Necator americanus Infection: A Possible Cause of Altered Dendritic Cell Differentiation and Eosinophil Profile in Chronically Infected Individuals

Abstract

BackgroundHookworms survive for several years (5 to 7 years) in the host lumen, inducing a robust but largely ineffective immune response. Among the most striking aspects of the immune response to hookworm (as with many other helminths) is the ablation of parasite-specific T cell proliferative response (hyporesponsiveness). While the role of the adaptive immune response in human helminth infection has been well investigated, the role of the innate immune responses (e.g., dendritic cells and eosinophils) has received less attention and remains to be clearly elucidated.Methodology/Principal FindingsWe report on the differentiation/maturation of host dendritic cells in vitro and the eosinophil activation/function associated with human hookworm infection. Mature DCs (mDCs) from Necator americanus (Necator)–infected individuals showed an impaired differentiation process compared to the mDCs of non-infected individuals, as evidenced by the differential expression of CD11c and CD14. These same hookworm-infected individuals also presented significantly down-regulated expression of CD86, CD1a, HLA-ABC, and HLA-DR. The lower expression of co-stimulatory and antigen presentation molecules by hookworm-infected–derived mDCs was further evidenced by their reduced ability to induce cell proliferation. We also showed that this alternative DC differentiation is partially induced by excreted-secreted hookworm products. Conversely, eosinophils from the same individuals showed a highly activated status, with an upregulation of major cell surface markers. Antigen-pulsed eosinophils from N. americanus–infected individuals induced significant cell proliferation of autologous PBMCs, when compared to non-infected individuals.ConclusionChronic N. americanus infection alters the host's innate immune response, resulting in a possible modulation of the maturation process of DCs, a functional change that may diminish their ability for antigen presentation and thus contribute to the ablation of the parasite-specific T cell proliferative response. Interestingly, a concomitant upregulation of the major cell surface markers of eosinophils was observed in hookworm-infected individuals, indicative of antigen-specific immune responses, especially antigen presentation. We showed that in addition to the postulated role of the eosinophils as effector cells against helminth infection, activated cells may also be recruited to sites of inflammation and contribute to the immune response acting as antigen presenting cells.

Hookworm products ameliorate dextran sodium sulfate-induced colitis in BALB/c mice

“…The fact that the immune system is capable of reacting vigorously to hookworm infection and yet does little to prevent primary infection or reinfection is a strong indication that the immune response to hookworms is highly downregulated. 20 In this work, we showed that the induction of colitis by DSS administration caused a clear Th1 response in the colon, which was significantly downregulated after the administration of A. ceylanicum products. However, the resistance to DSS-induced colitis related to hookworm products therapy was not simply associated with modulation through Th2 or regulatory cytokines.…”

“…Indeed, we have previously shown that hookworm infection, as well as some of their specific antigens, are associated with a profound ablation of cell proliferation. 17,18 Multiple factors such as regulatory cytokines, 18,19 altered function of antigen-presenting cells, [20][21][22][23][24] T-cell apoptosis, 25,26 modulation by regulatory T cells, 27 pro-and antiinflammatory cytokines, 28 and eosinophil recruitment/activation 20 have also been proposed as possible causes of the immune hyporesponsiveness observed in helminth infections. Abundant clinical, epidemiological, and experimental evidence support the therapeutic potential of helminth-derived molecules in the treatment of chronic inflammation and autoimmune diseases.…”

“…The mechanisms underlying hookworm-induced T-cell hyporesponsiveness have yet to be fully elucidated. However, several factors such as regulatory cytokines (e.g., IL-10), 18 secretion of IFN-c by NK cells, 44 cleavage of effector cell chemoattractants, 45 direct downmodulation by parasite antigens, 46 reduced expression of Toll-like receptors, 47 and impaired dendritic cell differentiation 20 have been proposed. It is well known that helminths can induce a robust Th2 immune response in the host, which primarily aims to provide protection against worm colonization.…”

Malaria and soil-transmitted intestinal helminth co-infection and its effect on anemia: a meta-analysis

“…69 It is not unreasonable to assume that helminth induced immune hyporesponsiveness could contribute towards increased susceptibility to other infections prevalent in the region, notably malaria. Hartgers and co-workers 63 reported that the immune hyporesponsiveness induced during chronic helminth infection affects responses not only to helminth antigens but also to bystander antigens.…”

Hookworm virulence factors: making the most of the host

“…Typically, individuals with hookworm heavy infections have compromised antigen-specific T-cell responses in peripheral blood populations [90], most evident in a lack of in vitro proliferation to N. americanus crude antigens and diminished IL-2 and IFN-g responses to these antigens. However, this does not mean that reactivity is altogether absent since in filariae infections, T cells were shown to still produce IL-4 in response to the parasite's crude adult antigen in vitro, even though IL-5 and IFN-g were suppressed.…”