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Human Vaccines Nov 2011The human hookworms Necator americanus and Ancylostoma duodenale remain among the most common infections of humans in areas of rural poverty in the developing regions of... (Review)
Review
The human hookworms Necator americanus and Ancylostoma duodenale remain among the most common infections of humans in areas of rural poverty in the developing regions of the world, with an estimated 1 billion people infected with one or more of these parasites. Herein, we review the nearly 100 years of research, development, animal testing, and fieldwork that have led to our current progress in recombinant hookworm vaccines. We begin with the identification of hookworm at the start of the 20th century in Southern US, then discuss the progress in developed countries to eliminate human hookworm infection, and then the industrial development and field use in the 1970s a canine hookworm vaccine(Ancylostoma caninum), and finally our progress to date in the development and clinical testing of an array of recombinant antigens to prevent human hookworm disease from N. americanus infection. Special attention is given to the challenges faced in the development of a vaccine against a blood-feeding nematode, including the epidemiology of infection (high prevalence of infection), pathogenesis (chronic infection that increases with the age of the host), and a robust immune response that fails to confer the protection in the host and a concomitant absence of correlates of protection by a successful vaccine could be developed and tested. Finally, we provide the optimal and acceptable profiles of a human hookworm vaccine, including the proposed indication, target population, and route of administration, as developed by the Human Hookworm Vaccine Initiative, the only group currently working on vaccines targeting this parasite.
Topics: Ancylostoma; Ancylostomatoidea; Ancylostomiasis; Animals; Antigens, Helminth; Dog Diseases; Dogs; Humans; Necator americanus; Necatoriasis; Vaccines, Synthetic
PubMed: 22064562
DOI: 10.4161/hv.7.11.18443 -
FEMS Immunology and Medical Microbiology Feb 2005Hookworms infect almost one billion people and are a major cause of iron-deficiency anaemia in developing countries of the tropics. Despite their prevalence and the... (Review)
Review
Hookworms infect almost one billion people and are a major cause of iron-deficiency anaemia in developing countries of the tropics. Despite their prevalence and the morbidity they cause, little is known about the immune response to this complex eukaryotic parasite. Recent publications have shed light on the human cellular immune responses to hookworms, as well as mechanisms that hookworms utilize to skew the immune response in its favour. Unlike most other human helminth infections, neither age- nor exposure-related immunity develops in the majority of infected people. A vaccine is therefore a highly desirable goal. To this end, gene sequencing efforts have resulted in the deposition of more than 10,000 hookworm cDNA sequences in the public domain, providing a molecular snapshot of this intriguing parasite and providing novel tools for the development of new control strategies. Significant progress has been made in the development of anti-hookworm recombinant vaccines, and clinical trials are expected to begin in the near future.
Topics: Ancylostoma; Ancylostomiasis; Animals; Cytokines; Humans; Immunity, Cellular; Necator americanus; Necatoriasis; Vaccines
PubMed: 15681140
DOI: 10.1016/j.femsim.2004.11.006 -
Parasites & Vectors Oct 2021Necator americanus is one of the major etiological agents of human ancylostomiasis. Historically, the epidemiology of ancylostomiasis in Henan Province of central China... (Review)
Review
BACKGROUND
Necator americanus is one of the major etiological agents of human ancylostomiasis. Historically, the epidemiology of ancylostomiasis in Henan Province of central China and the molecular characteristics of N. americanus have been poorly understood.
METHODS
In this study, we report a case of ancylostomiasis in Zhengzhou city of Henan Province. We also review the epidemiology of ancylostomiasis in Henan Province from 1949 to 2020. In addition, the complete mitochondrial (mt) genome of one clinical isolate is fully characterized using Illumina sequencing. All available mt genomes of hookworms in GenBank were included to reconstruct the phylogeny using both maximum likelihood (ML) and Bayesian inference (BI) methods.
RESULTS
A total of three worms were collected from the patient. These worms were identified as N. americanus based on morphological characteristics as well as confirmed by genotyping with the barcoding gene cox1. Although ancylostomiasis cases have dropped substantially in recent years, hookworm infection is still a public health problem in underdeveloped areas and remote rural areas in Henan Province. The mt genome features of the N. americanus contained 12 protein-coding genes (PCGs), 22 transfer RNA genes, two ribosomal RNA genes, and a major non-coding region. The nad1 gene showed high sequence variability among isolates, which is worth considering for future genetic studies of N. americanus. Phylogenetic analyses support the monophyly of hookworm isolates from different hosts and distinct geographical locations.
CONCLUSIONS
The mt genome of N. americanus presented here will serve as a useful data set for studying population genetics and phylogenetic relationships of hookworms. Positive measures for preventing and controlling ancylostomiasis are required by both health services and individuals in Henan Province.
Topics: Aged; Ancylostomiasis; Animals; China; DNA, Helminth; Female; Genome, Helminth; Humans; Molecular Diagnostic Techniques; Necator americanus; Necatoriasis
PubMed: 34649597
DOI: 10.1186/s13071-021-05035-3 -
Parasite Immunology 2004Advances in hookworm immunoepidemiology are reviewed. Recent studies demonstrate a mixed Th1/Th2 response in human hookworm infection, with immunosuppression of specific... (Review)
Review
Advances in hookworm immunoepidemiology are reviewed. Recent studies demonstrate a mixed Th1/Th2 response in human hookworm infection, with immunosuppression of specific and nonspecific IFN-gamma responses. There is increasing evidence for protective immunity in human hookworm infection, including anti-larval IL-5- and IgE-dependent mechanisms, and for immunological interactions between hookworm infection and other diseases.
Topics: Ancylostoma; Ancylostomiasis; Animals; Hookworm Infections; Humans; Necator americanus; Necatoriasis
PubMed: 15771680
DOI: 10.1111/j.0141-9838.2004.00727.x -
Parasitology Aug 2021Various host and parasite factors interact to determine the outcome of infection. We investigated the effects of two factors on the within-host dynamics of malaria in...
Various host and parasite factors interact to determine the outcome of infection. We investigated the effects of two factors on the within-host dynamics of malaria in mice: initial infectious dose and co-infection with a helminth that limits the availability of red blood cells (RBCs). Using a statistical, time-series approach to model the within-host ‘epidemiology’ of malaria, we found that increasing initial dose reduced the time to peak cell-to-cell parasite propagation, but also reduced its magnitude, while helminth co-infection delayed peak cell-to-cell propagation, except at the highest malaria doses. Using a mechanistic model of within-host infection dynamics, we identified dose-dependence in parameters describing host responses to malaria infection and uncovered a plausible explanation of the observed differences in single vs co-infections. Specifically, in co-infections, our model predicted a higher background death rate of RBCs. However, at the highest dose, when intraspecific competition between malaria parasites would be highest, these effects of co-infection were not observed. Such interactions between initial dose and co-infection, although difficult to predict a priori, are key to understanding variation in the severity of disease experienced by hosts and could inform studies of malaria transmission dynamics in nature, where co-infection and low doses are the norm.
Topics: Animals; Coinfection; Malaria; Mice; Mice, Inbred BALB C; Necator; Necatoriasis; Plasmodium chabaudi
PubMed: 33971991
DOI: 10.1017/S003118202100072X -
American Journal of Human Biology : the... Mar 2020Despite public health concerns about hookworm infection in pregnancy, little is known about immune profiles associated with hookworm (Necator americanus and Ancylostoma...
OBJECTIVES
Despite public health concerns about hookworm infection in pregnancy, little is known about immune profiles associated with hookworm (Necator americanus and Ancylostoma duodenale) infection during pregnancy. Fetal tolerance requirements may constrain maternal immune response to hookworm, thereby increasing susceptibility to new infections or increasing hemoglobin loss. To explore this possibility, we study systemic immune response and hemoglobin levels in a natural fertility population with endemic helminthic infection.
METHODS
We used Bayesian multilevel models to analyze mixed longitudinal data on hemoglobin, hookworm infection, reproductive state, eosinophils, and erythrocyte sedimentation rate (ESR) to examine the effects of pregnancy and hookworm infection on nonspecific inflammation, cellular parasite response, and hemoglobin among 612 Tsimane women aged 15-45 (1016 observations).
RESULTS
Pregnancy is associated with lower eosinophil counts and lower eosinophil response to hookworm, particularly during the second and third trimesters. Both hookworm and pregnancy are associated with higher ESR, with evidence for an interaction between the two causing further increases in the first trimester. Pregnancy is moderately associated with higher odds of hookworm infection (OR: 1.23, 95% CI: 0.83 to 1.83). Pregnancy and hookworm both decrease hemoglobin and may interact to accentuate this effect in the first-trimester of pregnancy (Interaction: β: -0.30 g/dL; CI: -0.870 to 0.24).
CONCLUSIONS
Our findings are consistent with a possible trade-off between hookworm immunity and successful pregnancy, and with the suggestion that hookworm and pregnancy may have synergistic effects, particularly in the first trimester.
Topics: Adolescent; Adult; Ancylostoma; Ancylostomiasis; Animals; Bolivia; Female; Horticulture; Humans; Indians, South American; Middle Aged; Necator americanus; Necatoriasis; Occupational Diseases; Pregnancy; Prevalence; Young Adult
PubMed: 31642576
DOI: 10.1002/ajhb.23337 -
Microbes and Infection Jan 2006This study examined the impact of concurrent parasite infections (amoebiasis, filariasis, necatoriasis) and the effect of anti-parasite treatment on cytokine and...
Cytokine and chemokine responses in patients co-infected with Entamoeba histolytica/dispar, Necator americanus and Mansonella perstans and changes after anti-parasite treatment.
This study examined the impact of concurrent parasite infections (amoebiasis, filariasis, necatoriasis) and the effect of anti-parasite treatment on cytokine and chemokine responses in singly and poly-parasitized patients. Cellular reactivity and parasite-specific Th1- and Th2-type cytokine and chemokine profiles were investigated before and six weeks after treatment. In those patients infected with three parasite species, cellular secretion of interleukin 5 (IL-5) and IL-12p40 by PBMC was strongly diminished (p<0.005) but IL-10 was elevated in parasite-infected patients (p<0.0001) in response to protozoa- and helminth-specific as well as bacteria-specific antigens. Macrophage inflammatory chemokines (MIP-1alpha/CCL3 and MIP-1beta/CCL4), macrophage-derived chemokine (MDC/CCL22) and neutrophil activating chemokine (IL-8/CXCL8) were produced by PBMC in similar amounts in endemic controls and singly and poly-parasitized patients, but thymus and activation-regulated chemokine (TARC/CCL17) was produced the highest by PBMC from patients with triple parasite infections (p<0.0001). Following anti-parasite therapy, secretion of IL-12p40 and IL-5 augmented significantly in treated patients while IL-10, MDC, MIP-1alpha, TARC and IL-8 substantially diminished (all p<10(-5)) when their PBMC were activated with parasite- and bacteria-specific antigens. In summary, PBMC from poly-parasitized patients responded to protozoa- and helminth-specific antigens with a compromised IL-5 and IL-12p40 but high IL-10 and a substantial chemokine release. Chemokines may attract and activate effector cells in peri-parasitic tissues to limit parasite proliferation and dissemination, while depressed IL-5 and IL-12p40 but prominent IL-10 may prevent eosinophil and cytotoxic cell-mediated inflammatory processes and pathogenesis to the host. The changes in this profile following anti-parasite therapy disclosed the dynamics of an immune adaptation associated with parasite accumulation and also with clearance of parasite infections.
Topics: Adult; Animals; Anthelmintics; Antibodies, Helminth; Antigens, Helminth; Chemokines; Cytokines; Entamoebiasis; Female; Humans; Male; Mansonelliasis; Middle Aged; Necator americanus; Necatoriasis
PubMed: 16239120
DOI: 10.1016/j.micinf.2005.06.019 -
Immunology Jun 2016Cellular and molecular investigation of parasitic helminth infections has greatly accelerated the understanding of type 2 immune responses. However, there remains... (Review)
Review
Cellular and molecular investigation of parasitic helminth infections has greatly accelerated the understanding of type 2 immune responses. However, there remains considerable debate regarding the specific leucocytes that kill parasites and whether these mechanisms are distinct from those responsible for tissue repair. Herein, we chronicle discoveries over the past decade highlighting current paradigms in type 2 immunity with a particular emphasis upon how CD4(+) T helper type 2 cells, type 2 innate lymphoid cells and alternatively activated macrophages coordinately control helminth-induced parasitism. Primarily, this review will draw from studies of the murine nematode parasite Nippostrongylus brasiliensis, which bears important similarities to the human hookworms Ancylostoma duodenale and Necator americanus. Given that one or more hookworm species currently infect millions of individuals across the globe, we propose that vaccine and/or pharmaceutical-based cure strategies targeting these affected human populations should incorporate the conceptual advances outlined herein.
Topics: Ancylostoma; Ancylostomiasis; Animals; Antigens, Helminth; Cell Differentiation; Complement Pathway, Alternative; Humans; Immunity, Innate; Macrophage Activation; Macrophages; Necator americanus; Necatoriasis; Nippostrongylus; Strongylida Infections; Th2 Cells
PubMed: 26928141
DOI: 10.1111/imm.12601 -
Parasites & Vectors Jul 2022Although there is unprecedented interest in experimental human hookworm infection, details of hookworm manufacture and characterisation have been sparsely reported. In...
BACKGROUND
Although there is unprecedented interest in experimental human hookworm infection, details of hookworm manufacture and characterisation have been sparsely reported. In this report, we detail the production and characterisation of Necator americanus larvae for use in a recently published clinical trial.
METHODS
Faeces was obtained from an experimentally infected donor. Faecal hookworm DNA was determined by quantitative PCR. Paired samples were incubated in either sterile water or sterile water mixed with antimicrobials (amphotericin and gentamicin). Coproculture was performed by modified Harada-Mori method. The harvested larvae were then processed in either sterile water or antiseptic solution. Larval yield was then calculated (larvae per gram), larval viability was determined by thermally induced motility assay and microbial burden was determined at the day of harvest, at 48 h and at 7 days.
RESULTS
Twenty-eight faecal cultures were performed over 16 months. The faecal hookworm DNA content was variable over this time. There was no association of larval yield with faecal hookworm DNA content. Pre-treatment of faeces with antimicrobials did not influence larval yield. Larval motility was 85.3% (95% CI 79.3-91.3%). Incubation of larvae in antiseptics did not reduce viability at 14 days with a marginal mean of 68.6% (95% CI 59.1-78.1%) washed in water vs. 63.3% (95% CI 53.8 - 72.9%) when incubated in betadine (p = 0.38). Larvae washed in sterile water did not meet microbial bioburden criteria. Incubation in antiseptic resulted in acceptable microbial bioburden at 48 h but not at 7 days. Although the addition of gentamicin did reduce the microbial bio-burden acceptable levels, it was found to significantly lower larval motility at 7 days compared to incubation in sterile water and motility at 7 days 37.8% (95% CI 4.7-70.9%) vs. 67.3% (95% CI 35.2-99.3%, p < 0.001), respectively.
CONCLUSIONS
Despite standardised culture methodologies and the use of a single donor, larval yield varied considerably between batches and had no association with faecal hookworm DNA. Larval viability decreases over time and the age of larvae at time of use are likely to be important. Microbial bioburden maybe temporarily reduced by incubation in antiseptics and has little effect on viability. Incubation of larvae in gentamicin is effective at reducing microbial bioburden but is deleterious to larval viability.
Topics: Ancylostomatoidea; Animals; Anti-Infective Agents, Local; Gentamicins; Hookworm Infections; Humans; Larva; Necator; Necator americanus; Necatoriasis; Water
PubMed: 35804460
DOI: 10.1186/s13071-022-05371-y -
International Journal For Parasitology.... Aug 2018Hookworms are intestinal nematode parasites that infect nearly half a billion people and are globally one of the most important contributors to iron-deficiency anemia....
Hookworms are intestinal nematode parasites that infect nearly half a billion people and are globally one of the most important contributors to iron-deficiency anemia. These parasites have significant impacts in developing children, pregnant women and working adults. Of all the soil-transmitted helminths or nematodes (STNs), hookworms are by far the most important, with disease burdens conservatively estimated at four million DALYs (Disability-Adjusted Life Years) and with productivity losses of up to US$139 billion annually. To date, mainly one drug, albendazole is used for hookworm therapy in mass drug administration, which has on average ∼80% cure rate that is lower (<40%) in some places. Given the massive numbers of people needing treatment, the threat of parasite resistance, and the inadequacy of current treatments, new and better cures against hookworms are urgently needed. Cry5B, a pore-forming protein produced by the soil bacterium Bacillus thuringiensis (Bt) has demonstrated good efficacy against Ancylostoma ceylanicum hookworm infections in hamsters. Here we broaden studies of Cry5B to include tests against infections of Ancylostoma caninum hookworms in dogs and against infections of the dominant human hookworm, Necator americanus, in hamsters. We show that Cry5B is highly effective against all hookworm parasites tested in all models. Neutralization of stomach acid improves Cry5B efficacy, which will aid in practical application of Cry5B significantly. Importantly, we also demonstrate that the anti-nematode therapeutic efficacy of Cry5B is independent of the host immune system and is not itself negated by repeated dosing. This study indicates that Bt Cry5B is a pan-hookworm anthelmintic with excellent properties for use in humans and other animals.
Topics: Ancylostoma; Ancylostomatoidea; Ancylostomiasis; Animals; Anthelmintics; Bacillus thuringiensis; Bacillus thuringiensis Toxins; Bacterial Proteins; Cricetinae; Dogs; Endotoxins; Hemolysin Proteins; Hookworm Infections; Intestinal Diseases, Parasitic; Necator americanus; Necatoriasis
PubMed: 29772478
DOI: 10.1016/j.ijpddr.2018.05.001