Complement activation by eggs and microfilariae of filarial parasites

Rao, U. R.; Chandrashekar, Ramaswamy; Subrahmanyam, D.

doi:10.1038/icb.1987.41

Cited by 3 publications

(3 citation statements)

References 13 publications

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“…C4 is rate-limiting, and not only does depletion reduce classical pathway activation, but addition of C4 has been shown to increase it ( 36 ). This may have relevance in evasion of the immune response by filarial nematodes because it is known that these organisms are capable of activating the complement system ( 44 ), and hence they may have evolved strategies to try and minimize this. It has been observed, for example, that microfilaria larva stages of the human parasite Loa loa acquire regulatory proteins from the host to evade complement attack ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

The Carbohydrate-linked Phosphorylcholine of the Parasitic Nematode Product ES-62 Modulates Complement Activation

Ahmed

Maller

Iqbal

et al. 2016

Journal of Biological Chemistry

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Parasitic nematodes manufacture various carbohydrate-linked phosphorylcholine (PCh)-containing molecules, including ES-62, a protein with an N-linked glycan terminally substituted with PCh. The PCh component is biologically important because it is required for immunomodulatory effects. We showed that most ES-62 was bound to a single protein, C-reactive protein (CRP), in normal human serum, displaying a calcium-dependent, high-avidity interaction and ability to form large complexes. Unexpectedly, CRP binding to ES-62 failed to efficiently activate complement as far as the C3 convertase stage in comparison with PCh-BSA and PCh-containing Streptococcus pneumoniae cell wall polysaccharide. C1q capture assays demonstrated an ES-62-CRP-C1q interaction in serum. The three ligands all activated C1 and generated C4b to similar extents. However, a C2a active site was not generated following ES-62 binding to CRP, demonstrating that C2 cleavage was far less efficient for ES-62-containing complexes. We proposed that failure of C2 cleavage was due to the flexible nature of carbohydrate-bound PCh and that reduced proximity of the C1 complex was the reason that C2 was poorly cleaved. This was confirmed using synthetic analogues that were similar to ES-62 only in respect of having a flexible PCh. Furthermore, ES-62 was shown to deplete early complement components, such as the rate-limiting C4, following CRP interaction and thereby inhibit classical pathway activation. Thus, flexible PCh-glycan represents a novel mechanism for subversion of complement activation. These data illustrate the importance of the rate-limiting C4/C2 stage of complement activation and reveal a new addition to the repertoire of ES-62 immunomodulatory mechanisms with possible therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

The Carbohydrate-linked Phosphorylcholine of the Parasitic Nematode Product ES-62 Modulates Complement Activation

Ahmed

Maller

Iqbal

et al. 2016

Journal of Biological Chemistry

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“…Nevertheless, the complement system is likely to be involved in the human defense against mf because the addition of fresh nonimmune human serum as a source of complement to immune serum increases eosinophil-mediated killing of O. volvulus mf in vitro [5]. Complement, together with specific antibodies, is required for opsonization and phagocytosis of other pathogenic mf species (e.g., Brugia malayi and Dipetalonema vitaea ) [6][7][8]. Studies of the pathogenic O. volvulus nematode and its mf have been hampered because the parasite cannot be cultivated in vitro.…”

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confidence: 99%

Onchocerca volvulusMicrofilariae Avoid Complement Attack by Direct Binding of Factor H

et al. 2002

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The filarial parasite Onchocerca volvulus is the causative agent of river blindness. The adult worms produce microfilariae (mf), which are responsible for the disease pathogenesis; mf activate the complement system, but the activation stops before the formation of terminal complement complexes. Because of the arrest of complement activation, this study analyzed binding of the main alternative pathway regulator, factor H (fH), to the mf. The mf bound fH after incubation in nonimmune human serum or with purified radiolabeled fH. In the presence of factor I, mf-bound fH promoted the cleavage of complement 3 molecule b (C3b) to iC3b. An analysis with recombinant constructs of fH showed that the C-terminal short consensus repeats (SCRs) 8-20 of fH bound to mf, whereas the N-terminal SCRs 1-7 containing the complement-regulatory domains in SCRs 1-5 did not. Thus, mf of the nematode O. volvulus may evade human complement by binding fH and by promoting inactivation of C3b into iC3b.

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“…Significant use of complement through the alternative pathway has also been observed with intrauterine eggs of many filarial species, and with microfilaria of Brugia pahangi , B. malayi , and Litomosoides carinii . 15 In addition, microfilaria can bind and inactivate complement and inhibit complementmediated granulocyte chemotaxis. 16 Despite these previous studies, there is a paucity of information on the interaction of CIC with the complement system.…”

Section: Introductionmentioning

confidence: 99%

Heightened Measures of Immune Complex and Complement Function and Immune Complex–Mediated Granulocyte Activation in Human Lymphatic Filariasis

Senbagavalli

Ray²,

Ramanathan³

et al. 2011

The American Society of Tropical Medicine and Hygiene

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The presence of circulating immune complexes (CICs) is a characteristic feature of human lymphatic filariasis. However, the role of CICs in modulating granulocyte function and complement functional activity in filarial infection is unknown. The levels of CICs in association with complement activation in clinically asymptomatic, filarial-infected patients (INF); filarial-infected patients with overt lymphatic pathologic changes (CPDT); and uninfected controls (EN) were examined. Significantly increased levels of CICs and enhanced functional efficiency of the classical and mannose-binding lectin pathways of the complement system was observed in INF compared with CPDT and EN. Polyethylene glycol–precipitated CICs from INF and CPDT induced significantly increased granulocyte activation compared with those from EN, determined by the increased production of neutrophil granular proteins and a variety of pro-inflammatory cytokines. Thus, CIC-mediated enhanced granulocyte activation and modulation of complement function are important features of filarial infection and disease.

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Complement activation by eggs and microfilariae of filarial parasites

Cited by 3 publications

References 13 publications

The Carbohydrate-linked Phosphorylcholine of the Parasitic Nematode Product ES-62 Modulates Complement Activation

The Carbohydrate-linked Phosphorylcholine of the Parasitic Nematode Product ES-62 Modulates Complement Activation

Onchocerca volvulusMicrofilariae Avoid Complement Attack by Direct Binding of Factor H

Heightened Measures of Immune Complex and Complement Function and Immune Complex–Mediated Granulocyte Activation in Human Lymphatic Filariasis

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