A hookworm glycoprotein that inhibits neutrophil function is a ligand of the integrin CD11b/CD18

Moyle, Matthew; Foster, David L.; McGrath, Douglas; Brown, Stuart A.; Laroche, Y; Meutter, Jan De; Stanssens, Patrick; Bogowitz, C A; Fried, V A; Ely, J A

doi:10.1016/s0021-9258(17)36982-x

Cited by 233 publications

(26 citation statements)

References 34 publications

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“…The hookworm Ancylostoma caninum produces a 41-kD heavily glycosylated protein called NIF, that inhibits neutrophil spreading and adhesion to endothelial cell monolayers, and binds to CR3 (40). In this communication we show that CR3 is the sole protein recognized by NIF in neutrophils, and demonstrate that the interaction of NIF with CR3 is divalentcation dependent and mediated through the A-domain.…”

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confidence: 69%

The A-domain of beta 2 integrin CR3 (CD11b/CD18) is a receptor for the hookworm-derived neutrophil adhesion inhibitor NIF.

Rieu

Ueda

Haruta

et al. 1994

The Journal of Cell Biology

106

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Abstract. The A-domain is a ,,o200-amino acid peptide present within structurally diverse proadhesive proteins including seven integrins. A recombinant form of the A-domain of/32 integrins CR3 and LFA-1 has been recently shown to bind divalent cations and to contain binding sites for protein ligands that play essential roles in leukocyte trafficking to inflammatory sites, phagocytosis and target cell killing. In this report we demonstrate that the neutrophil adhesion inhibitor, NIF produced by the hookworm Ancylostoma caninum is a selective CDllb A-domain binding protein. NIF bound directly, specifically and with high affinity (Kd of ~1 nM) to recombinant CD1 lb A-domain (rllbA). The binding reaction was characterized by rapid association and very slow dissociation, and was blocked by an anti-rllbA monoclonal antibody. No binding was observed to rCDllaA. The NIF-rllbA interaction required divalent cations, and was absent when the mutant rllbA D140GS/AGA (that lacks divalent cation binding capacity) was used. The NIF binding site in rllbA was mapped to four short peptides, one of which being an iC3b binding site. The interaction of NIF with CR3 in intact cells followed similar binding kinetics to those with rllbA, and occurred with similar affinity in resting and activated human neutrophils, suggesting that the NIF epitope is activation independent. Binding of NIF to CR3 blocked its ability to bind to its ligands iC3b, fibrinogen, and CD54, and inhibited the ability of human neutrophils to ingest serum opsonized particles. NIF thus represents the first example of a disintegrin that targets the integrin A-domain, and is likely to be used by the hookworm to evade the host's inflammatory response. The unique structure of NIF, which lacks a disintegrin motif, emphasizes basic structural differences in antagonists targeting A + and A-integrins, that should be valuable in drug design efforts aimed at generating novel therapeutics. Identification of the region in NIF mediating A-domain binding should also be useful in this regard, and may, as in the case of disintegrins, unravel a new structural motif with cellular counterparts mediating important physiologic functions.

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mentioning

confidence: 69%

The A-domain of beta 2 integrin CR3 (CD11b/CD18) is a receptor for the hookworm-derived neutrophil adhesion inhibitor NIF.

Rieu

Ueda

Haruta

et al. 1994

The Journal of Cell Biology

106

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“…These factors block the adhesion of activated human neutrophils to vascular endothelial cells and the release of H 2 O 2 from activated neutrophils (Anbu & Joshi, 2008). NIF derived from canine hookworm (Ancylostoma caninum) inhibits the integrin CD11b/CD18-dependent neutrophil function in vitro (Moyle et al, 1994;Schnyder-Candrian et al, 2012). In an acid-induced lung injury model in rabbits, NIF and anti-CD18 antibodies showed lung injury attenuation, but with a high number of accumulated neutrophils in the air space.…”

Section: Neutrophil Modulatory Moleculesmentioning

confidence: 99%

Neutrophils in respiratory syncytial virus infection: From harmful effects to therapeutic opportunities

Tahamtan

Besteman

Samadizadeh

et al. 2020

British J Pharmacology

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Respiratory syncytial virus (RSV) is an important infectious agent in infants and young children. In most cases, RSV infection only causes mild disease, but in some, it requires invasive ventilation. Although antiviral drugs are obvious candidates to treat viral illness, and some have shown antiviral effects in humans, antivirals such as GS-5806, ALX-0171 and ALS-8176 have not yet met their expectations. Since the inappropriate or dysregulated immune response against RSV leads to harmful immune pathology, a robust immune cascade is probably underway by the time patients reach the hospital. RSV infection is associated with a strong neutrophil influx into the airway. It not clear if these cells contribute to antiviral defence or to lung pathology. This article discusses the protective and harmful roles of neutrophils during RSV infection and provides an overview of mechanisms by which neutrophil function could be targeted to prevent tissue injury and preserve homeostasis.

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“…The Ancylostoma ASP is a front-running vaccine candidate against canine hookworm. Subsequently, related genes have been identified in a range of other nematode species, including products which block neutrophil activation (91) and induce angiogenesis in mice (92).…”

Section: Abundant Larval Transcripts (Bm-alt-1 -2)mentioning

confidence: 99%

Immune evasion genes from filarial nematodes

Maizels

Gomez-Escobar

Gregory

et al. 2001

International Journal for Parasitology

161

108

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Helminth parasites have large genomes (approximately 10(8) bp) which are likely to encode a spectrum of products able to block or divert the host immune response. We have employed three parallel approaches to identify the first generation of 'immune evasion genes' from parasites such as the filarial nematode Brugia malayi. The first strategy is a conventional route to characterise prominent surface or secreted antigens. In this way we have identified a 15-kDa protein, which is located on the surface of both L3 and adult B. malayi, and secreted by these parasites in vitro, as a member of the cystatin (cysteine protease inhibitor) family. This product, Bm-CPI-2, blocks conventional cysteine proteases such as papain, but also the aspariginyl endopeptidase involved in the Class II antigen processing pathway in human B cells. In parallel, we identified the major T cell-stimulating antigen from the microfilarial stage as a serpin (serine protease inhibitor), Bm-SPN-2. Microfilariae secrete this product which blocks two key proteases of the neutrophil, a key mediator of inflammation and innate immunity. The second route involves a priori hypotheses that helminth parasites encode homologues of mammalian cytokines such as TGF-beta which are members of broad, ancient metazoan gene families. We have identified two TGF-beta homologues in B. malayi, and shown that one form (Bm-TGH-2) is both secreted by adult parasites in vitro and able to bind to host TGF-beta receptors. Likewise, B. malayi expresses homologues of mammalian MIF, which are remarkably similar in both structure and function to the host protein, even though amino acid identity is only 28%. Finally, we deployed a third method of selecting critical genes, using an expression-based criterion to select abundant mRNAs taken from key points in parasite life histories. By this means, we have shown that the major transcript present in mosquito-borne infective larvae, Bm-ALT, is a credible vaccine candidate for use against lymphatic filariasis, while a second abundantly-expressed gene, Bm-VAL-1, is similar to a likely vaccine antigen being developed against hookworm parasites.

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A hookworm glycoprotein that inhibits neutrophil function is a ligand of the integrin CD11b/CD18

Cited by 233 publications

References 34 publications

The A-domain of beta 2 integrin CR3 (CD11b/CD18) is a receptor for the hookworm-derived neutrophil adhesion inhibitor NIF.

The A-domain of beta 2 integrin CR3 (CD11b/CD18) is a receptor for the hookworm-derived neutrophil adhesion inhibitor NIF.

Neutrophils in respiratory syncytial virus infection: From harmful effects to therapeutic opportunities

Immune evasion genes from filarial nematodes

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