EGF-mediated EGFR/ERK signaling pathway promotes germinative cell proliferation in Echinococcus multilocularis that contributes to larval growth and development

Cheng, Zhe; Liu, Fan; Li, Xiu; Dai, Mengya; Wu, Jian‐Jian; Guo, Xinrui; Tian, Huimin; Heng, Zhijie; Lü, Ying; Chai, Xiaoli; Wang, Yanhai

doi:10.1371/journal.pntd.0005418

Cited by 44 publications

(64 citation statements)

References 53 publications

(87 reference statements)

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“…A similar type of cytokine receptor interaction appears to involve epidermal growth factor (EGF)-like cytokines and cognate parasite receptors, of which three (EmER, EmERb, EmERc) are expressed by E. multilocularis larvae [3,12]. As recently shown by Cheng et al [13], host-derived EGF is able to stimulate germinative cell proliferation in in vitro cultivated parasite larvae and can stimulate at least one of the parasite EGF-receptors, EmER, when heterologously expressed in Xenopus oocytes. Although the parasite itself expresses several EGF-like molecules [14], which likely act on its EGF receptors, these data indicate that host-EGF could act as an additional stimulus, particularly in response to liver tissue damage as it is inflicted upon entry of the parasite into the host liver [4].…”

Section: Discussionmentioning

confidence: 98%

“…Using in vitro cultivation systems for metacestode vesicles and germinative cells [7-10], we also demonstrated that host insulin fosters parasite development by acting on evolutionarily conserved receptor kinases of the insulin receptor family that are expressed by the metacestode [11]. Evidence has also been obtained that host epidermal growth factor (EGF) stimulates Echinococcus germinative cell proliferation, most probably by acting on parasite receptor tyrosine kinases of the EGF receptor family [12,13]. These studies indicate that the interaction of host-derived hormones and cytokines with corresponding receptors of evolutionarily conserved signalling pathways that are expressed by the parasite may play an important role in AE host-parasite interaction.…”

Section: Introductionmentioning

confidence: 99%

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The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction

Förster

Koziol

Schäfer

et al. 2018

Preprint

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22Background: Alveolar echinococcosis (AE) is a lethal zoonosis caused by the metacestode 23 larva of the tapeworm Echinococcus multilocularis. The infection is characterized by tumour-24 like growth of the metacestode within the host liver, leading to extensive fibrosis and organ-25 failure. The molecular mechanisms of parasite organ tropism towards the liver and influences 26 of liver cytokines and hormones on parasite development are little studied to date. 27Methodology/Principal findings: We show that the E. multilocularis larval stage expresses 28 three members of the fibroblast growth factor (FGF) receptor family with homology to human 29 FGF receptors. Using the Xenopus expression system we demonstrate that all three 30 Echinococcus FGF receptors are activated in response to human acidic and basic FGF, which 31 are present in the liver. In all three cases, activation could be prevented by addition of the 32 tyrosine kinase inhibitor BIBF 1120, which is used to treat human cancer. At physiological 33 concentrations, acidic and basic FGF significantly stimulated the formation of metacestode 34 vesicles from parasite stem cells in vitro and supported metacestode growth. Furthermore, the 35 parasite's mitogen activated protein kinase signalling system was stimulated upon addition of 36 human FGF. The survival of metacestode vesicles and parasite stem cells were drastically 37 affected in vitro in the presence of BIBF 1120. 38 Conclusions/Significance: Our data indicate that mammalian FGF, which is present in the 39 liver and upregulated during fibrosis, supports the establishment of the Echinococcus 40 metacestode during AE by acting on an evolutionarily conserved parasite FGF signalling 41 system. These data are valuable for understanding molecular mechanisms of organ tropism 42 and host-parasite interaction in AE. Furthermore, our data indicate that the parasite's FGF 43 signalling systems are promising targets for the development of novel drugs against AE.44 3 45 Author summary 46 To ensure proper communication between their different cell populations, animals rely on 47 secreted hormones and cytokines that act on receptors of target cells. Most of the respective 48 cytokines, such as FGFs, evolved over 500 million years ago and are present in similar form 49 in all animals, including parasitic worms. The authors of this study show that the metacestode 50 larva of the tapeworm E. multilocularis, which grows like a malignant tumor within the host 51 liver, expresses molecules with homology to FGF receptors from mammals. The authors show 52 that human FGF, which is abundantly present in the liver, stimulates metacestode 53 development and that all parasite FGF receptors are activated by human FGF, despite 500 54 million years of evolutionary distance between both systems. This indicates that cells of the 55 Echinococcus metacestode can directly communicate with cells of the mammalian host using 56 evolutionarily conserved signaling molecules. This mode of host-pathogen interaction is 57 unique for helmint...

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction

Förster

Koziol

Schäfer

et al. 2018

Preprint

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show abstract

“…Due to the relatively close phylogenetic relationship between helminths and mammalian hosts, it is now clear that they can communicate via evolutionarily conserved signaling systems [66]. Examples are the induction of Epidermal Growth Factor (EGF) signalling in trematodes and cestodes by host derived EGF that binds to evolutionarily conserved EGF receptor kinases [67,68]. We previously demonstrated that also host insulin can stimulate Echinococcus development by acting on evolutionarily conserved insulin signaling systems [69].…”

Section: Discussionmentioning

confidence: 99%

A secreted Echinococcus multilocularis activin A homologue promotes regulatory T cell expansion

Nono

Lutz

Brehm

2019

Preprint

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21Background: Alveolar echinococcosis (AE), caused by the metacestode larval stage of 22 the fox-tapeworm Echinococcus multilocularis, is a chronic zoonosis associated with 23 significant modulation of the host immune response. A role of regulatory T-cells (Treg) in 24 generating an immunosuppressive environment around the metacestode during chronic 25 disease has been reported, but the molecular mechanisms of Treg induction by E. 26 multilocularis remain elusive so far. 27Methodology/Principal findings: We herein demonstrate that excretory/secretory (E/S) 28 products of the E. multilocularis metacestode promote the formation of Foxp3 + Treg from 29 CD4 + T-cells in vitro in a TGF--dependent manner. We also show that host T-cells 30 secrete elevated levels of the immunosuppressive cytokine IL-10 in response to 31 metacestode E/S products. Within the E/S fraction of the metacestode we identified an E. 32 multilocularis activin A homolog (EmACT) that displays significant similarities to 33 mammalian Transforming Growth Factor- (TGF-/activin subfamily members. EmACT 34 obtained from heterologous expression promoted host TGF--driven CD4 + Foxp3 + Treg 35 conversion in vitro. Furthermore, like in the case of metacestode E/S products, EmACT-36 treated CD4 + T-cells secreted higher levels of IL-10. These observations suggest a 37 contribution of EmACT in the in vitro expansion of Foxp3 + Treg by the E. multilocularis 38 metacestode. Using infection experiments we show that intraperitoneally injected 39 metacestode tissue expands host Foxp3 + Treg, confirming the expansion of this cell type 40 in vivo during parasite establishment. 3 41Conclusions/Significance: In conclusion, we herein show that E. multilocularis larvae 42 secrete a factor with clear structural and functional homologies to mammalian activin A. 43 Like its mammalian homolog, this protein induces the secretion of IL-10 by T-cells and 44 contributes to the expansion of TGF-β-driven Foxp3 + Treg, a cell type that has been 45 reported crucial for generating a tolerogenic environment to support parasite 46 establishment and proliferation. 47 48 AUTHOR SUMMARY 49The metacestode larval stage of the tapeworm E. multilocularis grows infiltratively, like a 50 malignant tumor, within the organs of its human host, thus causing the lethal disease 51 alveolar echinococcosis (AE). Immunosuppression plays an important role in both survival 52 and proliferation of the metacestode, which mainly depends on factors that are released 53 by the parasite. These parasite-derived molecules are potential targets for developing new 54 anti-echinococcosis drugs and/or improving the effectiveness of current therapies. 55Additionally, an optimized use of such factors could help minimize pathologies resulting 56 from over-reactive immune responses, like allergies and autoimmune diseases. The 57 authors herein demonstrate that the E. multilocularis metacestode releases a protein, 58EmACT, with significant homology to activin A, a cytokine that might support host TGF-...

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“…The report suggests that the human EGF interacts with helminth EGFR to bring about proliferation of germinal cells and larval growth in the pathogen. In line, inhibition of EGFR with CI‐1033 and BIBW2992 was found to impair the processes and control echinococcosis . The implication of EGFR pathway in regulating other forms of host cell death during infections remains unexplored.…”

Section: Intersection Of Egfr Pathway With Infection‐driven Immune Rementioning

confidence: 99%

Immunological implications of epidermal growth factor receptor signaling in persistent infections

Mukherjee

Balaji

2019

IUBMB Life

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Infectious diseases account for a large proportion of global health emergencies and are rising more so owing to the paucity of effective vaccination and chemotherapeutic strategies. The severity is compounded by the development of antibiotic resistance among major pathogenic strains, capable of residing in the hostile host microenvironment by hijacking its signaling mechanisms and molecular circuitry. Among such processes, studies on epidermal growth factor receptor (EGFR) have revealed specific contributions of this classical oncogenic signaling axis during distinct infection conditions. Here, we review the current status of EGFR family members in the context of host-pathogen interactions and speculate the possible dimensions of exploration and manipulation of the EGFR pathway for host-directed therapeutic purposes. K E Y W O R D S epidermal growth factor receptor, host-directed therapeutics, immune responses, immunotherapy, mitochondrial/nuclear EGFR, persistent infections

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EGF-mediated EGFR/ERK signaling pathway promotes germinative cell proliferation in Echinococcus multilocularis that contributes to larval growth and development

Cited by 44 publications

References 53 publications

The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction

The role of fibroblast growth factor signalling in Echinococcus multilocularis development and host-parasite interaction

A secreted Echinococcus multilocularis activin A homologue promotes regulatory T cell expansion

Immunological implications of epidermal growth factor receptor signaling in persistent infections

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