Group A Streptococcal M1 Protein Sequesters Cathelicidin to Evade Innate Immune Killing

LaRock, Christopher N.; Döhrmann, Simon; Todd, Jordan; Corriden, Ross; Olson, Joshua; Johannssen, Timo; Lepenies, Bernd; Gallo, Richard L.; Ghosh, Partho; Nizet, Victor

doi:10.1016/j.chom.2015.09.004

Cited by 51 publications

(78 citation statements)

References 34 publications

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“…8C to F). Recently, a study found LL-37 sequestration by a membrane-associated protein in a virulent bacterium (47). This protects the bacterium by neutralizing the activity of LL-37.…”

Section: Discussionmentioning

confidence: 99%

Blastocystis Isolate B Exhibits Multiple Modes of Resistance against Antimicrobial Peptide LL-37

2016

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Blastocystis is one of the most common eukaryotic organisms found in humans and many types of animals. Several reports have identified its role in gastrointestinal disorders, although its pathogenicity is yet to be clarified. Blastocystis is transmitted via the fecal-to-oral route and colonizes the large intestines. Epithelial cells lining the intestine secrete antimicrobial peptides (AMPs), including beta-defensins and cathelicidin, as a response to infection. This study explores the effects of host colonic antimicrobial peptides, particularly LL-37, a fragment of cathelicidin, on different Blastocystis subtypes. Blastocystis is composed of several subtypes that have genetic, metabolic, and biological differences. These subtypes also have various outcomes in terms of drug treatment and immune response. In this study, Blastocystis isolates from three different subtypes were found to induce intestinal epithelial cells to secrete LL-37. We also show that among the antimicrobial peptides tested, only LL-37 has broad activity on all the subtypes. LL-37 causes membrane disruption and causes Blastocystis to change shape. Blastocystis subtype 7 (ST7), however, showed relative resistance to LL-37. An isolate, ST7 isolate B (ST7-B), from this subtype releases proteases that can degrade the peptide. It also makes the environment acidic, which causes attenuation of LL-37 activity. The Blastocystis ST7-B isolate was also observed to have a thicker surface coat, which may protect the parasite from direct killing by LL-37. This study determined the effects of LL-37 on different Blastocystis isolates and indicates that AMPs have significant roles in Blastocystis infections. Blastocystis is an intestinal protistan parasite commonly detected in humans and many types of animals (1, 2). This organism is classified under the stramenopiles, although it lacks chloroplasts or structures for locomotion, which are common features of many members of this group. Blastocystis is widely distributed throughout the world. Parasitological surveys usually place Blastocystis as the most common eukaryotic parasite detected (3,4). This organism has a global distribution and has numerous animal hosts. There is little host specificity for this organism, and there are reports indicating the zoonotic potential of Blastocystis (5). This organism, in its cyst form, is transmitted via the fecal-tooral route. It then colonizes the large intestine and is excysted to its various forms. These forms may appear vacuolar, multivacuolar, avacuolar, or granular under a light microscope. Blastocystis has been implicated in a number of intestinal disorders, although its pathogenesis is yet to be elucidated. There are few reports associating it with gastrointestinal disease, the most common symptoms of which are diarrhea, vomiting, nausea, and urticaria (1, 5-7). Blastocystis is a species complex that is comprised of up to 19 subtypes (STs), with ST1 to ST9 having been isolated from humans (8). Recently, a report found that ST12 and another possible novel ST also in...

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“…8C to F). Recently, a study found LL-37 sequestration by a membrane-associated protein in a virulent bacterium (47). This protects the bacterium by neutralizing the activity of LL-37.…”

Section: Discussionmentioning

confidence: 99%

Blastocystis Isolate B Exhibits Multiple Modes of Resistance against Antimicrobial Peptide LL-37

2016

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“…Μ1 protein has also been demonstrated to promote resistance to LL‐37 that is present in the extracellular traps of human neutrophils and the human mast cell line 1; loss of M1 protein increased GAS killing by neutrophil NETs and mast cell MCETs . M1 protein appears to act by enabling GAS to evade LL‐37 killing by sequestering and neutralizing LL‐37 antimicrobial activity, as well as binding to the LL‐37 precursor human cationic antimicrobial protein 18 and preventing its maturation …”

Section: Innate Immune Response To Gas Pharyngitismentioning

confidence: 99%

Group A streptococcal pharyngitis: Immune responses involved in bacterial clearance and GAS-associated immunopathologies

Soderholm

Barnett

Sweet

et al. 2017

Journal of Leukocyte Biology

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Streptococcus pyogenes, the Group A Streptococcus (GAS), is the most common cause of bacterial pharyngitis in children and adults. Innate and adaptive host immune responses are fundamental for defense against streptococcal pharyngitis and are central to the clinical manifestation of disease. Host immune responses also contribute to the severe poststreptococcal immune diseases that constitute the major disease burden for this organism. However, until recently, little was known about the host responses elicited during infection. Cellular mediators of innate immunity used during host defense against GAS include epithelial cells, neutrophils, macrophages, and dendritic cells (DCs), which are reported to secrete a number of soluble inflammatory mediators, such as antimicrobial peptides (AMPs); eicosanoids, including PGE and leukotriene B4 (LTB ); chemokines; and proinflammatory cytokines. Th1 and Th17 responses play significant roles in adaptive immunity in both murine models of GAS pharyngitis and in human tonsil tissue. A number of inflammatory complications are associated with GAS pharyngitis, which can lead to chronic disease in patients. These include scarlet fever, tonsillar hypertrophy, and sleep apnea, as well as postinfectious sequelae, such as acute rheumatic fever (ARF), poststreptococcal glomerulonephritis, and guttate psoriasis (GP). This review aims to present the current state of knowledge on innate and adaptive immune responses elicited during GAS pharyngitis, mechanisms by which GAS evades these responses, the emerging role of the pharyngeal microbiota, and how the interplay among these factors can influence the outcome of infection and inflammation-related complications.

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“…M proteins also block membrane-lytic activities of host antimicrobial peptides and histones by sequestering them away from the bacterial membrane 11,12 . Soluble M proteins released during infection by neutrophil-derived granule proteases 13 can trigger inflammation by forming a supramolecular assembly with fibrinogen that activates neutrophils 13,14 .…”

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confidence: 99%

Group A streptococcal M protein activates the NLRP3 inflammasome

et al. 2017

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Group A Streptococcus (GAS) is among the top 10 causes of infection-related mortality in humans. M protein is the most abundant GAS surface protein, and M1 serotype GAS strains are associated with invasive infections including necrotizing fasciitis and toxic shock syndrome. Here we report that released, soluble M1 protein triggers programmed cell death in macrophages (Mϕ). M1 served as a second signal for caspase-1-dependent NLRP3 inflammasome activation, inducing maturation and release of proinflammatory cytokine IL-1β and macrophage pyroptosis. The structurally dynamic B-repeat domain of M1 was critical for inflammasome activation, which involved K+ efflux and M1 protein internalization by clathrin-mediated endocytosis. Mouse intraperitoneal challenge showed that soluble M1 was sufficient and specific for IL-1β activation, which may represent an early warning to activate host immunity against the pathogen. Conversely, in systemic infection, hyperinflammation associated with M1-mediated pyroptosis and IL-1β release could aggravate tissue injury.

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Group A Streptococcal M1 Protein Sequesters Cathelicidin to Evade Innate Immune Killing

Cited by 51 publications

References 34 publications

Blastocystis Isolate B Exhibits Multiple Modes of Resistance against Antimicrobial Peptide LL-37

Blastocystis Isolate B Exhibits Multiple Modes of Resistance against Antimicrobial Peptide LL-37

Group A streptococcal pharyngitis: Immune responses involved in bacterial clearance and GAS-associated immunopathologies

Group A streptococcal M protein activates the NLRP3 inflammasome

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