Hookworm Excretory/Secretory Products Induce Interleukin-4 (IL-4)+IL-10+CD4+T Cell Responses and Suppress Pathology in a Mouse Model of Colitis

Ferreira, Ivana; Smyth, Danielle J.; Gaze, Soraya; Aziz, Ammar; Giacomin, Paul; Ruyssers, Nathalie E.; Artis, David; Laha, Thewarach; Navarro, Séverine; Loukas, Alex; McSorley, Henry J.

doi:10.1128/iai.00563-12

Cited by 92 publications

(101 citation statements)

References 43 publications

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“…Many studies show that tissue extracts or E/S products from helminths can suppress mammalian immune cell activation in vitro (29)(30)(31)(32) and ameliorate the severity of inflammatory disease in murine model systems (14,18,19,29,30,33,34). The demonstration herein that systemic administration of a crude extract of adult H. diminuta parasites dosedependently inhibits DSS-induced colitis adds to awareness of the ability of helminth-derived molecules to suppress intestinal inflammation (19,21,35).…”

Section: Discussionmentioning

confidence: 86%

“…Moreover, individuals infected with a variety of species of helminths can be protected from concomitant disease as demonstrated in animal models of multiple sclerosis (2-4), joint (5-7) and gut (8)(9)(10) inflammation, and allergy (11,12). In addition, treatment with somatic extracts or secreted products can significantly attenuate disease severity in models of inflammatory diseases (13)(14)(15), raising the possibility that isolation and purification of helminth-derived molecules could result in new anti-inflammatory drugs.…”

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confidence: 99%

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Treatment with Cestode Parasite Antigens Results in Recruitment of CCR2 ⁺ Myeloid Cells, the Adoptive Transfer of Which Ameliorates Colitis

et al. 2016

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Awareness of the immunological underpinnings of host-parasite interactions may reveal immune signaling pathways that could be used to treat inflammatory disease in humans. Previously we showed that infection with the rat tapeworm, Hymenolepis diminuta, used as a model helminth, or systemic delivery of worm antigen (HdAg) significantly reduced the severity of dinitrobenzene sulfonic acid (DNBS)-induced colitis in mice. Extending these analyses, intraperitoneal injection of HdAg dosedependently suppressed dextran sodium sulfate (DSS)-induced colitis, and this was paralleled by reduced gamma interferon (IFN-␥), interleukin-17 (IL-17), and tumor necrosis factor alpha (TNF-␣) production and increased IL-10 production from mitogen-activated splenocytes. Until relatively recently, analysis of the host response to infection with helminth parasites focused almost invariably on TH2 immunity; however, it has emerged that helminth parasites trigger a complex regulatory network in their mammalian hosts that is characterized by cytokines (e.g., interleukin-10 [IL-10] and transforming growth factor ␤ [TGF-␤]) and cellular components (e.g., regulatory macrophages and T cells) (1). Indeed, the development of an immunoregulatory environment likely contributes to the chronicity of helminth infection and asymptomatic disease. Moreover, individuals infected with a variety of species of helminths can be protected from concomitant disease as demonstrated in animal models of multiple sclerosis (2-4), joint (5-7) and gut (8-10) inflammation, and allergy (11, 12). In addition, treatment with somatic extracts or secreted products can significantly attenuate disease severity in models of inflammatory diseases (13-15), raising the possibility that isolation and purification of helminth-derived molecules could result in new anti-inflammatory drugs.The inverse relationship between the geographical distribution of inflammatory bowel disease (IBD) (i.e., Crohn's disease and ulcerative colitis) and areas of endemic helminth infection suggests that infection with helminth parasites may protect against IBD (16). Testing this hypothesis, infections with Trichinella spiralis, Schistosoma mansoni, and Heligmosomoides polygyrus were shown to inhibit inflammation in dinitrobenzene sulfonic acid (DNBS)-and dextran-sodium sulfate (DSS)-induced colitis and piroxicam-treated IL-10 Ϫ/Ϫ mice, respectively (8, 9, 17)-all established mouse models of colitis that share some similarities to human IBD. Similarly, and as an alternative to viable infection, systemic administration of helminth-derived antigens can ameliorate colitis in animal models. As examples, the excretory/secretory (E/S) products from adult T. spiralis reduced DSS-induced colitis (18) and S. mansoni egg antigens ameliorated immunemediated colitis (19): in both instances, suppression of TH1 and TH17 cytokines correlated with the beneficial anticolitic effect. While encouraging, the precise mechanism of action of any helminth-derived extract or molecule to block colitis or other inflammatory dis...

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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 99%

Treatment with Cestode Parasite Antigens Results in Recruitment of CCR2 ⁺ Myeloid Cells, the Adoptive Transfer of Which Ameliorates Colitis

et al. 2016

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“…Briefly, colons were harvested, opened longitudinally, and washed with sterile phosphate buffer saline then placed under a microscope (Olympus SZ61, 0.67-4.5x). The tissues were assessed for changes in macroscopic appearance and scored for pathological changes as follows: adhesion (0 -3), bowel wall thickening (0 -3), mucosal edema (0 -3), ulceration (0 -3), and colon length as described previously (38). All animal experiments were conducted in duplicate to ensure reproducibility of the findings.…”

Section: Tnbs Colitis Assaymentioning

confidence: 99%

An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease

Caceres

Bansal

Navarro

et al. 2017

Journal of Biological Chemistry

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Edited by Wolfgang PetiInflammatory bowel diseases (IBDs) are a set of complex and debilitating diseases for which there is no satisfactory treatment. Recent studies have shown that small peptides show promise for reducing inflammation in models of IBD. However, these small peptides are likely to be unstable and rapidly cleared from the circulation, and therefore, if not modified for better stability, represent non-viable drug leads. We hypothesized that improving the stability of these peptides by grafting them into a stable cyclic peptide scaffold may enhance their therapeutic potential. Using this approach, we have designed a novel cyclic peptide that comprises a small bioactive peptide from the annexin A1 protein grafted into a sunflower trypsin inhibitor cyclic scaffold. We used native chemical ligation to synthesize the grafted cyclic peptide. This engineered cyclic peptide maintained the overall fold of the naturally occurring cyclic peptide, was more effective at reducing inflammation in a mouse model of acute colitis than the bioactive peptide alone, and showed enhanced stability in human serum. Our findings suggest that the use of cyclic peptides as structural backbones offers a promising approach for the treatment of IBD and potentially other chronic inflammatory conditions. Inflammatory bowel diseases (IBDs)3 are a set of chronic inflammatory disorders of the gastrointestinal tract; the two major forms are ulcerative colitis and Crohn's disease (1). Although there are several medications on the market for IBD, they generally only provide temporary relief, and 70% of IBD patients require surgical intervention (2). Because the current treatments are not satisfactory, new drug leads are being sought from a range of sources, including small molecules from plants and bioactive regions of larger proteins (3-6).Intriguingly, several small peptides, some comprising only three residues, have been shown to be effective in the treatment of experimental colitis in mice (7-11). One example is a tripeptide (MC-12) derived from annexin A1, a calcium-dependent phospholipid-binding, anti-inflammatory protein (12). Annexin A1 mediates expression of cytokines such as TNF-␣, IL-6, and IL-10. It is required for the inhibition of NF-B activity by anti-inflammatory drugs (13) and has recently been shown to be a potential biomarker of therapeutic efficacy for IBD (14). The N-terminal region of annexin A1 comprising residues 2-26 (Ac2-26) has been well studied (15, 16) and appears to have the same biological effects as the full-length protein (17). Analysis of a series of peptides based on the N-terminal sequence of annexin A1 showed that MC-12 (Ac-Gln-Ala-Trp) was the most potent inhibitor of NF-B activity in SW480 cells (13).Small peptides such as MC-12 are likely to be unstable and not viable drug leads, supported by the finding that high doses (25 mg/kg) of MC-12 were required to elicit an in vivo response in mouse colitis models, and it was more effective when injected compared with oral administration (18). Improving t...

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“…It is tempting to suggest that Na-ASP-2 has a similar function and blocks the production of reactive oxygen species that are toxic to invading hookworm larvae as they migrate through host tissues on their sohourn towards the gastrointestinal tract. In microglial cells, SK3 channels can modulate LPS-induced inflammatory responses (Dolga et al, 2012), and given the potent anti-inflammatory properties of hookworm ES products (Ferreira et al, 2013), it is reasonable to assume that Na-ASP-2 might also suppress production of pro-inflammatory cytokines. Taken together, these findings suggest a potential role for Na-ASP-2 in direct interactions with SK3 channels on T cells or granulocytes, blocking their activation and thereby interrupting inflammatory cascades in affected cells to promote parasite survival in the hostile host microenvironment.…”

Section: Implications Of Asp-2/sk3 Interactions At the Host-parasite mentioning

confidence: 99%

Probing the equatorial groove of the hookworm protein and vaccine candidate antigen, Na-ASP-2

Mason

Tribolet

Simon

et al. 2014

The International Journal of Biochemistry & Cell Biology

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Hookworm activation-associated secreted proteins can be structurally classified into at least three different groups. The hallmark feature of Group 1 activation-associated secreted proteins is a prominent equatorial groove, which is inferred to form a ligand binding site. Furthermore, a conserved tandem histidine motif is located in the centre of the groove and believed to provide or support a yet to be determined catalytic activity. Here, we report three-dimensional crystal structures of Na-ASP-2, an L3-secreted activationassociated secreted protein from the human hookworm Necator americanus, which demonstrate transition metal binding ability of the conserved tandem histidine motif. We further identified moderate phosphohydrolase activity of recombinant Na-ASP-2, which relates to the tandem histidine motif. By panning a random 12-mer peptide phage library, we identified a peptide with high similarity to the human calcium-activated potassium channel SK3, and confirm binding of the synthetic peptide to recombinant Na-ASP-2 by differential scanning fluorimetry. Potential binding modes of the peptide to Na-ASP-2 were studied by molecular dynamics simulations which clearly identify a preferred topology of the Na-ASP-2:SK3 peptide complex. KeywordsActivation-associated secreted proteins, Host-parasite interactions, Pathogenesis-related proteins, Protein structure, SCP/TAPS proteins Database Coordinates and structure factors have been deposited with the PDB, accession numbers 4nui, 4nuk, 4nun and 4nuo.

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Hookworm Excretory/Secretory Products Induce Interleukin-4 (IL-4)⁺IL-10⁺CD4⁺T Cell Responses and Suppress Pathology in a Mouse Model of Colitis

Cited by 92 publications

References 43 publications

Treatment with Cestode Parasite Antigens Results in Recruitment of CCR2 ⁺ Myeloid Cells, the Adoptive Transfer of Which Ameliorates Colitis

Treatment with Cestode Parasite Antigens Results in Recruitment of CCR2 ⁺ Myeloid Cells, the Adoptive Transfer of Which Ameliorates Colitis

An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease

Probing the equatorial groove of the hookworm protein and vaccine candidate antigen, Na-ASP-2

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Hookworm Excretory/Secretory Products Induce Interleukin-4 (IL-4)+IL-10+CD4+T Cell Responses and Suppress Pathology in a Mouse Model of Colitis

Cited by 92 publications

References 43 publications

Treatment with Cestode Parasite Antigens Results in Recruitment of CCR2 + Myeloid Cells, the Adoptive Transfer of Which Ameliorates Colitis

Treatment with Cestode Parasite Antigens Results in Recruitment of CCR2 + Myeloid Cells, the Adoptive Transfer of Which Ameliorates Colitis

An engineered cyclic peptide alleviates symptoms of inflammation in a murine model of inflammatory bowel disease

Probing the equatorial groove of the hookworm protein and vaccine candidate antigen, Na-ASP-2

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Product

Resources

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Hookworm Excretory/Secretory Products Induce Interleukin-4 (IL-4)⁺IL-10⁺CD4⁺T Cell Responses and Suppress Pathology in a Mouse Model of Colitis

Treatment with Cestode Parasite Antigens Results in Recruitment of CCR2 ⁺ Myeloid Cells, the Adoptive Transfer of Which Ameliorates Colitis

Treatment with Cestode Parasite Antigens Results in Recruitment of CCR2 ⁺ Myeloid Cells, the Adoptive Transfer of Which Ameliorates Colitis