Prolyl 4-Hydroxlase Activity Is Essential for Development and Cuticle Formation in the Human Infective Parasitic Nematode Brugia malayi

Winter, Alan D.; McCormack, Gillian; Myllyharju, Johanna; Page, Antony P.

doi:10.1074/jbc.m112.397604

Cited by 21 publications

(20 citation statements)

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“…Additional research will be needed to characterize the particular molecular mechanisms at play, and the assay we describe can be interfaced with reverse genetic approaches to provide a genetic and mechanistic basis for the observed responses. To this end, we have developed a robust and reliable in vivo RNAi protocol to suppress genes of interest in the B. malayi L3 stage (Song et al ., 2010), whilst others have shown that RNAi can be applied to other life stages of the parasite in vitro (Aboobaker and Blaxter, 2003; Ford et al ., 2009; Landmann et al ., 2012; Singh et al ., 2012; Winter et al ., 2013; Luck et al ., 2016; Misra et al ., 2017; Verma et al ., 2017). This receptiveness to RNAi, combined now with assays to interrogate sensory phenotypes, advances B. malayi as a tractable system to better understand sensory biology in filarial worm parasites.…”

Section: Discussionmentioning

confidence: 99%

Chemosensory structure and function in the filarial nematode, Brugia malayi

Srinivasan

et al. 2018

Preprint

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Nematode chemosensory behaviors underlie fundamental processes and activities in development, reproduction, tropisms and taxes. For parasitic species, chemosensation is essential for host seeking and host and tissue invasion behaviors. Such fundamental biology presents an attractive target for developing behavior-blocking anthelminthic drugs, but the anatomy and functional relevance of parasitic nematode chemosensory machinery are poorly understood. The goals of this study were to better understand the chemosensory apparatus and behaviors of infectious stage Brugia malayi (Spirurida: Onchocercidae), a mosquito-borne nematode and etiological agent of Lymphatic Filariasis. Scanning electron microscopy revealed that amphids, the major chemosensory organs, are present on adult B. malayi and arranged in a conserved manner. Internal sensory neuroanatomy display structural differences between life stages, and a simpler chemosensory architecture as compared to free-living nematodes. Positive and negative chemotactic behaviors were identified for a repertoire of chemicals with known chemostimulatory activity for the mosquito host that may facilitate host-selectivity and invasion. This is the first description of chemosensory anatomy and chemotactic behaviors in B. malayi that reveal the involvement of chemosensation in parasite transmission and host invasion.Key findings•Amphidial arrangement in B. malayi is less complex than free-living nematodes.•Chemosensory neuroanatomy is stage-specific and simpler than free-living nematodes.•B. malayi responses to stimuli can be measured using a plate-based assay.•Chemostimulants associated with mosquito host-seeking induce negative and positive tropisms for L3 stage B. malayi.

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Section: Discussionmentioning

confidence: 99%

Chemosensory structure and function in the filarial nematode, Brugia malayi

Srinivasan

et al. 2018

Preprint

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“…3′UTRs from Bm1_27305, Bm1_05425 and Bm1_25620 were amplified from B. pahangi genomic DNA (isolated as described previously [ 50 ]) using PfuUltra II Fusion HS DNA Polymerase (Agilent) (primers in Additional file 10 ). Products were cloned into pCR2.1-TOPO (Invitrogen) then subcloned into the Not I site downstream of firefly luciferase in pMir-Target (Origene) to generate plasmids pABR212 (Bm1_27305 3′UTR in pMir-Target), pABR210 (Bm1_05425 3′UTR in pMir-Target) and pABR211 (Bm1_25620 3′UTR in pMir-Target).…”

Section: Methodsmentioning

confidence: 99%

“…A ~1.7 kb Pst I/ Pst I fragment of this was cloned into pPD129.36 (Addgene) to create plasmid pADW0062 which was linearised with Not I and Hind III. In vitro transcription and preparation of endoribonuclease-prepared pools of complex siRNA (esiRNA) was carried out as described previously [ 50 ]. Larvae were harvested at either 4 or 5 days p.i.…”

Section: Methodsmentioning

confidence: 99%

A novel member of the let-7 microRNA family is associated with developmental transitions in filarial nematode parasites

et al. 2015

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BackgroundFilarial nematodes are important pathogens in the tropics transmitted to humans via the bite of blood sucking arthropod vectors. The molecular mechanisms underpinning survival and differentiation of these parasites following transmission are poorly understood. microRNAs are small non-coding RNA molecules that regulate target mRNAs and we set out to investigate whether they play a role in the infection event.ResultsmicroRNAs differentially expressed during the early post-infective stages of Brugia pahangi L3 were identified by microarray analysis. One of these, bpa-miR-5364, was selected for further study as it is upregulated ~12-fold at 24 hours post-infection, is specific to clade III nematodes, and is a novel member of the let-7 family, which are known to have key developmental functions in the free-living nematode Caenorhabditis elegans. Predicted mRNA targets of bpa-miR-5364 were identified using bioinformatics and comparative genomics approaches that relied on the conservation of miR-5364 binding sites in the orthologous mRNAs of other filarial nematodes. Finally, we confirmed the interaction between bpa-miR-5364 and three of its predicted targets using a dual luciferase assay.ConclusionsThese data provide new insight into the molecular mechanisms underpinning the transmission of third stage larvae of filarial nematodes from vector to mammal. This study is the first to identify parasitic nematode mRNAs that are verified targets of specific microRNAs and demonstrates that post-transcriptional control of gene expression via stage-specific expression of microRNAs may be important in the success of filarial infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1536-y) contains supplementary material, which is available to authorized users.

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“…elegans mutants with the orthologous gene from Brugia spp., even when the degree of conservation is significantly less than that of the respective Hsp90s [45]. While failure to rescue the mutant phenotype may reflect differences in the nature of the client proteins chaperoned by Hsp90 in Brugia and C.…”

Section: Hsp90 Differs In Free-living and Parasitic Nematodesmentioning

confidence: 99%

Hsp90 Inhibitors in Parasitic Nematodes: Prospects and Challenges

Devaney

Gillan²

2016

CTMC

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Hsp90 inhibitors are well characterized in relation to their effects in a variety of tumors, with several inhibitors in various phases of clinical development. In recent years, the same inhibitor classes have been tested for efficacy in other systems, such as Alzheimer's disease and a variety of infectious disease models, including fungal and parasitic targets. In this article we discuss the repurposing of Hsp90 inhibitors for parasitic disease with a focus on parasitic nematode infections. We summarize the data that indicates that Hsp90 is functionally diverse in different nematode species and we discuss the challenges and prospects for developing these inhibitors as next generation chemotherapeutic tools.

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Prolyl 4-Hydroxlase Activity Is Essential for Development and Cuticle Formation in the Human Infective Parasitic Nematode Brugia malayi

Cited by 21 publications

References 35 publications

Chemosensory structure and function in the filarial nematode, Brugia malayi

Chemosensory structure and function in the filarial nematode, Brugia malayi

A novel member of the let-7 microRNA family is associated with developmental transitions in filarial nematode parasites

Hsp90 Inhibitors in Parasitic Nematodes: Prospects and Challenges

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