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Heiko Herwald - One of the best experts on this subject based on the ideXlab platform.
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Cold Atmospheric Plasma Disarms M1 Protein, an Important Streptococcal Virulence Factor
Journal of Innate Immunity, 2019Co-Authors: Sandra T. Persson, Simon Ekström, Praveen Papareddy, Heiko HerwaldAbstract:Cold atmospheric plasma (CAP) has been demonstrated to be a successful antiseptic for chronic and infected wounds. Although experimental work has focused on elucidation of the curative power of CAP for wound healing, the molecular mechanisms behind this ability are less understood. To date, the direct effect of CAP on the activity of microbial virulence factors has not been investigated. In the present study, we therefore examined whether CAP can modulate the detrimental activity of M1 Protein, one of the most studied Streptococcus pyogenes virulence determinant. Our results show that CAP abolishes the ability of M1 Protein to trigger inflammatory host responses. Subsequent mass spectrometric analysis revealed that this effect was caused by oxidation of Met81 and Trp128 located at the sub-N-terminal region of M1 Protein provoking a conformational change. Notably, our results also show that CAP has an insignificant effect on the host immune system, supporting the benefits of using CAP to combat infections. Considering the growing number of antibiotic-resistant bacteria, novel antimicrobial therapeutic approaches are urgently needed that do not bear the risk of inducing additional resistance. Our study therefore may open new research avenues for the development of novel approaches for the treatment of skin and wound infections caused by S. pyogenes.
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Leucocyte recruitment and molecular fortification of keratinocytes triggered by streptococcal M1 Protein.
Cellular Microbiology, 2017Co-Authors: Sandra T. Persson, Simon Hauri, Johan Malmström, Heiko HerwaldAbstract:Streptococcus pyogenes of the M1 serotype is commonly associated with invasive streptococcal infections and development of streptococcal toxic shock syndrome. The M1 Protein is a powerful inducer of inflammatory responses for several human cell types, but the reason why M1 Protein-related strains is over-represented in invasive streptococcal diseases is still not understood. This study was undertaken to investigate if soluble M1 Protein can aggravate the severity of streptococcal skin infections in respect to inflammation, leucocyte recruitment, and tissue remodelling as seen in patients with cellulitis and necrotizing fasciitis. We found that HaCaT cells are able to recruit activated leucocytes when encountering M1 Protein. Neither the bacterial Protein nor activated leucocytes caused cell damage on HaCaT cells, instead HaCaT cells responded to the bacterial virulence factor by releasing several Proteins protective against bacterial infection and leucocyte responses. However, although not cytotoxic, M1 Protein completely abolished wound healing abilities of HaCaT cells. Taken together, our results demonstrate that M1 Protein is a critical virulence factor that can augment streptococcal skin infection suggesting that the Protein is an interesting target for drug development.
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Vigilant Keratinocytes Trigger PAMP Signaling in Response to Streptococcal M1 Protein
Infection and Immunity, 2015Co-Authors: Sandra T. Persson, Matthias Mörgelin, Laura Wilk, Heiko HerwaldAbstract:The human skin exerts many functions in order to maintain its barrier integrity and protect the host from invading microorganisms. One such pathogen is Streptococcus pyogenes, which can cause a variety of superficial skin wounds that may eventually progress into invasive deep soft tissue infections. Here we show that keratinocytes recognize soluble M1 Protein, a streptococcal virulence factor, as a pathogen-associated molecular pattern to release alarming inflammatory responses. We found that this interaction initiates an inflammatory intracellular signaling cascade involving the activation of the mitogen-activated Protein kinases extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal Protein kinase and the subsequent induction and mobilization of the transcription factors NF-κB and AP-1. We also determined the imprint of the inflammatory mediators released, such as interleukin-8 (IL-8), growth-related oncogene alpha, migration inhibitory factor, extracellular matrix metalloProteinase inducer, IL-1α, IL-1 receptor a, and ST2, in response to streptococcal M1 Protein. The expression of IL-8 is dependent on Toll-like receptor 2 activity and subsequent activation of the mitogen-activated Protein kinases ERK and p38. Notably, this signaling seems to be distinct for IL-8 release, and it is not shared with the other inflammatory mediators. We conclude that keratinocytes participate in a proinflammatory manner in streptococcal pattern recognition and that expression of the chemoattractant IL-8 by keratinocytes constitutes an important protective mechanism against streptococcal M1 Protein.
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STAT3-dependent CXC chemokine formation and neutrophil migration in streptococcal M1 Protein-induced acute lung inflammation.
American journal of physiology. Lung cellular and molecular physiology, 2015Co-Authors: Songen Zhang, Heiko Herwald, Rundk Hwaiz, Lingtao Luo, Henrik ThorlaciusAbstract:Streptococcus pyogenes cause infections ranging from mild pharyngitis to severe streptococcal toxic shock syndrome (STSS). The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, it was hypothesized that STAT3 signaling might be involved in M1 Protein-evoked lung inflammation. The STAT3 inhibitor, S3I-201, was administered to male C57Bl/6 mice before iv challenge with M1 Protein. Bronchoalveolar fluid and lung tissue were harvested for quantification of STAT3 activity, neutrophil recruitment, edema, and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Levels of IL-6 and HMGB1 were determined in plasma. CXCL2-induced neutrophil chemotaxis was studied in vitro. Administration of S3I-201 markedly reduced M1 Protein-provoked STAT3 activity, neutrophil recruitment, edema formation, and inflammatory changes in the lung. In addition, M1 Protein significantly increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Treatment with S3I-201 had no effect on M1 Protein-induced expression of Mac-1 on neutrophils. In contrast, inhibition of STAT3 activity greatly reduced M1 Protein-induced formation of CXC chemokines in the lung. Interestingly, STAT3 inhibition markedly decreased plasma levels of IL-6 and HMGB1 in animals exposed to M1 Protein. Moreover, we found that S3I-201 abolished CXCL2-induced neutrophil migration in vitro. In conclusion, these novel findings indicate that STAT3 signaling plays a key role in mediating CXC chemokine production and neutrophil infiltration in M1 Protein-induced acute lung inflammation.
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Streptococcal M1 Protein triggers chemokine formation, neutrophil infiltration, and lung injury in an NFAT-dependent manner.
Journal of Leukocyte Biology, 2015Co-Authors: Songen Zhang, Heiko Herwald, Su Zhang, Eliana Garcia-vaz, Maria F. Gomez, Henrik ThorlaciusAbstract:Streptococcus pyogenes of the M1 serotype can cause STSS, which is associated with significant morbidity and mortality. The purpose of the present study was to examine the role of NFAT signaling in M1 Protein-induced lung injury. NFAT-luc mice were treated with the NFAT inhibitor A-285222 before administration of the M1 Protein. Neutrophil infiltration, edema, and CXC chemokines were quantified in the lung, 4 h after challenge with the M1 Protein. Flow cytometry was used to determine Mac-1 expression. Challenge with the M1 Protein increased NFAT-dependent transcriptional activity in the lung, spleen, and liver in NFAT-luc mice. Administration of the NFAT inhibitor A-285222 abolished M1 Protein-evoked NFAT activation in the lung, spleen, and liver. M1 Protein challenge induced neutrophil recruitment, edema, and CXC chemokine production in the lung, as well as up-regulation of Mac-1 on circulating neutrophils. Inhibition of NFAT activity attenuated M1 Protein-induced neutrophil infiltration by 77% and edema formation by 50% in the lung. Moreover, administration of A-285222 reduced M1 Protein-evoked pulmonary formation of CXC chemokine >80%. In addition, NFAT inhibition decreased M1 Protein-triggered Mac-1 up-regulation on neutrophils. These findings indicate that NFAT signaling controls pulmonary infiltration of neutrophils in response to streptococcal M1 Protein via formation of CXC chemokines and neutrophil expression of Mac-1. Thus, the targeting of NFAT activity might be a useful way to ameliorate lung injury in streptococcal infections.
Henrik Thorlacius - One of the best experts on this subject based on the ideXlab platform.
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STAT3-dependent CXC chemokine formation and neutrophil migration in streptococcal M1 Protein-induced acute lung inflammation.
American journal of physiology. Lung cellular and molecular physiology, 2015Co-Authors: Songen Zhang, Heiko Herwald, Rundk Hwaiz, Lingtao Luo, Henrik ThorlaciusAbstract:Streptococcus pyogenes cause infections ranging from mild pharyngitis to severe streptococcal toxic shock syndrome (STSS). The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, it was hypothesized that STAT3 signaling might be involved in M1 Protein-evoked lung inflammation. The STAT3 inhibitor, S3I-201, was administered to male C57Bl/6 mice before iv challenge with M1 Protein. Bronchoalveolar fluid and lung tissue were harvested for quantification of STAT3 activity, neutrophil recruitment, edema, and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Levels of IL-6 and HMGB1 were determined in plasma. CXCL2-induced neutrophil chemotaxis was studied in vitro. Administration of S3I-201 markedly reduced M1 Protein-provoked STAT3 activity, neutrophil recruitment, edema formation, and inflammatory changes in the lung. In addition, M1 Protein significantly increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Treatment with S3I-201 had no effect on M1 Protein-induced expression of Mac-1 on neutrophils. In contrast, inhibition of STAT3 activity greatly reduced M1 Protein-induced formation of CXC chemokines in the lung. Interestingly, STAT3 inhibition markedly decreased plasma levels of IL-6 and HMGB1 in animals exposed to M1 Protein. Moreover, we found that S3I-201 abolished CXCL2-induced neutrophil migration in vitro. In conclusion, these novel findings indicate that STAT3 signaling plays a key role in mediating CXC chemokine production and neutrophil infiltration in M1 Protein-induced acute lung inflammation.
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Streptococcal M1 Protein triggers chemokine formation, neutrophil infiltration, and lung injury in an NFAT-dependent manner.
Journal of Leukocyte Biology, 2015Co-Authors: Songen Zhang, Heiko Herwald, Su Zhang, Eliana Garcia-vaz, Maria F. Gomez, Henrik ThorlaciusAbstract:Streptococcus pyogenes of the M1 serotype can cause STSS, which is associated with significant morbidity and mortality. The purpose of the present study was to examine the role of NFAT signaling in M1 Protein-induced lung injury. NFAT-luc mice were treated with the NFAT inhibitor A-285222 before administration of the M1 Protein. Neutrophil infiltration, edema, and CXC chemokines were quantified in the lung, 4 h after challenge with the M1 Protein. Flow cytometry was used to determine Mac-1 expression. Challenge with the M1 Protein increased NFAT-dependent transcriptional activity in the lung, spleen, and liver in NFAT-luc mice. Administration of the NFAT inhibitor A-285222 abolished M1 Protein-evoked NFAT activation in the lung, spleen, and liver. M1 Protein challenge induced neutrophil recruitment, edema, and CXC chemokine production in the lung, as well as up-regulation of Mac-1 on circulating neutrophils. Inhibition of NFAT activity attenuated M1 Protein-induced neutrophil infiltration by 77% and edema formation by 50% in the lung. Moreover, administration of A-285222 reduced M1 Protein-evoked pulmonary formation of CXC chemokine >80%. In addition, NFAT inhibition decreased M1 Protein-triggered Mac-1 up-regulation on neutrophils. These findings indicate that NFAT signaling controls pulmonary infiltration of neutrophils in response to streptococcal M1 Protein via formation of CXC chemokines and neutrophil expression of Mac-1. Thus, the targeting of NFAT activity might be a useful way to ameliorate lung injury in streptococcal infections.
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Ras regulates alveolar macrophage formation of CXC chemokines and neutrophil activation in streptococcal M1 Protein-induced lung injury.
European Journal of Pharmacology, 2014Co-Authors: Songen Zhang, Heiko Herwald, Milladur Rahman, Rundk Hwaiz, Henrik ThorlaciusAbstract:Streptococcal toxic shock syndrome (STSS) is associated with a high mortality rate. The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, we examined the role of Ras signaling in M1 Protein-induced lung injury. Male C57BL/6 mice received the Ras inhibitor (farnesylthiosalicylic acid, FTS) prior to M1 Protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Quantitative RT-PCR was used to determine gene expression of CXC chemokines in alveolar macrophages. Administration of FTS reduced M1 Protein-induced neutrophil recruitment, edema formation and tissue damage in the lung. M1 Protein challenge increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Inhibition of Ras activity decreased M1 Protein-induced expression of Mac-1 on neutrophils and secretion of CXC chemokines in the lung. Moreover, FTS abolished M1 Protein-provoked gene expression of CXC chemokines in alveolar macrophages. Ras inhibition decreased chemokine-mediated neutrophil migration in vitro. Taken together, our novel findings indicate that Ras signaling is a potent regulator of CXC chemokine formation and neutrophil infiltration in the lung. Thus, inhibition of Ras activity might be a useful way to antagonize streptococcal M1 Protein-triggered acute lung injury.
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Targeting CD162 protects against streptococcal M1 Protein-evoked neutrophil recruitment and lung injury.
American journal of physiology. Lung cellular and molecular physiology, 2013Co-Authors: Songen Zhang, Heiko Herwald, Lei Song, Yongzhi Wang, Henrik ThorlaciusAbstract:Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung damage. CD162 is an adhesion molecule that has been reported to mediate neutrophil recruitment in acute inflammatory reactions. In this study, the purpose was to investigate the role of CD162 in M1 Protein-provoked lung injury. Male C57BL/6 mice were treated with monoclonal antibody directed against CD162 or a control antibody before M1 Protein challenge. Edema, neutrophil infiltration, and CXC chemokines were determined in the lung, 4 h after M1 Protein administration. Fluorescence intravital microscopy was used to analyze leukocyte-endothelium interactions in the pulmonary microcirculation. Inhibition of CD162 reduced M1 Protein-provoked accumulation of neutrophils, edema, and CXC chemokine formation in the lung by >54%. Moreover, immunoneutralization of CD162 abolished leukocyte rolling and firm adhesion in pulmonary venules of M1 Protein-treated animals. In addition, inhibition of CD162 decreased M1 Protein-induced capillary trapping of leukocytes in the lung microvasculature and improved microvascular perfusion in the lungs of M1 Protein-treated animals. Our findings suggest that CD162 plays an important role in M1 Protein-induced lung damage by regulating leukocyte rolling in pulmonary venules. Consequently, inhibition of CD162 attenuates M1 Protein-evoked leukocyte adhesion and extravasation in the lung. Thus, our results suggest that targeting the CD162 might pave the way for novel opportunities to protect against pulmonary damage in streptococcal infections.
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Targeting Rac1 signaling inhibits streptococcal M1 Protein-induced CXC chemokine formation, neutrophil infiltration and lung injury.
PLOS ONE, 2013Co-Authors: Songen Zhang, Heiko Herwald, Su Zhang, Milladur Rahman, Lei Song, Henrik ThorlaciusAbstract:Infections with Streptococcus pyogenes exhibit a wide spectrum of infections ranging from mild pharyngitis to severe Streptococcal toxic shock syndrome (STSS). The M1 serotype of Streptococcus pyogenes is most commonly associated with STSS. In the present study, we hypothesized that Rac1 signaling might regulate M1 Protein-induced lung injury. We studied the effect of a Rac1 inhibitor (NSC23766) on M1 Protein-provoked pulmonary injury. Male C57BL/6 mice received NSC23766 prior to M1 Protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Quantitative RT-PCR was used to determine gene expression of CXC chemokines in alveolar macrophages. Treatment with NSC23766 decreased M1 Protein-induced neutrophil infiltration, edema formation and tissue injury in the lung. M1 Protein challenge markedly enhanced Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Inhibition of Rac1 activity had no effect on M1 Protein-induced expression of Mac-1 on neutrophils. However, Rac1 inhibition markedly decreased M1 Protein-evoked formation of CXC chemokines in the lung. Moreover, NSC23766 completely inhibited M1 Protein-provoked gene expression of CXC chemokines in alveolar macrophages. We conclude that these novel results suggest that Rac1 signaling is a significant regulator of neutrophil infiltration and CXC chemokine production in the lung. Thus, targeting Rac1 activity might be a potent strategy to attenuate streptococcal M1 Protein-triggered acute lung damage.
Songen Zhang - One of the best experts on this subject based on the ideXlab platform.
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STAT3-dependent CXC chemokine formation and neutrophil migration in streptococcal M1 Protein-induced acute lung inflammation.
American journal of physiology. Lung cellular and molecular physiology, 2015Co-Authors: Songen Zhang, Heiko Herwald, Rundk Hwaiz, Lingtao Luo, Henrik ThorlaciusAbstract:Streptococcus pyogenes cause infections ranging from mild pharyngitis to severe streptococcal toxic shock syndrome (STSS). The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, it was hypothesized that STAT3 signaling might be involved in M1 Protein-evoked lung inflammation. The STAT3 inhibitor, S3I-201, was administered to male C57Bl/6 mice before iv challenge with M1 Protein. Bronchoalveolar fluid and lung tissue were harvested for quantification of STAT3 activity, neutrophil recruitment, edema, and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Levels of IL-6 and HMGB1 were determined in plasma. CXCL2-induced neutrophil chemotaxis was studied in vitro. Administration of S3I-201 markedly reduced M1 Protein-provoked STAT3 activity, neutrophil recruitment, edema formation, and inflammatory changes in the lung. In addition, M1 Protein significantly increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Treatment with S3I-201 had no effect on M1 Protein-induced expression of Mac-1 on neutrophils. In contrast, inhibition of STAT3 activity greatly reduced M1 Protein-induced formation of CXC chemokines in the lung. Interestingly, STAT3 inhibition markedly decreased plasma levels of IL-6 and HMGB1 in animals exposed to M1 Protein. Moreover, we found that S3I-201 abolished CXCL2-induced neutrophil migration in vitro. In conclusion, these novel findings indicate that STAT3 signaling plays a key role in mediating CXC chemokine production and neutrophil infiltration in M1 Protein-induced acute lung inflammation.
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Streptococcal M1 Protein triggers chemokine formation, neutrophil infiltration, and lung injury in an NFAT-dependent manner.
Journal of Leukocyte Biology, 2015Co-Authors: Songen Zhang, Heiko Herwald, Su Zhang, Eliana Garcia-vaz, Maria F. Gomez, Henrik ThorlaciusAbstract:Streptococcus pyogenes of the M1 serotype can cause STSS, which is associated with significant morbidity and mortality. The purpose of the present study was to examine the role of NFAT signaling in M1 Protein-induced lung injury. NFAT-luc mice were treated with the NFAT inhibitor A-285222 before administration of the M1 Protein. Neutrophil infiltration, edema, and CXC chemokines were quantified in the lung, 4 h after challenge with the M1 Protein. Flow cytometry was used to determine Mac-1 expression. Challenge with the M1 Protein increased NFAT-dependent transcriptional activity in the lung, spleen, and liver in NFAT-luc mice. Administration of the NFAT inhibitor A-285222 abolished M1 Protein-evoked NFAT activation in the lung, spleen, and liver. M1 Protein challenge induced neutrophil recruitment, edema, and CXC chemokine production in the lung, as well as up-regulation of Mac-1 on circulating neutrophils. Inhibition of NFAT activity attenuated M1 Protein-induced neutrophil infiltration by 77% and edema formation by 50% in the lung. Moreover, administration of A-285222 reduced M1 Protein-evoked pulmonary formation of CXC chemokine >80%. In addition, NFAT inhibition decreased M1 Protein-triggered Mac-1 up-regulation on neutrophils. These findings indicate that NFAT signaling controls pulmonary infiltration of neutrophils in response to streptococcal M1 Protein via formation of CXC chemokines and neutrophil expression of Mac-1. Thus, the targeting of NFAT activity might be a useful way to ameliorate lung injury in streptococcal infections.
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Ras regulates alveolar macrophage formation of CXC chemokines and neutrophil activation in streptococcal M1 Protein-induced lung injury.
European Journal of Pharmacology, 2014Co-Authors: Songen Zhang, Heiko Herwald, Milladur Rahman, Rundk Hwaiz, Henrik ThorlaciusAbstract:Streptococcal toxic shock syndrome (STSS) is associated with a high mortality rate. The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, we examined the role of Ras signaling in M1 Protein-induced lung injury. Male C57BL/6 mice received the Ras inhibitor (farnesylthiosalicylic acid, FTS) prior to M1 Protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Quantitative RT-PCR was used to determine gene expression of CXC chemokines in alveolar macrophages. Administration of FTS reduced M1 Protein-induced neutrophil recruitment, edema formation and tissue damage in the lung. M1 Protein challenge increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Inhibition of Ras activity decreased M1 Protein-induced expression of Mac-1 on neutrophils and secretion of CXC chemokines in the lung. Moreover, FTS abolished M1 Protein-provoked gene expression of CXC chemokines in alveolar macrophages. Ras inhibition decreased chemokine-mediated neutrophil migration in vitro. Taken together, our novel findings indicate that Ras signaling is a potent regulator of CXC chemokine formation and neutrophil infiltration in the lung. Thus, inhibition of Ras activity might be a useful way to antagonize streptococcal M1 Protein-triggered acute lung injury.
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Targeting CD162 protects against streptococcal M1 Protein-evoked neutrophil recruitment and lung injury.
American journal of physiology. Lung cellular and molecular physiology, 2013Co-Authors: Songen Zhang, Heiko Herwald, Lei Song, Yongzhi Wang, Henrik ThorlaciusAbstract:Streptococcus pyogenes of the M1 serotype can cause streptococcal toxic shock syndrome and acute lung damage. CD162 is an adhesion molecule that has been reported to mediate neutrophil recruitment in acute inflammatory reactions. In this study, the purpose was to investigate the role of CD162 in M1 Protein-provoked lung injury. Male C57BL/6 mice were treated with monoclonal antibody directed against CD162 or a control antibody before M1 Protein challenge. Edema, neutrophil infiltration, and CXC chemokines were determined in the lung, 4 h after M1 Protein administration. Fluorescence intravital microscopy was used to analyze leukocyte-endothelium interactions in the pulmonary microcirculation. Inhibition of CD162 reduced M1 Protein-provoked accumulation of neutrophils, edema, and CXC chemokine formation in the lung by >54%. Moreover, immunoneutralization of CD162 abolished leukocyte rolling and firm adhesion in pulmonary venules of M1 Protein-treated animals. In addition, inhibition of CD162 decreased M1 Protein-induced capillary trapping of leukocytes in the lung microvasculature and improved microvascular perfusion in the lungs of M1 Protein-treated animals. Our findings suggest that CD162 plays an important role in M1 Protein-induced lung damage by regulating leukocyte rolling in pulmonary venules. Consequently, inhibition of CD162 attenuates M1 Protein-evoked leukocyte adhesion and extravasation in the lung. Thus, our results suggest that targeting the CD162 might pave the way for novel opportunities to protect against pulmonary damage in streptococcal infections.
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Targeting Rac1 signaling inhibits streptococcal M1 Protein-induced CXC chemokine formation, neutrophil infiltration and lung injury.
PLOS ONE, 2013Co-Authors: Songen Zhang, Heiko Herwald, Su Zhang, Milladur Rahman, Lei Song, Henrik ThorlaciusAbstract:Infections with Streptococcus pyogenes exhibit a wide spectrum of infections ranging from mild pharyngitis to severe Streptococcal toxic shock syndrome (STSS). The M1 serotype of Streptococcus pyogenes is most commonly associated with STSS. In the present study, we hypothesized that Rac1 signaling might regulate M1 Protein-induced lung injury. We studied the effect of a Rac1 inhibitor (NSC23766) on M1 Protein-provoked pulmonary injury. Male C57BL/6 mice received NSC23766 prior to M1 Protein challenge. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Quantitative RT-PCR was used to determine gene expression of CXC chemokines in alveolar macrophages. Treatment with NSC23766 decreased M1 Protein-induced neutrophil infiltration, edema formation and tissue injury in the lung. M1 Protein challenge markedly enhanced Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Inhibition of Rac1 activity had no effect on M1 Protein-induced expression of Mac-1 on neutrophils. However, Rac1 inhibition markedly decreased M1 Protein-evoked formation of CXC chemokines in the lung. Moreover, NSC23766 completely inhibited M1 Protein-provoked gene expression of CXC chemokines in alveolar macrophages. We conclude that these novel results suggest that Rac1 signaling is a significant regulator of neutrophil infiltration and CXC chemokine production in the lung. Thus, targeting Rac1 activity might be a potent strategy to attenuate streptococcal M1 Protein-triggered acute lung damage.
Matthias Mörgelin - One of the best experts on this subject based on the ideXlab platform.
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Supplementary Material for: M1 Protein-Dependent Intracellular Trafficking Promotes Persistence and Replication of Streptococcus pyogenes in Macrophages
2017Co-Authors: Erika Hertzén, Linda Johansson, Matthias Mörgelin, Robert Wallin, Heike Schmidt, Mirko Kroll, Anders P. Rehn, Malak Kotb, Anna Norrby-teglundAbstract:Streptococcus pyogenes is an important human pathogen that causes a variety of diseases including life-threatening invasive diseases, such as toxic shock and deep tissue infections. Although S. pyogenes are classically considered extracellular pathogens, a clinical significance of an intracellular source has been emphasized. In patients with deep tissue infections, an intracellular reservoir of S. pyogenes within macrophages was shown to contribute to prolonged bacterial persistence. Here we demonstrate that intracellular survival of S. pyogenes in macrophages is associated with an M1 Protein-dependent intracellular trafficking in the phagosomal-lysosomal pathway, which results in impaired fusion with lysosomes. The phagocytic vacuoles harbouring M1 Protein-expressing bacteria not only served as a safe haven for the bacteria, but also as a replicating niche. An M1 Protein-dependent modulation of macrophages was further supported by differences in NF-ĸB signalling between cells infected with either the wild-type or M1 Protein-deficient strains, thereby indicating a suppressed inflammatory response when M1 Protein was involved. Evidence of egress of bacteria out of their host cell and subsequent re-infection of new cells emphasize the importance of intracellular bacteria as a reservoir for dissemination of infection and continued tissue injury.
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Vigilant Keratinocytes Trigger PAMP Signaling in Response to Streptococcal M1 Protein
Infection and Immunity, 2015Co-Authors: Sandra T. Persson, Matthias Mörgelin, Laura Wilk, Heiko HerwaldAbstract:The human skin exerts many functions in order to maintain its barrier integrity and protect the host from invading microorganisms. One such pathogen is Streptococcus pyogenes, which can cause a variety of superficial skin wounds that may eventually progress into invasive deep soft tissue infections. Here we show that keratinocytes recognize soluble M1 Protein, a streptococcal virulence factor, as a pathogen-associated molecular pattern to release alarming inflammatory responses. We found that this interaction initiates an inflammatory intracellular signaling cascade involving the activation of the mitogen-activated Protein kinases extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal Protein kinase and the subsequent induction and mobilization of the transcription factors NF-κB and AP-1. We also determined the imprint of the inflammatory mediators released, such as interleukin-8 (IL-8), growth-related oncogene alpha, migration inhibitory factor, extracellular matrix metalloProteinase inducer, IL-1α, IL-1 receptor a, and ST2, in response to streptococcal M1 Protein. The expression of IL-8 is dependent on Toll-like receptor 2 activity and subsequent activation of the mitogen-activated Protein kinases ERK and p38. Notably, this signaling seems to be distinct for IL-8 release, and it is not shared with the other inflammatory mediators. We conclude that keratinocytes participate in a proinflammatory manner in streptococcal pattern recognition and that expression of the chemoattractant IL-8 by keratinocytes constitutes an important protective mechanism against streptococcal M1 Protein.
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The Membrane Bound LRR LipoProtein Slr, and the Cell Wall-Anchored M1 Protein from Streptococcus pyogenes Both Interact with Type I Collagen
PLOS ONE, 2011Co-Authors: Marta Bober, Ulrich Von Pawel-rammingen, Anders I Olin, Matthias Mörgelin, Mattias CollinAbstract:Streptococcus pyogenes is an important human pathogen and surface structures allow it to adhere to, colonize and invade the human host. Proteins containing leucine rich repeats (LRR) have been indentified in mammals, viruses, archaea and several bacterial species. The LRRs are often involved in Protein-Protein interaction, are typically 20–30 amino acids long and the defining feature of the LRR motif is an 11-residue sequence LxxLxLxxNxL (x being any amino acid). The streptococcal leucine rich (Slr) Protein is a hypothetical lipoProtein that has been shown to be involved in virulence, but at present no ligands for Slr have been identified. We could establish that Slr is a membrane attached horseshoe shaped lipoProtein by homology modeling, signal peptidase II inhibition, electron microscopy (of bacteria and purified Protein) and immunoblotting. Based on our previous knowledge of LRR Proteins we hypothesized that Slr could mediate binding to collagen. We could show by surface plasmon resonance that recombinant Slr and purified M1 Protein bind with high affinity to collagen I. Isogenic slr mutant strain (MB1) and emM1 mutant strain (MC25) had reduced binding to collagen type I as shown by slot blot and surface plasmon resonance. Electron microscopy using gold labeled Slr showed multiple binding sites to collagen I, both to the monomeric and the fibrillar structure, and most binding occurred in the overlap region of the collagen I fibril. In conclusion, we show that Slr is an abundant membrane bound lipoProtein that is co-expressed on the surface with M1, and that both these Proteins are involved in recruiting collagen type I to the bacterial surface. This underlines the importance of S. pyogenes interaction with extracellular matrix molecules, especially since both Slr and M1 have been shown to be virulence factors.
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M1 Protein-Dependent Intracellular Trafficking Promotes Persistence and Replication of Streptococcus pyogenes in Macrophages
Journal of Innate Immunity, 2010Co-Authors: Erika Hertzén, Linda Johansson, Matthias Mörgelin, Robert Wallin, Heike Schmidt, Mirko Kroll, Anders P. Rehn, Malak Kotb, Anna Norrby-teglundAbstract:Streptococcus pyogenes is an important human pathogen that causes a variety of diseases including life-threatening invasive diseases, such as toxic shock and deep tissue infections. Although S. pyogenes are classically considered extracellular pathogens, a clinical significance of an intracellular source has been emphasized. In patients with deep tissue infections, an intracellular reservoir of S. pyogenes within macrophages was shown to contribute to prolonged bacterial persistence. Here we demonstrate that intracellular survival of S. pyogenes in macrophages is associated with an M1 Protein-dependent intracellular trafficking in the phagosomal-lysosomal pathway, which results in impaired fusion with lysosomes. The phagocytic vacuoles harbouring M1 Protein-expressing bacteria not only served as a safe haven for the bacteria, but also as a replicating niche. An M1 Protein-dependent modulation of macrophages was further supported by differences in NF-kappa B signalling between cells infected with either the wild-type or M1 Protein-deficient strains, thereby indicating a suppressed inflammatory response when M1 Protein was involved. Evidence of egress of bacteria out of their host cell and subsequent re-infection of new cells emphasize the importance of intracellular bacteria as a reservoir for dissemination of infection and continued tissue injury. Copyright (C) 2010 S. Karger AG, Basel (Less)
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M1 Protein from streptococcus pyogenes induces nitric oxide-mediated vascular hyporesponsiveness to phenylephrine: involvement of toll-like receptor activation.
Shock, 2010Co-Authors: Thorgerdur Sigurdardottir, Heiko Herwald, Matthias Mörgelin, Viveka Björck, Sigurbjörg Rutardottir, Johan Törnebrant, Mikael BodelssonAbstract:Streptococcus pyogenes carrying M1 Protein causes the severe and increasingly prevalent streptococcal toxic shock syndrome and necrotizing fasciitis. M1 Protein is an important virulence factor of Streptococcus pyogenes and induces an inflammatory response in human monocytes. We wanted to investigate if purified M1 Protein in solution could induce vascular nitric oxide (NO) production leading to vasopressor hyporesponsiveness. Rat aorta segments were incubated with M1 Protein or lipopolysaccharide (LPS) in vitro. M1 Protein (10 mug ml) and LPS (1 ng ml) to a similar extent induced NO production and hyporesponsiveness to the vasoconstrictor phenylephrine. Immuno-gold electron microscopy demonstrated that M1 Protein binds to toll-like receptor (TLR) 2 as well as TLR4 in mouse aorta but only to TLR2 in human omental artery. Incubation with M1 Protein caused a reduction in the contractile response to phenylephrine in aorta segments from wild type and TLR2 knockout but not from TLR4 knockout mice. In conclusion, M1 Protein causes vascular NO production leading to hyporesponsiveness to vasopressors via a mechanism involving TLR but the subtypes may be species-dependent. M1 Protein could contribute to the circulatory disturbances accompanying severe invasive streptococcal infections. (Less)
Anna Norrby-teglund - One of the best experts on this subject based on the ideXlab platform.
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Supplementary Material for: M1 Protein-Dependent Intracellular Trafficking Promotes Persistence and Replication of Streptococcus pyogenes in Macrophages
2017Co-Authors: Erika Hertzén, Linda Johansson, Matthias Mörgelin, Robert Wallin, Heike Schmidt, Mirko Kroll, Anders P. Rehn, Malak Kotb, Anna Norrby-teglundAbstract:Streptococcus pyogenes is an important human pathogen that causes a variety of diseases including life-threatening invasive diseases, such as toxic shock and deep tissue infections. Although S. pyogenes are classically considered extracellular pathogens, a clinical significance of an intracellular source has been emphasized. In patients with deep tissue infections, an intracellular reservoir of S. pyogenes within macrophages was shown to contribute to prolonged bacterial persistence. Here we demonstrate that intracellular survival of S. pyogenes in macrophages is associated with an M1 Protein-dependent intracellular trafficking in the phagosomal-lysosomal pathway, which results in impaired fusion with lysosomes. The phagocytic vacuoles harbouring M1 Protein-expressing bacteria not only served as a safe haven for the bacteria, but also as a replicating niche. An M1 Protein-dependent modulation of macrophages was further supported by differences in NF-ĸB signalling between cells infected with either the wild-type or M1 Protein-deficient strains, thereby indicating a suppressed inflammatory response when M1 Protein was involved. Evidence of egress of bacteria out of their host cell and subsequent re-infection of new cells emphasize the importance of intracellular bacteria as a reservoir for dissemination of infection and continued tissue injury.
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M1 Protein-Dependent Intracellular Trafficking Promotes Persistence and Replication of Streptococcus pyogenes in Macrophages
Journal of Innate Immunity, 2010Co-Authors: Erika Hertzén, Linda Johansson, Matthias Mörgelin, Robert Wallin, Heike Schmidt, Mirko Kroll, Anders P. Rehn, Malak Kotb, Anna Norrby-teglundAbstract:Streptococcus pyogenes is an important human pathogen that causes a variety of diseases including life-threatening invasive diseases, such as toxic shock and deep tissue infections. Although S. pyogenes are classically considered extracellular pathogens, a clinical significance of an intracellular source has been emphasized. In patients with deep tissue infections, an intracellular reservoir of S. pyogenes within macrophages was shown to contribute to prolonged bacterial persistence. Here we demonstrate that intracellular survival of S. pyogenes in macrophages is associated with an M1 Protein-dependent intracellular trafficking in the phagosomal-lysosomal pathway, which results in impaired fusion with lysosomes. The phagocytic vacuoles harbouring M1 Protein-expressing bacteria not only served as a safe haven for the bacteria, but also as a replicating niche. An M1 Protein-dependent modulation of macrophages was further supported by differences in NF-kappa B signalling between cells infected with either the wild-type or M1 Protein-deficient strains, thereby indicating a suppressed inflammatory response when M1 Protein was involved. Evidence of egress of bacteria out of their host cell and subsequent re-infection of new cells emphasize the importance of intracellular bacteria as a reservoir for dissemination of infection and continued tissue injury. Copyright (C) 2010 S. Karger AG, Basel (Less)
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Soluble M1 Protein of Streptococcus pyogenes triggers potent T cell activation
Cellular Microbiology, 2007Co-Authors: Lisa I. Påhlman, Anders I Olin, Heiko Herwald, Matthias Mörgelin, Malak Kotb, Jessica Darenberg, Anna Norrby-teglundAbstract:Streptococcus pyogenes of the M1 serotype is commonly associated with large outbreaks of invasive streptococcal infections and development of streptococcal toxic shock syndrome (STSS). The pathogenesis behind these infections is believed to involve bacterial superantigens that induce potent inflammatory responses, but the reason why strains of the M1 serotype are over-represented in STSS is still not understood. In the present investigation, we show that a highly purified soluble form of the M1 Protein from S. pyogenes, which lacks the membrane-spanning region, is a potent inducer of T cell proliferation and release of Th1 type cytokines. M1 Protein-evoked T cell proliferation was HLA class II-dependent but not MHC-restricted, did not require intracellular processing and was Vβ-restricted. Extensive mass spectrometry studies indicated that there were no other detectable Proteins in the preparation. Taken together, our data demonstrate that soluble M1 Protein is a novel streptococcal superantigen, which likely contributes to the excessive T cell activation and hyperinflammatory response seen in severe invasive streptococcal infections
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Soluble M1 Protein of Streptococcus pyogenes triggers potent T cell activation.
Cellular Microbiology, 2007Co-Authors: Lisa I. Påhlman, Anders I Olin, Heiko Herwald, Matthias Mörgelin, Malak Kotb, Jessica Darenberg, Anna Norrby-teglundAbstract:Streptococcus pyogenes of the M1 serotype is commonly associated with large outbreaks of invasive streptococcal infections and development of streptococcal toxic shock syndrome (STSS). The pathogenesis behind these infections is believed to involve bacterial superantigens that induce potent inflammatory responses, but the reason why strains of the M1 serotype are over-represented in STSS is still not understood. In the present investigation, we show that a highly purified soluble form of the M1 Protein from S. pyogenes, which lacks the membrane-spanning region, is a potent inducer of T cell proliferation and release of Th1 type cytokines. M1 Protein-evoked T cell proliferation was HLA class II-dependent but not MHC-restricted, did not require intracellular processing and was Vβ-restricted. Extensive mass spectrometry studies indicated that there were no other detectable Proteins in the preparation. Taken together, our data demonstrate that soluble M1 Protein is a novel streptococcal superantigen, which likely contributes to the excessive T cell activation and hyperinflammatory response seen in severe invasive streptococcal infections. (Less)
