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Co-Administration of Adjuvanted Recombinant Ov-103 and Ov-RAL-2 Vaccines Confer Protection against Natural Challenge in A Bovine Onchocerca ochengi Infection Model of Human Onchocerciasis

Luu, Lisa ; Bah, Germanus S. ; Okah-Nnane, Ndode Herman ; [et al.]

MDPI AG ; 2022

In: Vaccines Vol. 10, No. 6 ( 2022-05-27), p. 861-

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In: Vaccines, MDPI AG, Vol. 10, No. 6 ( 2022-05-27), p. 861-

Abstract: Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, is a neglected tropical disease mainly of sub-Saharan Africa. Worldwide, an estimated 20.9 million individuals live with infection and a further 205 million are at risk of disease. Current control methods rely on mass drug administration of ivermectin to kill microfilariae and inhibit female worm fecundity. The identification and development of efficacious vaccines as complementary preventive tools to support ongoing elimination efforts are therefore an important objective of onchocerciasis research. We evaluated the protective effects of co-administering leading O. volvulus-derived recombinant vaccine candidates (Ov-103 and Ov-RAL-2) with subsequent natural exposure to the closely related cattle parasite Onchocerca ochengi. Over a 24-month exposure period, vaccinated calves (n = 11) were shown to acquire infection and microfilaridermia at a significantly lower rate compared to unvaccinated control animals (n = 10). Furthermore, adult female worm burdens were negatively correlated with anti-Ov-103 and Ov-RAL-2 IgG1 and IgG2 responses. Peptide arrays identified several Ov-103 and Ov-RAL-2-specific epitopes homologous to those identified as human B-cell and helper T-cell epitope candidates and by naturally-infected human subjects in previous studies. Overall, this study demonstrates co-administration of Ov-103 and Ov-RAL-2 with Montanide™ ISA 206 VG is highly immunogenic in cattle, conferring partial protection against natural challenge with O. ochengi. The strong, antigen-specific IgG1 and IgG2 responses associated with vaccine-induced protection are highly suggestive of a mixed Th1/Th2 associated antibody responses. Collectively, this evidence suggests vaccine formulations for human onchocerciasis should aim to elicit similarly balanced Th1/Th2 immune responses.

Type of Medium: Online Resource

ISSN: 2076-393X

URL: Article

DOI: 10.3390/vaccines10060861

Language: English

Publisher: MDPI AG

Publication Date: 2022

detail.hit.zdb_id: 2703319-3

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A worm's best friend: recruitment of neutrophils by Wolbachia confounds eosinophil degranulation against the filarial nematode Onchocerca ochengi

Hansen, Rowena D. E. ; Trees, Alexander J. ; Bah, Germanus S. ; [et al.]

The Royal Society ; 2011

In: Proceedings of the Royal Society B: Biological Sciences Vol. 278, No. 1716 ( 2011-08-07), p. 2293-2302

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In: Proceedings of the Royal Society B: Biological Sciences, The Royal Society, Vol. 278, No. 1716 ( 2011-08-07), p. 2293-2302

Abstract: Onchocerca ochengi , a filarial parasite of cattle, represents the closest relative of the human pathogen, Onchocerca volvulus . Both species harbour Wolbachia endosymbionts and are remarkable in that adult female worms remain viable but sessile for many years while surrounded by host cells and antibodies. The basis of the symbiosis between filariae and Wolbachia is thought to be metabolic, although a role for Wolbachia in immune evasion has received little attention. Neutrophils are attracted to Wolbachia , but following antibiotic chemotherapy they are replaced by eosinophils that degranulate on the worm cuticle. However, it is unclear whether the eosinophils are involved in parasite killing or if they are attracted secondarily to dying worms. In this study, cattle infected with Onchocerca ochengi received adulticidal regimens of oxytetracycline or melarsomine. In contrast to oxytetracycline, melarsomine did not directly affect Wolbachia viability. Eosinophil degranulation increased significantly only in the oxytetracycline group; whereas nodular gene expression of bovine neutrophilic chemokines was lowest in this group. Moreover, intense eosinophil degranulation was initially associated with worm vitality, not degeneration. Taken together, these data offer strong support for the hypothesis that Wolbachia confers longevity on O. ochengi through a defensive mutualism, which diverts a potentially lethal effector cell response.

Type of Medium: Online Resource

ISSN: 0962-8452 , 1471-2954

URL: Article

DOI: 10.1098/rspb.2010.2367

Language: English

Publisher: The Royal Society

Publication Date: 2011

detail.hit.zdb_id: 1460975-7

SSG: 12

SSG: 25

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Immunotherapy with mutated onchocystatin fails to enhance the efficacy of a sub-lethal oxytetracycline regimen against Onchocerca ochengi

Bah, Germanus S. ; Tanya, Vincent N. ; Makepeace, Benjamin L.

Elsevier BV ; 2015

In: Veterinary Parasitology Vol. 212, No. 1-2 ( 2015-08), p. 25-34

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In: Veterinary Parasitology, Elsevier BV, Vol. 212, No. 1-2 ( 2015-08), p. 25-34

Type of Medium: Online Resource

ISSN: 0304-4017

URL: Article

DOI: 10.1016/j.vetpar.2015.06.005

Language: English

Publisher: Elsevier BV

Publication Date: 2015

detail.hit.zdb_id: 1498947-5

SSG: 12

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Emodepside targets SLO-1 channels of Onchocerca ochengi and induces broad anthelmintic effects in a bovine model of onchocerciasis

Bah, Germanus S. ; Schneckener, Sebastian ; Hahnel, Steffen R. ; [et al.]

Public Library of Science (PLoS) ; 2021

In: PLOS Pathogens Vol. 17, No. 6 ( 2021-6-2), p. e1009601-

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In: PLOS Pathogens, Public Library of Science (PLoS), Vol. 17, No. 6 ( 2021-6-2), p. e1009601-

Abstract: Onchocerciasis (river blindness), caused by the filarial worm Onchocerca volvulus , is a neglected tropical disease mostly affecting sub-Saharan Africa and is responsible for 〉 1.3 million years lived with disability. Current control relies almost entirely on ivermectin, which suppresses symptoms caused by the first-stage larvae (microfilariae) but does not kill the long-lived adults. Here, we evaluated emodepside, a semi-synthetic cyclooctadepsipeptide registered for deworming applications in companion animals, for activity against adult filariae ( i . e ., as a macrofilaricide). We demonstrate the equivalence of emodepside activity on SLO-1 potassium channels in Onchocerca volvulus and Onchocerca ochengi , its sister species from cattle. Evaluation of emodepside in cattle as single or 7-day treatments at two doses (0.15 and 0.75 mg/kg) revealed rapid activity against microfilariae, prolonged suppression of female worm fecundity, and macrofilaricidal effects by 18 months post treatment. The drug was well tolerated, causing only transiently increased blood glucose. Female adult worms were mostly paralyzed; however, some retained metabolic activity even in the multiple high-dose group. These data support ongoing clinical development of emodepside to treat river blindness.

Type of Medium: Online Resource

ISSN: 1553-7374

URL: Article

DOI: 10.1371/journal.ppat.1009601

DOI: 10.1371/journal.ppat.1009601.g001

DOI: 10.1371/journal.ppat.1009601.g002

DOI: 10.1371/journal.ppat.1009601.g003

DOI: 10.1371/journal.ppat.1009601.g004

DOI: 10.1371/journal.ppat.1009601.g005

DOI: 10.1371/journal.ppat.1009601.g006

DOI: 10.1371/journal.ppat.1009601.g007

DOI: 10.1371/journal.ppat.1009601.g008

DOI: 10.1371/journal.ppat.1009601.t001

DOI: 10.1371/journal.ppat.1009601.t002

DOI: 10.1371/journal.ppat.1009601.s001

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2021

detail.hit.zdb_id: 2205412-1

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Extracellular Onchocerca-derived small RNAs in host nodules and blood

Quintana, Juan F ; Makepeace, Benjamin L ; Babayan, Simon A ; [et al.]

Springer Science and Business Media LLC ; 2015

In: Parasites & Vectors Vol. 8, No. 1 ( 2015-12)

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In: Parasites & Vectors, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2015-12)

Type of Medium: Online Resource

ISSN: 1756-3305

URL: Article

DOI: 10.1186/s13071-015-0656-1

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2015

detail.hit.zdb_id: 2409480-8

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Efficacy of Three-Week Oxytetracycline or Rifampin Monotherapy Compared with a Combination Regimen against the Filarial Nematode Onchocerca ochengi

Bah, Germanus S. ; Ward, Emma L. ; Srivastava, Abhishek ; [et al.]

American Society for Microbiology ; 2014

In: Antimicrobial Agents and Chemotherapy Vol. 58, No. 2 ( 2014-02), p. 801-810

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In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 58, No. 2 ( 2014-02), p. 801-810

Abstract: Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus , is a major cause of visual impairment and dermatitis in sub-Saharan Africa. As O. volvulus contains an obligatory bacterial symbiont ( Wolbachia ), it is susceptible to antibiotic chemotherapy, although current regimens are considered too prolonged for community-level control programs. The aim of this study was to compare the efficacies of oxytetracycline and rifampin, administered separately or in combination, against a close relative of O. volvulus ( Onchocerca ochengi ) in cattle. Six animals per group were treated with continuous or intermittent oxytetracycline regimens, and effects on adult worm viability, dermal microfilarial loads, and Wolbachia density in worm tissues were assessed. Subsequently, the efficacies of 3-week regimens of oxytetracycline and rifampin alone and a combination regimen were compared, and rifampin levels in plasma and skin were quantified. A 6-month regimen of oxytetracycline with monthly dosing was strongly adulticidal, while 3-week and 6-week regimens exhibited weaker adulticidal effects. However, all three regimens achieved 〉 2-log reductions in microfilarial load. In contrast, rifampin monotherapy and oxytetracycline-rifampin duotherapy failed to induce substantive reductions in either adult worm burden or microfilarial load, although a borderline effect on Wolbachia density was observed following duotherapy. Dermal rifampin levels were maintained above the MIC for 〉 24 h after a single intravenous dose. We conclude that oxytetracycline-rifampin duotherapy is less efficacious against O. ochengi than oxytetracycline alone. Further studies will be required to determine whether rifampin reduces oxytetracycline bioavailability in this system, as suggested by human studies using other tetracycline-rifampin combinations.

Type of Medium: Online Resource

ISSN: 0066-4804 , 1098-6596

URL: Article

DOI: 10.1128/AAC.01995-13

RVK:

XA 24552

Language: English

Publisher: American Society for Microbiology

Publication Date: 2014

detail.hit.zdb_id: 1496156-8

SSG: 12

SSG: 15,3

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Analysis of gene expression from the Wolbachia genome of a filarial nematode supports both metabolic and defensive roles within the symbiosis

Darby, Alistair C. ; Armstrong, Stuart D. ; Bah, Germanus S. ; [et al.]

Cold Spring Harbor Laboratory ; 2012

In: Genome Research Vol. 22, No. 12 ( 2012-12), p. 2467-2477

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In: Genome Research, Cold Spring Harbor Laboratory, Vol. 22, No. 12 ( 2012-12), p. 2467-2477

Abstract: The α-proteobacterium Wolbachia is probably the most prevalent, vertically transmitted symbiont on Earth. In contrast with its wide distribution in arthropods, Wolbachia is restricted to one family of animal-parasitic nematodes, the Onchocercidae. This includes filarial pathogens such as Onchocerca volvulus , the cause of human onchocerciasis, or river blindness. The symbiosis between filariae and Wolbachia is obligate, although the basis of this dependency is not fully understood. Previous studies suggested that Wolbachia may provision metabolites (e.g., haem, riboflavin, and nucleotides) and/or contribute to immune defense. Importantly, Wolbachia is restricted to somatic tissues in adult male worms, whereas females also harbor bacteria in the germline. We sought to characterize the nature of the symbiosis between Wolbachia and O. ochengi , a bovine parasite representing the closest relative of O. volvulus . First, we sequenced the complete genome of Wolbachia strain w Oo, which revealed an inability to synthesize riboflavin de novo. Using RNA-seq, we also generated endobacterial transcriptomes from male soma and female germline. In the soma, transcripts for membrane transport and respiration were up-regulated, while the gonad exhibited enrichment for DNA replication and translation. The most abundant Wolbachia proteins, as determined by geLC-MS, included ligands for mammalian Toll-like receptors. Enzymes involved in nucleotide synthesis were dominant among metabolism-related proteins, whereas the haem biosynthetic pathway was poorly represented. We conclude that Wolbachia may have a mitochondrion-like function in the soma, generating ATP for its host. Moreover, the abundance of immunogenic proteins in w Oo suggests a role in diverting the immune system toward an ineffective antibacterial response.

Type of Medium: Online Resource

ISSN: 1088-9051

URL: Article

DOI: 10.1101/gr.138420.112

RVK:

XA 10000

Language: English

Publisher: Cold Spring Harbor Laboratory

Publication Date: 2012

detail.hit.zdb_id: 1483456-X

SSG: 12

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Stage-specific Proteomes from Onchocerca ochengi, Sister Species of the Human River Blindness Parasite, Uncover Adaptations to a Nodular Lifestyle

Armstrong, Stuart D. ; Xia, Dong ; Bah, Germanus S. ; [et al.]

Elsevier BV ; 2016

In: Molecular & Cellular Proteomics Vol. 15, No. 8 ( 2016-08), p. 2554-2575

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In: Molecular & Cellular Proteomics, Elsevier BV, Vol. 15, No. 8 ( 2016-08), p. 2554-2575

Type of Medium: Online Resource

ISSN: 1535-9476

URL: Article

DOI: 10.1074/mcp.M115.055640

Language: English

Publisher: Elsevier BV

Publication Date: 2016

detail.hit.zdb_id: 2071375-7

SSG: 12

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