Stage- and Gender-Specific Proteomic Analysis of Brugia malayi Excretory-Secretory Products

Moreno, Yovany; Geary, Timothy G.

doi:10.1371/journal.pntd.0000326

Cited by 138 publications

(171 citation statements)

References 75 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.

123

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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.

123

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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%

“…The proteins released in vitro by Bma-mf differ from those released by adults and are associated with modulation and evasion of the host immune system, among other potential functions (32,33). As it is accepted that parasite protein secretion plays a fundamental role in host immunomodulation (18), it is reasonable to infer that inhibition of protein secretion would result in the inability of the parasite to neutralize preexisting and induced host effectors at the local and systemic levels.…”

Section: Discussionmentioning

confidence: 99%

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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.

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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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“…These data suggest that understanding fully the nature of the excretory/secretory proteins [49][50][51] of the parasite may provide additional insights into those parasiteand Wolbachia -derived molecules that mediate the lymphatic dysfunction seen in LF.…”

Section: Discussionmentioning

confidence: 93%

Elevated Levels of Plasma Angiogenic Factors Are Associated with Human Lymphatic Filarial Infections

Bennuru¹,

Maldarelli²,

Kumaraswami³

et al. 2010

The American Society of Tropical Medicine and Hygiene

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Lymphatic dilatation, dysfunction, and lymphangiogenesis are hallmarks of patent lymphatic filariasis, observed even in those with subclinical microfilaremia, through processes associated, in part, by vascular endothelial growth factors (VEGFs). A panel of pro-angiogenic factors was measured in the plasma of subjects from filaria-endemic regions using multiplexed immunological assays. Compared with endemic normal control subjects, those with both subclinical microfilaremia, and those with longstanding lymphedema had significantly elevated levels of VEGF-A, VEGF-C, VEGF-D, and angiopoeitins (Ang-1/Ang-2), with only levels of basic fibroblast growth factor (bFGF) and placental growth factor (PlGF) being elevated only if lymphedema was evident. Furthermore, levels of these factors 1-year post-treatment with doxycycline were similar to pretreatment levels suggesting a minimal role, if any, for Wolbachia. Our data support the concept that filarial infection per se is associated with elevated levels of most of the known pro-angiogenic factors, with only a few being associated with the serious pathologic consequences associated with Wuchereria bancrofti infection.

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Stage- and Gender-Specific Proteomic Analysis of Brugia malayi Excretory-Secretory Products

Cited by 138 publications

References 75 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

Elevated Levels of Plasma Angiogenic Factors Are Associated with Human Lymphatic Filarial Infections

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