Impaired resistance in early secondary Nippostrongylus brasiliensis infections in mice with defective eosinophilopoeisis

Abstract

Eosinophils are an important feature of immune responses to infections with many of the tissue-invasive helminth parasites. The cytokine IL-5 and a high-affinity double GATA-binding site within the GATA-1 promoter are critical for eosinophilopoiesis. In this study, we believe we demonstrate for the first time that defects in eosinophilopoiesis are associated with impaired resistance to Nippostrongylus brasiliensis. Primary and secondary infections were established in wildtype (WT), IL-5(-/-) and DeltadblGATA mice. Resistance to secondary infections was impaired in IL-5(-/-) and DeltadblGATA mice, with significantly more larvae able to reach the lungs 2 days p.i. Pulmonary inflammation was minimal in all strains in the first 2 days of both primary and secondary infections, suggesting that eosinophil-dependent resistance occurred before larvae reached this site. Intestinal worm burdens and/or parasite egg production in primary infections were greater in animals with defective eosinophilopoiesis. While larvae did reach the gut by day 3 of secondary infections of WT and IL-5(-/-) mice, worms were expelled by day 7, even in the complete absence of eosinophils in tissues of the small intestine. This and our previous studies indicate that N. brasiliensis are likely to be exquisitely sensitive to attack by eosinophils soon after entry into the skin. Eosinophils in the gut may make a modest contribution to resistance on first exposure to the parasite, but are not required for expulsion in either primary or secondary infections. In order to mount an effective immune response it may be vital for the host to identify and attack the parasite before it implements immune evasion strategies and migrates to other anatomical sites. These observations may be of particular significance for the development of successful vaccines against hookworms and other nematodes.

Immunity to gastrointestinal nematode infections

“…[194][195][196] Eosinophils have also been shown to promote the survival of long-lived plasma cells in the bone marrow 197 as well as the generation of IgA-secreting plasma cells in the gastrointestinal tract 179,198 (at least in the small intestine 199 ) via the production of IL-1b, suggesting that they might affect secondary challenge infections where antibodies presumably play a larger role. Indeed, both IL-5 and eosinophildeficient mice harbor increased numbers of N. brasiliensis larvae after secondary infection, 89 with similar results during secondary T. spiralis infection. 200 Furthermore, eosinophils negatively regulate Th17 cells 201 and promote the expansion of regulatory T cells in the steady state 198,202 that might affect overall inflammation, illustrating their complex contribution to tissue homeostasis.…”

“…86 If anything, eosinophils act positively on the fecundity of H. polygyrus worms. 87 However, mice that overexpress IL-5 have massive systemic eosinophilia and are less susceptible to N. brasiliensis, 88 whereas eosinophil-deficient mice are unimpaired in their ability to expel, 89 illustrating that IL-5 has additional unknown functions beyond those associated with eosinophils.…”

IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms

“…Immunity against N. brasiliensis rechallenge was impaired in mice made eosinophil deficient by targeted deletion of the erythroid transcription factor (GATA-1) or IL-5 (27,28,43). Mechanistically, IL-33 could promote eosinophilic lung inflammation through inducing IL-5 and IL-13 production from CD4 + T cells and ILC2s (19), or by directly activating eosinophils through TI/ST2.…”

“…Between 6-12 d postinfection, IL-4-and IL-13-dependent effects cause intestinal epithelial cells (IECs) to expel adult worms from the intestinal lumen through mechanisms that require resistin-like molecule beta (RELMβ), a goblet cell-specific protein that interferes with worm nutrition (23,24). If previously infected animals are rechallenged, STAT-6-dependent processes drive rapid expulsion of worms, potentially via IL-4 and CD4 + T cells, but there is lack of consensus on the exact mechanism (25)(26)(27)(28). Given that human hookworm infections are characterized by poor memory responses and high rates of reinfection (29), it is possible that better understanding of host protection in rodents will lead to novel approaches for reducing the burden of human disease.…”

Hookworm-related cutaneous larva migrans in patients living in an endemic community in Brazil: Immunological patterns before and after ivermectin treatment

“…IL-5 serum concentrations were signifi cantly higher in Hr-CLM patients than in endemic controls. A role of IL-5-mediated protection against nematode larvae is supported by data obtained in the above-mentioned murine N. brasiliensis model where IL-5 knock-out mice with defective eosinophilopoeisis showed an impaired resistance in early secondary infection to this parasite, i.e., signifi cantly more larvae reached the lungs than in wild-type animals [24]. Likewise, IL-5 knock out mice are more susceptible to secondary T. spiralis infection [25].…”