One Wolbachia to rule them all? Testing divergence in the symbiotic biology of clade C and clade D Wolbachia during filarial parasite development

The symbiont, Wolbachia, is a validated drug target in filariasis, although genetic divergences between nematode Wolbachia clades within their filarial hosts may influence aspects of the symbiosis and drug response. The student will therefore investigate comparative biology of a clade D Wolbachia within the veterinary and human zoonotic filarial parasite, Dirofilaria immitis (heartworm) compared with a clade C Wolbachia within the human lymphatic filarial parasite, Brugia malayi. 

Wolbachia growth dynamics will be determined by QPCR and imaging analyses at check-points of filarial larval development, utilising novel in vitro and small animal in vivo model systems recently established by the investigators. The anti-Wolbachia and parasitological treatment responses against a panel of registered and novel anti-Wolbachia drugs in development will then be evaluated. Finally, inhibition and rescue type in vitro experiments will be designed to test whether specific metabolic and biosynthetic products provided either by clade C or clade D Wolbachia contribute to their filarial host’s larval development. The project will offer links to multiple industrial partners either researching Wolbachia-based drug targets or developing / repurposing anti-Wolbachia drugs for medical and veterinary use. Further the project may afford field visits to Southern Italy and USA to collect isolates of D. immitis.

Where does the project lie on the Translational Pathway?

T1 (Basic Research)

Expected Outputs

Authorship of major research articles detailing the comparative symbiotic requirements of clade C and D Wolbachia and treatment responses

Proof-of-concept of prophylactic and/or transmission blocking drug targeting clade D Wolbachia  

Training Opportunities

Biostatistics

Molecular parasitology

Whole animal physiology

Bioimaging (laser confocal microscopy)

Skills Required

Some prior experience of molecular biology and/or whole animal physiology would be beneficial but not essential

Key Publications associated with this project

New macrolides as short-course oral anti-Wolbachia therapy for filariasis

Taylor MJ, von Geldern T, Ford L, Hübner M, Marsh K, Johnston K, Sjoberg H, Specht S, Pionnier N, Tyrer H, Clare R, Cook D, Murphy E, Steven A, Archer J, Bloemker D, Lenz F, Koschel E, Ehrens A, Metuge H, Chunda V, Chounna P, Njouendou A, Fombad F, Carr R, Morton H, Aljayyoussi G, Hoerauf A, Wanji S, Kempf D, Turner JD and Ward SA.Science Translational Medicine 2018 accepted

Interdomain lateral gene transfer of an essential ferrochelatase gene in human parasitic nematodes.

Wu B, Novelli J, Jiang D, Dailey HA, Landmann F, Ford L, Taylor MJ, Carlow CK, Kumar S, Foster JM, Slatko BE.

Proc Natl Acad Sci U S A. 2013 May 7;110(19):7748-53. doi: 10.1073/pnas.1304049110. Epub 2013 Apr 22

The Wolbachia endosymbiont as an anti-filarial nematode target.

Slatko BE, Taylor MJ, Foster JM.

Symbiosis. 2010 Jul;51(1):55-65. Epub 2010 Jun 5.

PeerJ. 2016 Mar 28;4:e1840. doi: 10.7717/peerj.1840. eCollection 2016.

Breakdown of coevolution between symbiotic bacteria Wolbachia and their filarial hosts.

Lefoulon EBain OMakepeace BLd'Haese CUni SMartin CGavotte L.

 

LSTM Themes and Topics – Key Words

Neglected Tropical Diseases

The call for applications for the 2020-21 round of studentships is now OPEN. Deadline for receipt of complete application 23:59 13th February 2020

Further information on the programme and application process can be found here