The Impact of Concurrent and Treated<i>Ancylostoma ceylanicum</i>Hookworm Infections on the Immunogenicity of a Recombinant Hookworm Vaccine in Hamsters

Ghosh, Kashinath; Wu, Wenhui; Antoine, A. D.; Bottazzi, María Elena; Valenzuela, Jesús G.; Hotez, Peter J.; Méndez, Susana

doi:10.1086/498528

Cited by 25 publications

(28 citation statements)

References 43 publications

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“…The results presented here confirm previous observations that A. ceylanicum infection is associated with impaired lymphocyte proliferation (23,45), a phenomenon that has also been observed in filarial nematode infections (25,26,54). By day 70 p.i., there were very few adult worms remaining in the intestine (Fig.…”

Section: Discussionsupporting

confidence: 92%

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Role for Nitric Oxide in Hookworm-Associated Immune Suppression

Dondji¹,

Bungiro²,

Harrison³

et al. 2008

Infect Immun

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Hookworm infection is a major cause of anemia and malnutrition in resource-poor countries. Human and animal studies suggest that infection with these intestinal nematodes is associated with impaired cellular immunity, characterized by reduced lymphocyte proliferation in response to both parasite and heterologous antigens. We report here data from studies aimed at defining mechanisms through which hookworms modulate the host cellular immune response. Splenocytes and mesenteric lymph node (MLN) cells from hamsters infected with Ancylostoma ceylanicum showed minimal proliferation in response to mitogen at days 20 and 30 postinfection (p.i.), with partial recovery noted at day 70 p.i. The proliferative capacity of enriched splenocyte T-cell preparations from infected animals following stimulation with hookworm antigens was partially restored in the presence of antigen-presenting cells from uninfected hamsters. Analysis by fluorescence-activated cell sorting revealed that hookworm infection is associated with reduced percentages of both CD4؉ and surface immunoglobulin G-positive lymphocytes in the spleen and MLN cells. Splenocytes from infected hamsters also secreted more nitric oxide (NO) in culture than did those from naïve animals. Inhibition of NO secretion was associated with partial restoration of the proliferative capacity of splenocytes from infected animals in response to concanavalin A, suggesting a role for NO in mediating this effect. Together, these data demonstrate that hookworm infection is associated with impaired function of antigen-presenting cells and depletion of important lymphocyte subpopulations and also suggests a role for NO in parasite-induced immunosuppression.It is estimated that more than 700 million people in resourcepoor countries are infected with hookworms, bloodfeeding intestinal nematodes that cause anemia and malnutrition (8,14). Together with Ascaris lumbricoides and Trichuris trichiura, the hookworms Ancylostoma duodenale and Necator americanus comprise the group of soil-transmitted nematodes that are now recognized as a major cause of global morbidity (2, 56). Significant clinical features of hookworm infection in humans include irondeficiency anemia, hypoproteinemia, and growth delay (13, 53). Although control strategies relying on targeted delivery of benzimidazole antihelminthics are generally effective at eliminating adult worms, reinfection occurs quickly and frequent treatments may be necessary for sustained improvement in the health of at-risk populations (50,52).Although sterile immunity does not appear to develop following natural infection, data from human and animal studies confirm that hookworms elicit humoral and cellular immune responses in mammalian hosts (18). Although the nature of this response has yet to be elucidated fully, infection appears to be associated with a mixed Th1/Th2 host cytokine profile (22,49). It has also been reported that hookworm infection is associated with suppression of host cellular responses to hookworm-specific and heterologous antige...

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Section: Discussionsupporting

confidence: 92%

“…However, few studies have attempted to probe the mechanisms underlying this phenomenon in human and/or laboratory animal hosts (23,45,46). In the present study, we utilized the hamster model of A. ceylanicum to characterize the modulation of host cellular immune responses and potential mechanisms underlying such immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

Role for Nitric Oxide in Hookworm-Associated Immune Suppression

Dondji¹,

Bungiro²,

Harrison³

et al. 2008

Infect Immun

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“…26 Several studies have shown that elimination of helminth parasites before immunization seems to restore normal vaccine responsiveness. [26][27][28][29] In conclusion, our study adds additional support to earlier observations of an association between the presence of intestinal helminth infection and the development of clinical malaria.…”

Section: Discussionsupporting

confidence: 87%

Epidemiological Study of the Association Between Malaria and Helminth Infections in Nigeria

Efunshile

Olawale

Stensvold

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. The relationship between intestinal helminth infection and susceptibility to malaria remains unclear. We studied the relationship between these infections. Seven schools in Ilero, Nigeria referred all pupils with febrile illness to our study center for free malaria treatment during a 3-month study period. At the end, all pupils submitted a stool sample for microscopic investigation for helminth eggs. We used an unmatched case-control design to calculate the odds ratios for helminth infection in children with at least one attack of malaria (cases) and children with no malaria episodes during the study (controls). We recorded 115 malaria cases in 82 of 354 (23.2%), 16 of 736 (2.2%), and 17 of 348 (4.7%) children ages 5, 6-10, and 11-15 years old, respectively (P = 0.001). Helminth infection rate in cases was 21 of 115 (18.3%) compared with 456 of 1,327 (34.4%) in controls. Weighted odds ratio stratified by age group for helminth infection in cases versus controls was 0.50 (95% confidence interval = 0.2-0.84, P 0.01). Ascaris and hookworm were the most common helminths detected, with prevalence rates of 14 (12.2%) and 6 (5.2%) among cases compared with 333 (25.1%) and 132 (10.0%) in controls, respectively (P = 0.001). The negative association between helminth infection and malaria may be of importance in the design of deworming programs.

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“…An antibody titer reduction following larval challenge is a common phenomenon for hookworm vaccine trials (43,69), putatively because of antibody absorption by specific antigen produced by the challenged hookworms. No efforts were made to further characterize the cytokine responses, although some hamster reagents are beginning to become available (24,42). Only hamsters vaccinated with rNa-GST-1 achieved protection levels comparable to those reported previously with Ac-GST-1 (65,69).…”

Section: Discussionmentioning

confidence: 83%

Molecular Cloning, Biochemical Characterization, and Partial Protective Immunity of the Heme-Binding GlutathioneS-Transferases from the Human HookwormNecator americanus

et al. 2010

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Hookworm glutathione S-transferases (GSTs) are critical for parasite blood feeding and survival and represent potential targets for vaccination. Three cDNAs, each encoding a full-length GST protein from the human hookworm Necator americanus (and designated Na-GST-1, Na-GST-2, and Na-GST-3, respectively) were isolated from cDNA based on their sequence similarity to Ac-GST-1, a GST from the dog hookworm Ancylostoma caninum. The open reading frames of the three N. americanus GSTs each contain 206 amino acids with 51% to 69% sequence identity between each other and Ac-GST-1. Sequence alignment with GSTs from other organisms shows that the three Na-GSTs belong to a nematode-specific nu-class GST family. All three Na-GSTs, when expressed in Pichia pastoris, exhibited low lipid peroxidase and glutathione-conjugating enzymatic activities but high heme-binding capacities, and they may be involved in the detoxification and/or transport of heme. In two separate vaccine trials, recombinant Na-GST-1 formulated with Alhydrogel elicited 32 and 39% reductions in adult hookworm burdens (P < 0.05) following N. americanus larval challenge relative to the results for a group immunized with Alhydrogel alone. In contrast, no protection was observed in vaccine trials with Na-GST-2 or Na-GST-3. On the basis of these and other preclinical data, Na-GST-1 is under possible consideration for further vaccine development.

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The Impact of Concurrent and TreatedAncylostoma ceylanicumHookworm Infections on the Immunogenicity of a Recombinant Hookworm Vaccine in Hamsters

Cited by 25 publications

References 43 publications

Role for Nitric Oxide in Hookworm-Associated Immune Suppression

Role for Nitric Oxide in Hookworm-Associated Immune Suppression

Epidemiological Study of the Association Between Malaria and Helminth Infections in Nigeria

Molecular Cloning, Biochemical Characterization, and Partial Protective Immunity of the Heme-Binding GlutathioneS-Transferases from the Human HookwormNecator americanus

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