SLS is associated with increased neutrophils during skin infection in mice [24].…”

Section: Plos Pathogenssupporting

confidence: 90%

Streptolysin S is required for Streptococcus pyogenes nasopharyngeal and skin infection in HLA-transgenic mice

Shannon,

Hurst,

Flannagan

et al. 2024

PLoS Pathog

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Streptococcus pyogenes is a human-specific pathogen that commonly colonizes the upper respiratory tract and skin, causing a wide variety of diseases ranging from pharyngitis to necrotizing fasciitis and toxic shock syndrome. S. pyogenes has a repertoire of secreted virulence factors that promote infection and evasion of the host immune system including the cytolysins streptolysin O (SLO) and streptolysin S (SLS). S. pyogenes does not naturally infect the upper respiratory tract of mice although mice transgenic for MHC class II human leukocyte antigens (HLA) become highly susceptible. Here we used HLA-transgenic mice to assess the role of both SLO and SLS during both nasopharyngeal and skin infection. Using S. pyogenes MGAS8232 as a model strain, we found that an SLS-deficient strain exhibited a 100-fold reduction in bacterial recovery from the nasopharynx and a 10-fold reduction in bacterial burden in the skin, whereas an SLO-deficient strain did not exhibit any infection defects in these models. Furthermore, depletion of neutrophils significantly restored the bacterial burden of the SLS-deficient bacteria in skin, but not in the nasopharynx. In mice nasally infected with the wildtype S. pyogenes, there was a marked change in localization of the tight junction protein ZO-1 at the site of infection, demonstrating damage to the nasal epithelia that was absent in mice infected with the SLS-deficient strain. Overall, we conclude that SLS is required for the establishment of nasopharyngeal infection and skin infection in HLA-transgenic mice by S. pyogenes MGAS8232 and provide evidence that SLS contributes to nasopharyngeal infection through the localized destruction of nasal epithelia.

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Section: Plos Pathogenssupporting

confidence: 90%

Streptolysin S is required for Streptococcus pyogenes nasopharyngeal and skin infection in HLA-transgenic mice

Shannon,

Hurst,

Flannagan

et al. 2024

PLoS Pathog

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“…For example, a recent report by Lei et al details the differences in neutrophil response to Group A Streptococcus in the lungs compared to the skin. While this bacterial species is efficiently cleared from the lungs of mice by a nicotinamide adenine dinucleotide phosphate oxidase (NOX)-dependent mechanism, clearance is impaired in the skin [55]. This discrepancy may be due to creation of an anoxic environment in the skin, which favors the growth of this organism but hampers oxidative burst by neutrophils.…”

Section: Bacterial Infectionsmentioning

confidence: 99%

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

Giacalone

Margaroli

Mall

et al. 2020

IJMS

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Neutrophils have a prominent role in all human immune responses against any type of pathogen or stimulus. The lungs are a major neutrophil reservoir and neutrophilic inflammation is a primary response to both infectious and non-infectious challenges. While neutrophils are well known for their essential role in clearance of bacteria, they are also equipped with specific mechanisms to counter viruses and fungi. When these defense mechanisms become aberrantly activated in the absence of infection, this commonly results in debilitating chronic lung inflammation. Clearance of bacteria by phagocytosis is the hallmark role of neutrophils and has been studied extensively. New studies on neutrophil biology have revealed that this leukocyte subset is highly adaptable and fulfills diverse roles. Of special interest is how these adaptations can impact the outcome of an immune response in the lungs due to their potent capacity for clearing infection and causing damage to host tissue. The adaptability of neutrophils and their propensity to influence the outcome of immune responses implicates them as a much-needed target of future immunomodulatory therapies. This review highlights the recent advances elucidating the mechanisms of neutrophilic inflammation, with a focus on the lung environment due to the immense and growing public health burden of chronic lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), and acute lung inflammatory diseases such as transfusion-related acute lung injury (TRALI).

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“…Additional roles of SLS during host infections are also becoming clear, since the toxin is highly upregulated during invasive GAS infections, and it has been shown that GAS lacking the toxin exhibit significant deficiencies in causing skin lesions and disseminating in vivo ( Datta et al., 2005 ; Hirose et al., 2019 ). SLS has also been shown to contribute to the degradation of epithelial cell junctions to promote invasive disease, induce lysis of multiple nonerythrocytic cell types, and have other significant effects in both in vivo and in vitro infection models ( Ginsburg, 1972 ; Betschel et al., 1998 ; Miyoshi-akiyama et al., 2005 ; Sumitomo et al., 2011 ; Flaherty et al., 2015 ; Hirose et al., 2019 ; Lei et al., 2019 ). These include the ability of SLS to exacerbate the host inflammatory response, thereby disrupting the ability of the host immune system to clear the infection without over-activation that results in damaging hyperinflammation ( Flaherty et al., 2015 ; Castiglia et al., 2016 ; Flaherty et al., 2018 ; von Beek et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Streptolysin S targets the sodium-bicarbonate cotransporter NBCn1 to induce inflammation and cytotoxicity in human keratinocytes during Group A Streptococcal infection

Donahue

Tucker

Ashfeld

et al. 2022

Front. Cell. Infect. Microbiol.

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Group A Streptococcus (GAS, Streptococcus pyogenes) is a Gram-positive human pathogen that employs several secreted and surface-bound virulence factors to manipulate its environment, allowing it to cause a variety of disease outcomes. One such virulence factor is Streptolysin S (SLS), a ribosomally-produced peptide toxin that undergoes extensive post-translational modifications. The activity of SLS has been studied for over 100 years owing to its rapid and potent ability to lyse red blood cells, and the toxin has been shown to play a major role in GAS virulence in vivo. We have previously demonstrated that SLS induces hemolysis by targeting the chloride-bicarbonate exchanger Band 3 in erythrocytes, indicating that SLS is capable of targeting host proteins to promote cell lysis. However, the possibility that SLS has additional protein targets in other cell types, such as keratinocytes, has not been explored. Here, we use bioinformatics analysis and chemical inhibition studies to demonstrate that SLS targets the electroneutral sodium-bicarbonate cotransporter NBCn1 in keratinocytes during GAS infection. SLS induces NF-κB activation and host cytotoxicity in human keratinocytes, and these processes can be mitigated by treating keratinocytes with the sodium-bicarbonate cotransport inhibitor S0859. Furthermore, treating keratinocytes with SLS disrupts the ability of host cells to regulate their intracellular pH, and this can be monitored in real time using the pH-sensitive dye pHrodo Red AM in live imaging studies. These results demonstrate that SLS is a multifunctional bacterial toxin that GAS uses in numerous context-dependent ways to promote host cell cytotoxicity and increase disease severity. Studies to elucidate additional host targets of SLS have the potential to impact the development of therapeutics for severe GAS infections.

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Tissue Tropism in Streptococcal Infection: Wild-Type M1T1 Group AStreptococcusIs Efficiently Cleared by Neutrophils Using an NADPH Oxidase-Dependent Mechanism in the Lung but Not in the Skin

Cited by 5 publications

References 54 publications

Streptolysin S is required for Streptococcus pyogenes nasopharyngeal and skin infection in HLA-transgenic mice

Streptolysin S is required for Streptococcus pyogenes nasopharyngeal and skin infection in HLA-transgenic mice

Neutrophil Adaptations upon Recruitment to the Lung: New Concepts and Implications for Homeostasis and Disease

Streptolysin S targets the sodium-bicarbonate cotransporter NBCn1 to induce inflammation and cytotoxicity in human keratinocytes during Group A Streptococcal infection

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