Entamoeba histolytica Induces Intestinal Cathelicidins but Is Resistant to Cathelicidin-Mediated Killing

Cobo, Eduardo R.; He, Chen; Hirata, Ken; Hwang, Grace; Tran, UyenPhuong C.; Eckmann, Lars; Gallo, Richard L.; Reed, Sharon L.

doi:10.1128/iai.05029-11

Cited by 30 publications

(33 citation statements)

References 32 publications

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“…In addition, Blastocystis could also induce epithelial cells to express antimicrobial peptides as part of the host's innate immune response. This is seen in other gastrointestinal infections by protistan parasites such as Entamoeba (29) and Cryptosporidium (30). In this study, we have also found that all 3 represented Blastocystis STs are capable of inducing the expression and secretion of LL-37 by intestinal epithelial cells (Fig.…”

Section: Discussionsupporting

confidence: 61%

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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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Section: Discussionsupporting

confidence: 61%

“…6). A study on the effect of LL-37 on an intestinal parasite, Entamoeba histolytica, also revealed the same outcome (29). The resistance of E. histolytica to LL-37 was partly due to its ability to release cysteine proteases that could degrade LL-37.…”

Section: Discussionmentioning

confidence: 65%

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

2016

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“…Synthetic cathelicidin-derived peptides were shown to impair E. histolytica integrity and viability (14). Moreover, although E. histolytica-secreted cysteine proteinases degrade cathelicidins, the fragmented cathelicidin peptides have potent bactericidal effects over enteric bacteria that could control E. histolytica colonization (13). Thus, the absence of mucin and/or the insufficient butyrate that leads to deficient cathelicidin responses weakens epithelial innate defenses and likely induces colonic dysbiosis that could play a role the patho-genesis of E. histolytica.…”

Section: Discussionmentioning

confidence: 99%

“…Prolonged contact of E. histolytica with the colonic epithelium induced the synthesis of cathelicidins in humans and mouse, which were degraded by E. histolytica cysteine proteinases (13). Even though E. histolytica is resistant to killing by LL-37 (13), one report showed that shortened peptides derived from cleaved LL-37 affected E. histolytica integrity and viability (14). Altered production of colonic mucin and antimicrobial peptides is also characteristic of chronic inflammatory bowel diseases (IBDs).…”

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confidence: 99%

“…In Muc2 Ϫ/Ϫ mice, E. histolytica inoculated in colonic loops elicited robust secretory and acute proinflammatory responses, aberrant protein secretions, and altered tight junction permeability (12). Prolonged contact of E. histolytica with the colonic epithelium induced the synthesis of cathelicidins in humans and mouse, which were degraded by E. histolytica cysteine proteinases (13). Even though E. histolytica is resistant to killing by LL-37 (13), one report showed that shortened peptides derived from cleaved LL-37 affected E. histolytica integrity and viability (14).…”

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MUC2 Mucin and Butyrate Contribute to the Synthesis of the Antimicrobial Peptide Cathelicidin in Response to Entamoeba histolytica- and Dextran Sodium Sulfate-Induced Colitis

et al. 2017

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Embedded in the colonic mucus are cathelicidins, small cationic peptides secreted by colonic epithelial cells. Humans and mice have one cathelicidin-related antimicrobial peptide (CRAMP) each, LL-37/hCAP-18 and Cramp, respectively, with related structure and functions. Altered production of MUC2 mucin and antimicrobial peptides is characteristic of intestinal amebiasis. The interactions between MUC2 mucin and cathelicidins in conferring innate immunity against Entamoeba histolytica are not well characterized. In this study, we quantified whether MUC2 expression and release could regulate the expression and secretion of cathelicidin LL-37 in colonic epithelial cells and in the colon. The synthesis of LL-37 was enhanced with butyrate (a product of bacterial fermentation) and interleukin-1␤ (IL-1␤) (a proinflammatory cytokine in colitis) in the presence of exogenously added purified MUC2. The LL-37 responses to butyrate and IL-1␤ were higher in high-MUC2-producing cells than in lentivirus short hairpin RNA (shRNA) MUC2-silenced cells. Activation of cyclic adenylyl cyclase (AMP) and mitogen-activated protein kinase (MAPK) signaling pathways was necessary for the simultaneous expression of MUC2 and cathelicidins. In Muc2 mucin-deficient (Muc2 Ϫ/Ϫ ) mice, murine cathelicidin (Cramp) was significantly reduced compared to that in Muc2 ϩ/Ϫ and Muc2 ϩ/ϩ littermates. E. histolyticainduced acute inflammation in colonic loops stimulated high levels of cathelicidin in Muc2 ϩ/ϩ but not in Muc2 Ϫ/Ϫ littermates. In dextran sodium sulfate (DSS)-induced colitis in Muc2 ϩ/ϩ mice, which depletes the mucus barrier and goblet cell mucin, Cramp expression was significantly enhanced during restitution. These studies demonstrate regulatory mechanisms between MUC2 and cathelicidins in the colonic mucosa where an intact mucus barrier is essential for expression and secretion of cathelicidins in response to E. histolytica-and DSS-induced colitis. KEYWORDS Entamoeba histolytica, MUC2, antimicrobial peptides, mucinT he innate defenses of the colon and first barrier against pathogens include glycosylated MUC2 mucin secreted by goblet cells that forms an inner sterile layer firmly attached to the epithelium and an outer layer with an expanded volume and that is colonized by bacteria (1). Embedded in colonic mucus are cathelicidins, small cationic peptides (23 to 37 amino acids) secreted by neutrophils and epithelial cells, including colonic epithelium, with broad antimicrobial activity (2, 3). The only cathelicidin described in humans is LL-37/hCAP-18, which is homologous to mouse cathelicidinrelated antimicrobial peptide (CRAMP) (2, 3). Both LL-37 and CRAMP have related structure and antimicrobial and chemotactic functions (2, 3). Sodium butyrate pro-

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Unique features of human cathelicidinLL‐37

et al. 2015

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Cathelicidins are antimicrobial peptides produced by humans and animals in response to various pathogenic microbes. This review intends to provide a brief overview of the expression, structure, properties and function of human cathelicidin LL-37 which may be a therapeutic agent against a variety of bacterial and viral diseases, cancers, and hard-to-heal wounds. Cathelicidins act as a primary defense against bacteria and other pathogens in the case of inflammation. They are able to kill bacteria and fungi, inhibit and destroy bacterial biofilms, and possess antiviral and antiparasitics properties. They can also play a role in angiogenesis, wound healing, and the regulation of apoptosis. The host defense peptide LL-37 has emerged as a novel modulator of tumor growth and metastasis in carcinogenesis of various types of cancers. LL-37 is an antimicrobial peptide able of inducing various effects. It acts as an anti- and pro- inflammatory factor. Cathelicidins are able to directly and selectively destroy membranes of various microbes and cancer cells, but they do not attack normal cells. The role of cathelicidins in cancer is double-sided. They play an important role in killing cancer cells and may provide a new possibility for the development of cancer therapeutics. However, they also can participate in carcinogenesis. Due to its activity spectrum LL-37 could be applied in pharmacotherapy. Cathelicidin peptides could serve as a template for the development of modern anti-microbial and anti-viral drugs. LL-37 is an excellent candidate to develop into therapeutics for infected wounds.

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Entamoeba histolytica Induces Intestinal Cathelicidins but Is Resistant to Cathelicidin-Mediated Killing

Cited by 30 publications

References 32 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

MUC2 Mucin and Butyrate Contribute to the Synthesis of the Antimicrobial Peptide Cathelicidin in Response to Entamoeba histolytica- and Dextran Sodium Sulfate-Induced Colitis

Unique features of human cathelicidinLL‐37

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