Role of myeloid cells in mediating protection against parasitic helminth larvae

Helminth infections affect around one fourth of the world population living in the poorest regions of our planet. Helminths mainly cause debilitating chronic effects on health, development and nutritional status of infected people. The development of a vaccine is currently thought to be the more promising solution to eradicate helminths. However, further research efforts are required to unravel host-pathogen interactions, evasion strategies and killing mechanisms. The work presented in this thesis expands our knowledge in these domains, with a special focus given to the functions employed by myeloid immune cells against various soil-transmitted helminths. Our laboratory has previously showed that macrophages can efficiently trap and kill H. polygyrus larvae in immune mice by upregulating the enzyme Arginase 1. By contrast, following primary infection, H. polygyrus can establish chronicity because protective adaptive immune mechanisms do not arise quickly enough to block larval development. In a primary setting, we observed that myeloid cells accumulate around larvae and specifically express the inducible form of nitric oxide synthase (iNOS) in response to the parasite. Furthermore, iNOS deficient mice displayed reduced worm burdens as compared to wild type controls, indicating that iNOS expression favors larval survival. Induction of iNOS by the larvae constitutes a novel mechanism of innate immune response evasion. Although the exact mechanism by which iNOS expression attenuates protection is still unclear, current evidence indicates that it involves alterations to myeloid cell function. We next sought to determine whether the described protective role for antibody-activated macrophages during rodent helminth infection hold true in a human setting. To this end, we compared the ability of antibody activated human blood-derived macrophages and eosinophils to attack A. suum larvae, a close relative to the human parasite A. lumbricoides. Eosinophils were included in the analyses as former studies on porcine eosinophils had shown that they efficiently kill Ascaris larvae. We observed that immune serum stimulated human macrophages adhered to A. suum larvae and impaired their motility. Surprisingly, Ascaris trapping mechanism was somehow different from what has been described in rodent models. Interestingly, macrophages were also less efficient than eosinophils to trap the larvae. Gene expression analysis revealed that macrophages stimulated with immune serum and larvae upregulated the eosinophil chemoattractant CCL24, suggesting that they may function more as helper cells that attract eosinophils, which in turn kill the parasite. In the final project, we investigated how macrophages detect and bind to helminth larvae given that only limited knowledge is available regarding larval recognition mechanisms. We could show that complement and/or antibodies were sufficient for the recognition of H. polygyrus and A. suum larvae, while IL-4 activation, and thus type 2 polarization, is sufficient for induction of recognition of N. brasiliensis larvae. We further explored the role of carbohydrates in this process and showed that soluble β-glucans could inhibit larval-macrophage interaction. This led to the discovery that the β-glucan binding site of the complement receptor 3 (CR3) played a crucial role in mouse macrophage recognition of N. brasiliensis larvae.

    Keywords: immune response ; helminth ; macrophages ; iNOS ; recognition ; glucans ; CR3

    Thèse École polytechnique fédérale de Lausanne EPFL, n° 8219 (2017)
    Programme doctoral Approches moléculaires du vivant
    Faculté des sciences de la vie
    Institut de recherche en infectiologie
    Unité de la Prof. Harris
    Jury: Prof. Melanie Blokesch (présidente) ; Prof. Nicola Harris (directeur de thèse) ; Prof. Bruno Lemaitre, Prof. Fabienne Tacchini-Cottier, Prof. Salomé LeibundGut-Landmann (rapporteurs)

    Public defense: 2017-12-8


    Record created on 2017-11-28, modified on 2017-11-29


  • Thesis submitted - Forthcoming publication

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