Molecular mechanisms of hookworm disease: Stealth, virulence, and vaccines

Pearson, Mark S.; Tribolet, Leon; Cantacessi, Cinzia; Periago, María Victoria; Valerio, Maria Adela; Jariwala, Amar; Hotez, Peter J.; Diemert, David; Loukas, Alex; Bethony, Jeffrey M.

doi:10.1016/j.jaci.2012.05.029

Cited by 39 publications

(28 citation statements)

References 112 publications

(142 reference statements)

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“…Such information will be vital for the development of new vaccination concepts for the induction of early barrier immunity. This approach will also be useful for helping to maintain tissue integrity and preventing the development of egg-producing, blood-feeding, and immunosuppressive adult helminth stages (65,66).…”

Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Trapping of Helminth Larvae Requires CD11b and Fcγ Receptor I

Bieren

Volpe

Kulagin

et al. 2015

The Journal of Immunology

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Infections with intestinal helminths severely impact on human and veterinary health, particularly through the damage that these large parasites inflict when migrating through host tissues. Host immunity often targets the motility of tissue-migrating helminth larvae, which ideally should be mimicked by anti-helminth vaccines. However, the mechanisms of larval trapping are still poorly defined. We have recently reported an important role for Abs in the rapid trapping of tissue-migrating larvae of the murine parasite Heligmosomoides polygyrus bakeri. Trapping was mediated by macrophages (MΦ) and involved complement, activating FcRs, and Arginase-1 (Arg1) activity. However, the receptors and Ab isotypes responsible for MΦ adherence and Arg1 induction remained unclear. Using an in vitro coculture assay of H. polygyrus bakeri larvae and bone marrow–derived MΦ, we now identify CD11b as the major complement receptor mediating MΦ adherence to the larval surface. However, larval immobilization was largely independent of CD11b and instead required the activating IgG receptor FcγRI (CD64) both in vitro and during challenge H. polygyrus bakeri infection in vivo. FcγRI signaling also contributed to the upregulation of MΦ Arg1 expression in vitro and in vivo. Finally, IgG2a/c was the major IgG subtype from early immune serum bound by FcγRI on the MΦ surface, and purified IgG2c could trigger larval immobilization and Arg1 expression in MΦ in vitro. Our findings reveal a novel role for IgG2a/c-FcγRI–driven MΦ activation in the efficient trapping of tissue-migrating helminth larvae and thus provide important mechanistic insights vital for anti-helminth vaccine development.

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Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Trapping of Helminth Larvae Requires CD11b and Fcγ Receptor I

Bieren

Volpe

Kulagin

et al. 2015

The Journal of Immunology

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“…Helminth effects on the host immune system can come about by direct competition for niche space in the GI tract, or primarily through host immunomodulation. The direct helminth-induced host immune responses include down-regulation of inflammation, mainly via a protective Th2 response [50, 51]. These changes have resistance and tolerance roles, establishing an environment that promotes parasite survival and a prolonged reproductive phase [50–53].…”

Section: Main Textmentioning

confidence: 99%

Gut microbiota disturbance during helminth infection: can it affect cognition and behaviour of children?

et al. 2017

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BackgroundBidirectional signalling between the brain and the gastrointestinal tract is regulated at neural, hormonal, and immunological levels. Recent studies have shown that helminth infections can alter the normal gut microbiota. Studies have also shown that the gut microbiota is instrumental in the normal development, maturation and function of the brain. The pathophysiological pathways by which helminth infections contribute to altered cognitive function remain poorly understood.DiscussionWe put forward the hypothesis that gastrointestinal infections with parasitic worms, such as helminths, induce an imbalance of the gut-brain axis, which, in turn, can detrimentally manifest in brain development. Factors supporting this hypothesis are: 1) research focusing on intelligence and school performance in school-aged children has shown helminth infections to be associated with cognitive impairment, 2) disturbances in gut microbiota have been shown to be associated with important cognitive developmental effects, and 3) helminth infections have been shown to alter the gut microbiota structure. Evidence on the complex interactions between extrinsic (parasite) and intrinsic (host-derived) factors has been synthesised and discussed.SummaryWhile evidence in favour of the helminth-gut microbiota-central nervous system hypothesis is circumstantial, it would be unwise to rule it out as a possible mechanism by which gastrointestinal helminth infections induce childhood cognitive morbidity. Further empirical studies are necessary to test an indirect effect of helminth infections on the modulation of mood and behaviour through its effects on the gut microbiota.

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“…[1] [2] Necator Americanus (NA) species of hookworm constitutes the majority of these infections (~85%) [3] The clinical manifestation of the disease includes anemia, malnutrition in pregnant women, and cognitive and/or physical development impairment in children [4] . These helminth blood feeders on reaching maturity can feed up to 9ml of blood per day in an infected individual by attaching themselves to the intestinal mucosa of the host, through cutting plates as in NA [5] . Iron deficiency anemia is the direct effect of the hookworm's blood feeding [6] , resulting in other subsidiary consequences of the hookworm disease [7] [8] .…”

Section: Introductionmentioning

confidence: 99%

“…The parasite eventually reaches gastrointestinal tract as fourth stage larvae (L4) to develop into blood feeding adult stage hookworms [1] An array of diverse enzymes and molecules in NA's biomolecule repertoire facilitate the pathogen's survival in the host for up to seven years or longer during the different stages of its lifecycle [5] . The most important therapeutic targets are the enzymes involved in interaction with host and in nutrient acquisition.…”

Section: Introductionmentioning

confidence: 99%

“…These are often found in the excretorysecretory (ES) products of the worm. The ES proteins have been shown to engage in crucial functions like tissue degradation for host invasion [5] [11] , fibrinogen degradation [12] for preventing blood clots, hemoglobin degradation [12] for nutrient acquisition, and evasion of the host immune system [13] . The enzymes in the ES potpourri of NA are not yet completely characterized.…”

Section: Introductionmentioning

confidence: 99%

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Cysteine proteases of human hookwormNecator Americanus as virulencefactors and implications for drug design with anti-heparin and heparin analogs: A bioinformatics study

Banerjee

Widmer

et al. 2017

Preprint

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Abstract:Human hookworm Necator Americanus (NA) causes iron deficiency anemia, as the parasite ingests blood from the gastrointestinal tract of its human host. This bioinformatics-based study focuses on eight of the cathepsin B-like cysteine proteases (CPs) of the worm to explore their pathogenic potential. CP1 -CP6, which harbored the active site cysteine residue for enzymatic activity, were relevantly observed to have Nterminal signal peptide for extracellular localization. The secretory CPs could be releasing indigenous worm heparin at the host-pathogen interface for anticoagulation purposes. CP2 and CP3 showed a novel hemoglobinase motif that could be a prerequisite for hemoglobin degradation. CP1 and CP6 shared similar enzymatic-pocket features with cathepsin B and cruzain that cleave high molecular weight kininogen for blood-thinning activity. CP1, CP2, CP3, CP5 and CP6 were predicted to bind heparin, at their C terminal domain, like human cathepsin B and cruzain non-covalently bind heparin to enhance their activity. NA CPs' action in concert with heparin, have implications for anti-heparin and heparin analog design against hookworm infection.

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Molecular mechanisms of hookworm disease: Stealth, virulence, and vaccines

Cited by 39 publications

References 112 publications

Antibody-Mediated Trapping of Helminth Larvae Requires CD11b and Fcγ Receptor I

Antibody-Mediated Trapping of Helminth Larvae Requires CD11b and Fcγ Receptor I

Gut microbiota disturbance during helminth infection: can it affect cognition and behaviour of children?

Cysteine proteases of human hookwormNecator Americanus as virulencefactors and implications for drug design with anti-heparin and heparin analogs: A bioinformatics study

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