Biology ETDs

Publication Date

Fall 12-1-2018

Abstract

Schistosomiasis is a neglected tropical disease (NTD) that infects 206 million individuals worldwide. This disease is caused by dioecious trematodes of the genus Schistosoma, and its pathology is associated with the large number of eggs that are released by the female. Entrapped eggs lead to host immune and inflammatory responses resulting in disease progression. Chemotherapy provides the main means of control and praziquantel (PZQ) is the only widely available drug that is used in all mass drug administration (MDA) programs. As the number of individuals receiving PZQ continues to grow, the development of PZQ resistance is a concern and increases as the drug pressure placed on the parasites increases. We employed Next Generation Sequencing (NGS) to provide transcriptomic data related to four areas of attention: 1) What is the effect of PZQ on the murine host- S. mansoni interaction, and how does PZQ effect S. mansoni in vivo?, 2) What is the effect at the molecular level of PZQ on male S. mansoni in vivo?, 3) What is the respective contribution of R- and S- enantiomers to the S. mansoni transcriptomic response?, and 4) What is the molecular basis for reduced PZQ susceptibility in lab strains of S. mansoni exposed to increasing sub-lethal doses of the drug?

We found that the murine hepatic response to infection follows a T helper 1 (Th1) response followed by a T helper 2 (Th2) response upon the increase in egg burden that, in turn, leads to significant granuloma formation and fibrosis. While infected mice treated with PZQ have a significantly reduced egg burden and granuloma formation, the immune response remains relatively similar. Additionally quantitative real-time PCR allowed in vivo examination of ATP-binding cassette (ABC) transporters in juvenile and adult S. mansoni. Results show juvenile schistosomes had induced activity of multiple members of this gene family and provides support that these transporters may provide juveniles natural resistance to PZQ.

The examination of the effects of the enantiomers of PZQ on male S. mansoni resulted in more differentially expressed transcripts in the R-PZQ treated parasites then S-PZQ treated compared to control, with a total of 101 up- and down-regulated transcripts in R-PZQ, and 22 in the S-PZQ treated group. The enantiomers shared 4 up-regulated transcripts and 7 down-regulated transcripts, with S-PZQ having one unique up-regulated transcript (Smp_125510, putative cadherin). The up-regulated transcripts identified for R-PZQ contained 26 hypothetical or uncharacterized proteins, 3 major egg antigens, and three heat shock proteins. The R-PZQ enantiomer is the main anti-schistosomal effector, perhaps explaining the differences in transcripts expressed between the parasites treated with each enantiomer.

Lastly the examination of reduced PZQ sensitivity in PR1 S. mansoni revealed a shift in sex ratio to a prominently female population combined with reduced length in female parasites compared to the control parasites. Moreover, we found no association between PZQ insensitivity and specific gene products or pathways perhaps pointing to a single loss of function gene mutation or epigenetic interactions involving multiple genes.

Keywords

Schistosomiasis, Schistosoma mansoni, Praziquantel, Host-Parasite Interaction, Praziquantel insensitive Schistosoma mansoni

Document Type

Dissertation

Degree Name

Biology

Level of Degree

Doctoral

Department Name

UNM Biology Department

First Committee Member (Chair)

Charles Cunningham

Second Committee Member

Eris S. Loker

Third Committee Member

Irene Salinas

Fourth Committee Member

Darrell L. Dinwiddie

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