Expression of the Microfilarial Sheath Protein 2 (shp2) of the Filarial ParasitesLitomosoides sigmodontisandBrugia malayi

Conraths, Franz J.; Hirzmann, Jörg; Hobom, Gerd; Zahner, Horst

doi:10.1006/expr.1996.4138

Cited by 5 publications

(4 citation statements)

References 17 publications

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“…Finally, as can be seen in the young microfilarial pretzel stage, the staining is limited to only the uterine lining ( Fig 1C ), and the signal is significantly less than earlier stages ( Fig 2 ). Interestingly, these changes mimic what was seen in a previous study examining the localization of the microfilarial sheath protein 2 [ 33 ]. Additionally, the effect of imatinib on developing microfilariae is similar to effects observed on the reproductive apparatus of Schistosoma mansoni [ 34 ], and in Echinococcus multilocularis [ 35 ].…”

Section: Discussionsupporting

confidence: 80%

Defining the target and the effect of imatinib on the filarial c-Abl homologue

et al. 2017

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BackgroundPreviously we demonstrated the micro- and macrofilaricidal properties of imatinib in vitro. Here we use electron and multiphoton microscopy to define the target of imatinib in the adult and microfilarial stages of Brugia malayi and assess the effects of pharmacologically relevant levels of imatinib on the adult parasites.MethodsAfter fixation of adult B. malayi males and females, sections were stained with polyclonal rabbit anti-c-Abl antibody (or isotype control) and imaged with multiphoton fluorescent microscopy. Microfilariae were fixed and labeled with rabbit anti-c-Abl IgG primary antibody followed by anti-rabbit gold conjugated secondary antibody and imaged using transmission electron microscopy (TEM; immunoEM). In addition, adult B. malayi males and females were exposed to 0 or 10μM of imatinib for 7 days following which they were prepared for transmission electron microscopy (TEM) to assess the drug’s effect on filarial ultrastructure.ResultsFluorescent localization of anti-c-Abl antibody demonstrated widespread uptake in the adult filariae, but the most intense signal was seen in the reproductive organs, muscle, and intestine of both male and female worms. Fluorescence was significantly more intense in the early microfilarial stage (i.e. early morula) compared with later development stages (i.e. pretzel). Anti-c-Abl antibody in the microfilariae localized to the nuclei. Based on TEM assessment following imatinib exposure, imatinib appeared to be detrimental to embryogenesis in the adult female B. malayi.ConclusionsAt pharmacologically achievable concentrations of imatinib, embryogenesis is impaired and possibly halted in adult filariae. Imatinib is likely a slow microfilaricide due to interference in intra-nuclear processes, which are slowly detrimental to the parasite and not immediately lethal, and thus may be used to lower the levels of L. loa microfilariae before they are treated within the context of conventional mass drug administration.

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Section: Discussionsupporting

confidence: 80%

Defining the target and the effect of imatinib on the filarial c-Abl homologue

et al. 2017

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“…Overall, it is noteworthy that filarial blood microfilariae appear to induce NETs independent of their ensheathment status. The microfilarial sheath is generally regarded as parasite-derived tool for improved immune evasion and was described to contain sheath-specific antigens ( 57 , 58 ). The fact that both, ensheathed [ B. malayi ( 50 )] and non-ensheathed ( D. immitis , this study) blood microfilariae significantly induce NET formation raises the question on surface-derived triggering molecules of these stages.…”

Section: Discussionmentioning

confidence: 99%

Dirofilaria immitis Microfilariae and Third-Stage Larvae Induce Canine NETosis Resulting in Different Types of Neutrophil Extracellular Traps

et al. 2018

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Heartworm disease is a zoonotic vector-borne disease caused by Dirofilaria immitis mainly affecting canids. Infectious third-stage larvae (L3) are transmitted to the definitive hosts via culicid mosquitoes; adult nematodes reside in the pulmonary arteries and in the right heart releasing unsheathed first-stage larvae (microfilariae) into the bloodstream leading to chronic and sometimes fatal disease. So far, early innate immune reactions triggered by these different D. immitis stages in the canine host have scarcely been investigated. Therefore, D. immitis microfilariae and L3 were analyzed for their capacity to induce neutrophil extracellular traps (NETs) in canine polymorphonuclear neutrophils (PMN). Overall, scanning electron microscopy analysis revealed both larval stages as strong inducers of canine NETosis. Co-localization of PMN-derived extracellular DNA with granulocytic histones, neutrophil elastase, or myeloperoxidase in parasite-entrapping structures confirmed the classical characteristics of NETosis. Quantitative analyses showed that both larval stages triggered canine NETs in a time-dependent but dose-independent manner. Moreover, parasite-induced NET formation was not influenced by the parasites viability since heat-inactivated microfilariae and L3 also induced NETs. In addition, parasite/PMN confrontation promoted significant entrapment but not killing of microfilariae and L3. Both, NETosis and larval entrapment was significantly reversed via DNase I treatments while treatments with the NADPH oxidase inhibitor diphenyleneiodonium failed to significantly influence these reactions. Interestingly, different types of NETs were induced by microfilariae and L3 since microfilarial stages merely induced spread and diffuse NETs while the larger L3 additionally triggered aggregated NET formation.

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“…Using L. sigmodontis as their model, four further SHP proteins have been defined (76). One of these additional products ( Bm ‐SHP‐2) has been fully characterized from B. malayi (77), and SHP‐3 homologues are present in the EST database. In general, the mRNAs for these products are expressed only in the female uterus.…”

Section: Microfilarial Surface and Secreted Antigensmentioning

confidence: 99%

Immunological genomics of Brugia malayi: filarial genes implicated in immune evasion and protective immunity

Maizels

Blaxter

Scott

2001

Parasite Immunology

100

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Filarial nematodes are metazoan parasites with genome sizes of> 100 million base pairs, probably encoding 15 000-20 000 genes. Within this considerable gene complement, it seems likely that filariae have evolved a spectrum of immune evasion products which underpin their ability to live for many years within the human host. Moreover, no suitable vaccine currently exists for human filarial diseases, and few markers have yet been established for diagnostic use. In this review, we bring together biochemical and immunological data on prominent filarial proteins with the exciting new information provided by the Filarial Genome Project's expressed sequence tag (EST) database. In this discussion, we focus on those genes with the highest immunological profile, such as inhibitors of host enzymes, cytokine homologues and stage-specific surface proteins, as well as products associated with the mosquito-borne infective larva which offer the best opportunity for an anti-filarial vaccine. These gene products provide a fascinating glimpse of the molecular repertoire which helminth parasites have evolved to manipulate and evade the mammalian immune response.

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Expression of the Microfilarial Sheath Protein 2 (shp2) of the Filarial ParasitesLitomosoides sigmodontisandBrugia malayi

Cited by 5 publications

References 17 publications

Defining the target and the effect of imatinib on the filarial c-Abl homologue

Defining the target and the effect of imatinib on the filarial c-Abl homologue

Dirofilaria immitis Microfilariae and Third-Stage Larvae Induce Canine NETosis Resulting in Different Types of Neutrophil Extracellular Traps

Immunological genomics of Brugia malayi: filarial genes implicated in immune evasion and protective immunity

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