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Ageing is associated with several alterations in the immune system. Our aim in this study was to compare the development of immunity to Schistosoma mansoni infection in young versus aged C57Bl/6 mice using the liver as the main organ to evaluate pathological alterations and immune responses. In the acute phase, young mice had large liver granulomas with fibrosis and inflammatory cells. Chronic phase in young animals was associated with immunomodulation of granulomas that became reduced in size and cellular infiltrate. On the other hand, aged animals presented granulomas of smaller sizes already in the acute phase. Chronic infection in these mice was followed by no alteration in any of the inflammatory parameters in the liver. In concert with this finding, there was an increase in activated CD4+ T, CD19+ B and NK liver cells in young mice after infection whereas old mice had already higher frequencies of activated B, NK and CD4+ T liver cells and infection does not change these frequencies. After infection, liver production of inflammatory and regulatory cytokines such as IFN‐γ, IL‐4 and IL‐10 increased in young but not in old mice that had high levels of IL‐4 and IL‐10 regardless of their infection status. Our data suggest that the unspecific activation status of the immune system in aged mice impairs inflammatory as well as regulatory immune responses to S. mansoni infection in the liver, where major pathological alterations and immunity are at stage. This poor immune reactivity may have a beneficial impact on disease development.

Multiple schistosome and soil-transmitted nematode infections are frequently reported in human populations living in tropical areas of developing countries. In addition to exposure factors, the host immune response plays an important role in helminth control and morbidity in hosts with multiple infections; however, these aspects are difficult to evaluate in human populations. In the current study, female Swiss mice were simultaneously co-infected with Strongyloides venezuelensis and Schistosoma mansoni or infected with St. venezuelensis at 2, 4, or 14 weeks after Sc. mansoni infection. The simultaneously infected mice showed a similar parasite burden for St. venezuelensis compared with mono-infected mice. In contrast, there was a significant reduction of St. venezuelensis burden (primarily during the migration of the larvae) in mice that were previously infected with Sc. mansoni at the acute or chronic phase. Independent of the stage of Sc. mansoni infection, the St. venezuelensis co-infection was capable of inducing IL-4 production in the small intestine, increasing the IgE concentration in the serum and increasing eosinophilia in the lungs and intestine. This result suggests that the nematode infection stimulates local type 2 immune responses independently of the schistosomiasis stage. Moreover, previous Sc. mansoni infection stimulated early granulocyte infiltration in the lungs and trematode-specific IgM and IgG1 production that recognized antigens from St. venezuelensis infective larvae; these immune responses would act in the early control of St. venezuelensis larvae. Our data suggest that the effect of multiple helminth infections on host susceptibility and morbidity largely depends on the species of parasite and the immune response.

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Strongyloidiasis is a neglected chronic nematode infection, in which the control of autoinfection rate and severity of disease is dependent on type 2 immune responses. Strongyloides also causes Th2 responses in the lung of infected animals and changes in airway function, including airway hyperresponsiveness (AHR). Mechanisms of AHR during Strongyloides venezuelensis infection are not entirely known, and we investigate here the role of IL-4, eosinophils, and IL-33/ST2. AHR was evaluated in infected mice by determining changes in lung function after increasing doses of methacholine. Balb/C, but no C57Bl/6, mice developed AHR, tissue eosinophilia, and increased local IL-4 and IL-5 production. Functional changes peaked at day 4 and 7, after the larva had left the lungs. AHR was clearly dependent on IL-4 but not on eosinophils, as evaluated by experiments in IL-4 and Gata-1-deficient mice. Experiments in ST2-deficient mice showed that this pathway was not needed for induction of AHR but was necessary for the maintenance of AHR and for Th2 responses in the lung. These studies clearly show a crucial role for IL-4 in the induction of AHR following S. venezuelensis infection and for IL-33/ST2 in maintaining AHR and lung Th2 responses.