Inefficient and abortive classical complement pathway activation by the calcium inositol hexakisphosphate component of the Echinococcus granulosus laminated layer

Barrios, Anabella A.; Grezzi, Leticia; Miles, Sebastián; Mariconti, Mara; Mourglia‐Ettlin, Gustavo; Seoane, Paula I.; Díaz, Álvaro

doi:10.1016/j.imbio.2019.05.009

Cited by 11 publications

(18 citation statements)

References 55 publications

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“…In addition, there was as previously mentioned Clec4F-independent uptake by non-KC CD11b + liver cells and by LSEC (Figures 4 a –c, 5 a - c, 6 a – c, and S6 a – c). Clec4F-independent uptake may be mediated by natural anti- carbohydrate antibodies that bind the LL mucins, either directly or via complement activation (35). In the context of chronic experimental infection, the possibilities for Clec4F-independent uptake are even broader than after LL mucin injection.…”

Section: Discussionmentioning

confidence: 99%

“…calcium inositol hexakisphosphate (calcium InsP 6 ) (36)(37)(38). Calcium InsP 6 binds host C1q and initiates limited activation of complement (35,39). In fact, the observed uptake of LL materials by phagocytes at the experimental infection site (Figure 7 a) must be Clec4F-independent, as peritoneal macrophages are not expected to express Clec4F (16).…”

Section: Discussionmentioning

confidence: 99%

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Mucins shed from the laminated layer in cystic echinococcosis are captured by Kupffer cells via the lectin receptor Clec4F

Barrios

Mouhape

Schreiber

et al. 2022

Preprint

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Cystic echinococcosis is caused by the larval stages (hydatids) of cestode parasites belonging to the species cluster Echinococcus granulosus sensu lato. Hydatids are bladder-like structures that attain large sizes within various internal organs of livestock ungulates and humans. Hydatids are protected by the massive acellular laminated layer (LL), composed mainly by mucins. Parasite growth requires LL turnover, and abundant LL-derived particles are found at infection sites and draining lymph nodes in infected humans. These observations raise the question of whether LL materials circulate systemically, and if so how they are dealt with by the hosts. We previously reported that LL mucins are bound by a recombinant version of the lectin receptor Clec4F. In rodents, Clec4F is expressed only in Kupffer cells, the liver macrophages exposed to the vascular space. In this article, we show that Kupffer cells take up LL mucins in vivo in a manner dependent on the mucin glycans and Clec4F. In mice harbouring intraperitoneal infections, LL mucins were found essentially only at the infection site and in the liver, where they were taken up by Kupffer cells via Clec4F. It seems likely that the composition of the LL was adjusted through evolution so that LL debris were taken up by the major phagocytes of the rodent liver, which is the ancestral infection site for Echinococcus larvae. However, our data reveal that Kupffer cells act as a sink for LL materials even when the parasite grows in sites other than the liver, as it happens in natural E. granulosus infections.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mucins shed from the laminated layer in cystic echinococcosis are captured by Kupffer cells via the lectin receptor Clec4F

Barrios

Mouhape

Schreiber

et al. 2022

Preprint

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“…LL 34,35 . In CE, the LL seems to prevent the exogenic budding that characterizes AE lesions; in addition, as complement-activating antibodies are part of the protective immune response 36 , LL represents a first barrier against the host’s immune attack; in addition, we may hypothesize that its composition may attract and trigger the activation of the host’s cells involved in the development of the AL, which constitutes a second barrier when the cyst is fully established 12 . Different excretory/secretory metabolic products have been identified in the HF of E. granulosus s.s .…”

Section: Discussionmentioning

confidence: 99%

The local immune response during Echinococcus granulosus growth in a quantitative hepatic experimental model

Zhang

et al. 2019

Sci Rep

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The local immune mechanisms responsible for the establishment and development of Echinococcus granulosus sensu stricto infection in the liver, have been little explored. We developed a suitable experimental model that mimics naturally infected livers using portal injection of protoscoleces. Opposite to Echinococcus multilocularis infection which is dose-dependent, fully mature hydatid cysts can be established in the liver whatever the injection dose; although most of the infection sites were seen at the establishment phase as inflammatory granulomas associated with fibrosis, they never matured into cysts. At the establishment phase, a strong immune response was composed of T and B cells, with T1-type, T2-type cells and cytokines and IL-10-secreting CD8+ T cells in the liver. At the established phase, results suggested a local production of antibodies by B cells, and an involvement of NK and NKT cells. Infection outcome and local immune response in the liver, were different in the mouse models of Echinococcus granulosus sensu stricto and Echinococcus multilocularis respectively; however, only early specificities at the microenvironment level might explain the major differences found between the lesions induced by the two species. Our quantitative experimental model appears fully appropriate to further study this microenvironment and its relationship with each cestode species.

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“…Complement evasion strategies have been reviewed for several different helminth parasites, and mainly involve the acquisition or expression of host-like complement regulators on their surface [6,[50][51][52]. Avoidance of complement attack by schistosome parasites, flatworms related to F. hepatica that also migrate through mammalian host tissues at early stages and feed on blood as adults, is thought to be intricately linked to their decades-long survival within the host.…”

Section: Discussionmentioning

confidence: 99%

“…It is not surprising, therefore, that attention has been focused on uncovering parasite-specific mechanisms and molecules involved in this complement escape. Helminth parasites of the genus Schistosoma and Echinococcus, and protozoans of the genus Trypanosoma and Leishmania have been shown to avoid complement attack or complement mediated responses mainly by (1) avoiding recognition by complement activators, e.g., antibodies and mannosebinding lectins, (2) varying or changing their surface components, and (3) expressing regulators of complement activation as secreted or membrane-associated products [1,4,[6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Fasciola hepatica is refractory to complement killing by preventing attachment of mannose binding lectin (MBL) and inhibiting MBL-associated serine proteases (MASPs) with serpins

et al. 2022

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The complement system is a first-line innate host immune defence against invading pathogens. It is activated via three pathways, termed Classical, Lectin and Alternative, which are mediated by antibodies, carbohydrate arrays or microbial liposaccharides, respectively. The three complement pathways converge in the formation of C3-convertase followed by the assembly of a lethal pore-like structure, the membrane attack complex (MAC), on the pathogen surface. We found that the infectious stage of the helminth parasite Fasciola hepatica, the newly excysted juvenile (NEJ), is resistant to the damaging effects of complement. Despite being coated with mannosylated proteins, the main initiator of the Lectin pathway, the mannose binding lectin (MBL), does not bind to the surface of live NEJ. In addition, we found that recombinantly expressed serine protease inhibitors secreted by NEJ (rFhSrp1 and rFhSrp2) selectively prevent activation of the complement via the Lectin pathway. Our experiments demonstrate that rFhSrp1 and rFhSrp2 inhibit native and recombinant MBL-associated serine proteases (MASPs), impairing the primary step that mediates C3b and C4b deposition on the NEJ surface. Indeed, immunofluorescence studies show that MBL, C3b, C4b or MAC are not deposited on the surface of NEJ incubated in normal human serum. Taken together, our findings uncover new means by which a helminth parasite prevents the activation of the Lectin complement pathway to become refractory to killing via this host response, in spite of presenting an assortment of glycans on their surface.

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Inefficient and abortive classical complement pathway activation by the calcium inositol hexakisphosphate component of the Echinococcus granulosus laminated layer

Cited by 11 publications

References 55 publications

Mucins shed from the laminated layer in cystic echinococcosis are captured by Kupffer cells via the lectin receptor Clec4F

Mucins shed from the laminated layer in cystic echinococcosis are captured by Kupffer cells via the lectin receptor Clec4F

The local immune response during Echinococcus granulosus growth in a quantitative hepatic experimental model

Fasciola hepatica is refractory to complement killing by preventing attachment of mannose binding lectin (MBL) and inhibiting MBL-associated serine proteases (MASPs) with serpins

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