Hsp90 as a modulator of pathogenicity, virulence and transmission in Theileria and Babesia

Issued: Thu, 03 Jul 2014 12:42:00 BST

Devaney, Shiels

The tick-borne apicomplexan parasites Theileria annulata and Babesia spp. are important pathogens of domestic animals and a major threat to global food security. Tropical theileriosis, caused by T. annulata, is a significant disease of bovines in India with losses estimated at $400 million per annum. Babesiosis caused by Babesia bovis, B. bigemina and B. divergens is a comparatively neglected disease in India. However it is endemic in India and a growing threat to the livestock industry due to the spread of the tick vector.

We hypothesize that Hsp90 plays a critical role in these organisms, facilitating the transmission between vector and mammalian host, influencing virulence and pathogenicity and modulating the response to other stresses such as drug exposure. Hsp90 is an essential protein in all eukaryotic cells, acting as a molecular chaperone for a select group of client proteins such as transcription factors, kinases and other signalling molecules.

When Hsp90 is inhibited, client proteins are targeted for degradation via the proteasomal pathway resulting in cell death. The central role that Hsp90 plays in many cell types has led to the development of many small molecule inhibitors, several of which are in advanced stage clinical trials for the treatment of specific cancers. Studies on tumour cells have identified an extracellular Hsp90 that is a determinant of cellular invasiveness via the chaperoning of matrix metalloproteinases (MMPs).

Since infection with Theileria results in the uncontrolled proliferation and MMP-mediated metastasis of infected cells, determining whether parasite Hsp90 may play a similar role is important to understanding the pathogenesis of tropical theileriosis. As well as providing novel insight on the basic biology and host-parasite relationship, information from this project could be exploited to examine the potential of Hsp90 as a novel drug target in apicomplexan parasites, including those endemic in the UK.

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