The secretome of the filarial parasite, Brugia malayi: Proteomic profile of adult excretory–secretory products

Hewitson, James P.; Harcus, Yvonne; Curwen, Rachel S.; Dowle, Adam; Kurniawan, Agnes; Ashton, Peter D.; Wilson, A. J.; Maizels, Rick M.

doi:10.1016/j.molbiopara.2008.02.007

Cited by 234 publications

(245 citation statements)

References 81 publications

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“…The spectra were searched against the genomic databases for Bm and its endosymbiont Wolbachia (wBm). A total of 72,318 unique peptides were matched to 6,981 proteins (3,653,3,688,3,135,2,672, and 4,843 proteins) from AM, AF, MF, L3 larvae, and UTMF, respectively (SI Appendix, Table S1). Combining these data with those from a study performed previously on the Bm secretome (1) (that included 122 proteins not found in the current analyses) and 164 additional proteins (based on peptide matches that identified more than one protein; SI Appendix, Table S2) resulted in the definitive identification of a total of 7,103 proteins of the 11,610 proteins (∼61%) predicted from the genome (4) [ Fig.…”

Section: Resultsmentioning

confidence: 99%

Stage-specific proteomic expression patterns of the human filarial parasiteBrugia malayiand its endosymbiontWolbachia

Bennuru

Meng

Ribeiro

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

121

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Global proteomic analyses of pathogens have thus far been limited to unicellular organisms (e.g., protozoa and bacteria). Proteomic analyses of most eukaryotic pathogens (e.g., helminths) have been restricted to specific organs, specific stages, or secretomes. We report here a large-scale proteomic characterization of almost all the major mammalian stages of Brugia malayi, a causative agent of lymphatic filariasis, resulting in the identification of more than 62% of the products predicted from the Bm draft genome. The analysis also yielded much of the proteome of Wolbachia, the obligate endosymbiont of Bm that also expressed proteins in a stage-specific manner. Of the 11,610 predicted Bm gene products, 7,103 were definitively identified from adult male, adult female, blood-borne and uterine microfilariae, and infective L3 larvae. Among the 4,956 gene products (42.5%) inferred from the genome as "hypothetical," the present study was able to confirm 2,336 (47.1%) as bona fide proteins. Analysis of protein families and domains coupled with stage-specific expression highlight the important pathways that benefit the parasite during its development in the host. Gene set enrichment analysis identified extracellular matrix proteins and those with immunologic effects as enriched in the microfilarial and L3 stages. Parasite sex-and stage-specific protein expression identified those pathways related to parasite differentiation and demonstrates stage-specific expression by the Bm endosymbiont Wolbachia as well.filaria | nematode D isease associated with infection by Brugia malayi (Bm) and Wuchereria bancrofti, the two major causative organisms of human lymphatic filariasis, is the second leading cause of morbidity/disability worldwide, in large part because of the parasites' ability to alter the structural and functional integrity of the lymphatics, leading to lymphedema and elephantiasis. Invasion, establishment of infection within the host and development are essential processes within the complex parasite life cycle (SI Appendix, Fig. S1), with many of the parasitic stages being targets for therapeutic intervention or vaccines. Each of the filarial life cycle stages has characteristics that are shared and others that are stage-specific.Filarial infections are often characterized by a series of discrete host responses directed at the parasite and its endosymbiont Wolbachia that evolve during the course of infection. Because proteins are usually the effectors of most biological functions, proteomic data enable a more direct understanding of these important processes compared with those inferred from genomic studies. Absolute quantification of genome-wide expressed proteins is not yet within our reach for most eukaryotes. However, spectral counts of massive MS-based data (e.g., observed frequencies of each peptide) allow for relative quantification. Proteomic data also allow for clearer genomic curation by improving annotation and the identification of translational sites, stop codon read-throughs, frame shifts, and predict...

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Section: Resultsmentioning

confidence: 99%

Stage-specific proteomic expression patterns of the human filarial parasiteBrugia malayiand its endosymbiontWolbachia

Bennuru

Meng

Ribeiro

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

121

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“…Overcoming this limitation using highly sensitive approaches has lead to the identification of most of these proteins in B. malayi (31)(32)(33). However, information about the anatomy and physiology of the protein secretory pathways in filarial nematodes has not been intensively investigated.…”

Section: Discussionmentioning

confidence: 99%

Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi

Moreno

Nabhan

Solomon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

145

139

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Ivermectin (IVM) is a broad-spectrum anthelmintic used in filariasis control programs. By binding to nematode glutamate-gated chloride channels (GluCls), IVM disrupts neurotransmission processes regulated by GluCl activity. IVM treatment of filarial infections is characterized by an initial dramatic drop in the levels of circulating microfilariae, followed by long-term suppression of their production, but the drug has little direct effect on microfilariae in culture at pharmacologically relevant concentrations. We localized Brugia malayi GluCl expression solely in a muscle structure that surrounds the microfilarial excretory-secretory (ES) vesicle, which suggests that protein release from the ES vesicle is regulated by GluCl activity. Consistent with this hypothesis, exposure to IVM in vitro decreased the amount of protein released from microfilariae. To better understand the scope of IVM effects on protein release by the parasite, three different expression patterns were identified from immunolocalization assays on a representative group of five microfilarial ES products. Patterns of expression suggest that the ES apparatus is the main source of regulated ES product release from microfilariae, as it is the only compartment that appears to be under neuromuscular control. Our results show that IVM treatment of microfilariae results in a marked reduction of protein release from the ES apparatus. Under in vivo conditions, the rapid microfilarial clearance induced by IVM treatment is proposed to result from suppression of the ability of the parasite to secrete proteins that enable evasion of the host immune system. filarial nematode | macrocyclic lactone | glutamate-gated chloride channels

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“…In addition, classical excretorysecretory (ES) proteins of S. haematobium were predicted (on the basis of the presence of a signal peptide at the N terminus) using SignalP v.3.0 (ref. 40; using both the neural network and hidden Markov models) and the absence of a transmembrane domain using TMHMM 41 , and by BLASTp 42 homology-searching of the validated signal peptide database (SPD) 43 and an ES database containing published proteomic data for nematodes (Brugia malayi and Meloidogyne incognita) and trematodes (S. mansoni, S. japonicum, O. viverrini and F. hepatica) 13,14,[44][45][46][47][48][49][50] . The secondary structure of genes specific to S. haematobium were predicted using PSIPRED 51 .…”

Section: Methodsmentioning

confidence: 99%

Whole-genome sequence of Schistosoma haematobium

et al. 2012

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Schistosomiasis is a neglected tropical disease caused by blood flukes (genus Schistosoma; schistosomes) and affecting 200 million people worldwide 1 . No vaccines are available, and treatment relies on one drug, praziquantel 2 . Schistosoma haematobium has come into the spotlight as a major cause of urogenital disease, as an agent linked to bladder cancer 1,3 and as a predisposing factor for HIV/AIDS 4,5 . The parasite is transmitted to humans from freshwater snails 1 . Worms dwell in blood vessels and release eggs that become embedded in the bladder wall to elicit chronic immune-mediated disease 6 and induce squamous cell carcinoma 7 . Here we sequenced the 385-Mb genome of S. haematobium using Illumina-based technology at 74-fold coverage and compared it to sequences from related parasites 8,9 . We included genome annotation based on function, gene ontology, networking and pathway mapping. This genome now provides an unprecedented resource for many fundamental research areas and shows great promise for the design of new disease interventions.

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The secretome of the filarial parasite, Brugia malayi: Proteomic profile of adult excretory–secretory products

Cited by 234 publications

References 81 publications

Stage-specific proteomic expression patterns of the human filarial parasiteBrugia malayiand its endosymbiontWolbachia

Stage-specific proteomic expression patterns of the human filarial parasiteBrugia malayiand its endosymbiontWolbachia

Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi

Whole-genome sequence of Schistosoma haematobium

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