Stage‐specific immune responses in human <i> Necator americanus</i> infection

Geiger, Stefan Michael; Caldas, Iramaya Rodrigues; Glone, B. E. Mc; Campi-Azevedo, Ana Carolina; Oliveira, Luciana M.; Brooker, Simon; Diemert, David; Corrêa-Oliveira, Rodrigo; Bethony, Jeffrey M.

doi:10.1111/j.1365-3024.2007.00950.x

Cited by 63 publications

(75 citation statements)

References 43 publications

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“…of infection. Our data corroborate reports from Nigeria and Brazil that describe reduced lymphocyte proportions of CD4 ϩ T cells in human hookworm infection (21,47). A decline in the proportion of CD4 ϩ T cells has also been reported for other infectious diseases associated with depressed cellular immunity, most notably human immunodeficiency virus (HIV) infection (12,27,37,38) but also those caused by other viral (58), bacterial (34), protozoan (11,24), and helminth (17,33,55) pathogens.…”

Section: Discussionsupporting

confidence: 92%

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%

Role for Nitric Oxide in Hookworm-Associated Immune Suppression

Dondji¹,

Bungiro²,

Harrison³

et al. 2008

Infect Immun

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“…In support of this, we observed that NK cells isolated from Necator-infected patients and cultured directly ex vivo without further stimulation expressed significantly higher intracellular levels of IFN-␥ than NK cells from egg-negative individuals from both areas of endemicity and areas of nonendemicity, suggesting that these cells could have been primed to secrete IFN-␥ in vivo. Previous studies examining cytokine profiles in individuals infected with hookworms have shown a "mixed" cytokine production profile that includes the presence of IFN-␥ (15,16,28,29). Our findings that N. americanus ES products have the capacity to induce NK cell recruitment fits well with the idea that NK cells might be actively recruited by adult worms during infection, enabling them to interact with and be activated by ES products in situ.…”

Section: Discussionsupporting

confidence: 87%

“…Our studies demonstrated that neither the presence of IL-10 nor that of TGF-␤ altered the capacity of NK cells from egg-negative individuals to bind ES products, suggesting that these cytokines have little impact on receptors for NKBP interaction. These observations are further supported by the findings of Geiger et al (15,16), showing that high levels of IL-10 are present in all individuals resident in areas of hookworm endemicity. Despite the presence of elevated IL-10 in egg-negative individuals from areas of endemicity, their NK cells were clearly not affected in their capacity to interact with Necator ES products (Fig.…”

Section: Discussionsupporting

confidence: 78%

“…The second mechanism that we considered to explain the impaired interaction of ES products with NK cells from Necator-infected individuals was the presence of IL-10, a well-established immunomodulator during chronic helminth infections (4,27). As reported by Geiger et al (15,16), IL-10 is highly elevated in individuals resident in areas of Necator transmission. To determine whether IL-10 might have the capacity to affect receptors important for binding of NK cells to ES products, we conducted in vitro binding experiments in which NK cells from egg-negative individuals were incubated for up to 72 h with different doses of IL-10 (1 to 125 ng/ml) prior to interaction with bioES.…”

Section: Cd3mentioning

confidence: 89%

“…However, our antibody preblocking studies suggest that decreased expression of these two markers is unlikely to be responsible for a lack of NKPB binding. We also explored the possibility that immunoregulatory cytokines, such as IL-10 and TGF-␤, which are documented to be elevated in individuals from areas of Necator endemicity (15,16) and are known regulators of receptor expression on circulating leukocytes (27), might affect NKBP receptor expression. Our studies demonstrated that neither the presence of IL-10 nor that of TGF-␤ altered the capacity of NK cells from egg-negative individuals to bind ES products, suggesting that these cytokines have little impact on receptors for NKBP interaction.…”

Section: Discussionmentioning

confidence: 99%

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