Department

Pathology, Biochemistry

Philip T. LoVerde, PhD

Professor

Research

chistosomiasis is a major cause of morbidity in 78 countries of the world where it afflicts more than 260 million people. Our studies are aimed at elucidating molecular mechanisms of schistosome-host interactions. An understanding of the role schistosome genes and gene products play in these interactions will lead to vaccine candidates, improved diagnostics, and a basis for rationale drug design. We have contributed continuously to molecular studies on Schistosoma, For example, we were one of the 4 major contributors that brought the sequence of the schistosome genome to fruition, then re-sequenced the genome to make it a reference genome, with Tim Anderson developed a 5 cM genetic map for S. mansoni. Using the genetic map, RNAi and biochemical assays, Anderson and I have identified the gene responsible for oxamniquine (OXA) drug resistance, worked out the mode of action of OXA (a first for a drug that treats human helminth infections) and in collaboration with P. John Hart determined the structure of the enzyme (Sulfotransferase)-co-factor and drug. We then identified and crystallyzed the sulfotransferases from S. haematobium and S. japonicum. In collaboration with Stan McHardy, CIDD we have synthesized and evaluated over 200 derivatives of OXA. Using an iterative approach, we have identified derivatives that will kill all the major human species of Schistosoma. We developed X-QTL, a method that involves exome sequencing F2 progeny to identify SNPs that co-segregate with a phenotype in this case drug resistance. The research on OXA provides the proof of principal for our approach. We have taken the same genetic approach as with OXA and selected a PZQ resistant strain, performed crosses between PZQ sensitive and resistant schistosomes and identified a quantitative trait locus (QTL) that contains the gene for PZQ drug resistance. We have identified 47 candidate genes and are currently using molecular techniques to identify the one responsible for drug resistance. Pathogenesis is due to eggs (produced by mature female worms) that lodge in tissues and incite a granulomatous inflammatory reaction. It turns out that female schistosomes will not develop or become reproductively active without a direct stimulation by the male parasite. The male stimulus regulates the development of the vitelline cells of the female that supply the eggshell precursors and nutrients for embryonation. We have characterized two small gene families that each encode a major eggshell protein, and demonstrated that these genes are regulated in a stage-, tissue and temporal-specific manner in response to a male-stimulus. Currently, we are studying the signal pathways that the male stimulus might follow to regulate female-specific gene expression. In this regard we have been studying nuclear receptors (NR) and the TGF-beta signaling pathway. We have identified 21 NR in S. mansoni. Of these we have demonstrated by gel shift assay and the yeast one-hybrid system that NR of the RXR subfamily (SmRXR1 and SmRXR2), Constitutive Androstane Receptor (CAR), and fushi tarazu factor 1 (FTZ-F1) to be involved in the regulation of these eggshell precursor genes. As part of these studies, we are also elucidating the TGF-beta signaling pathway. We have isolated and characterized two BMP-like ligands, Type II and I TGF-beta receptor, SmSmads 1, 2 and 4 . We have been able to demonstrate by RNAi knockdown that human TGF-beta will bind to schistosome TBRII and transduce a signal to regulate a schistosome gene that encodes a gynecophoric canal protein. The gynecophoric canal protein is thought to play an important role in worm pairing. This coupled with our in situ hybridization and immunolocalization data that shows the presence TBRI, SmSmad 2 and 4 in the vitelline cells suggests an important role for the TGF-beta pathway in female reproductive development. Our goal is to understand what genes and gene products contribute to female reproductive development and what factors in what manner regulate the expression of these genes. Our results to date have provided us with information on potential signaling pathways in the male-female interaction and in host-parasite interactions. As regards the latter, we are interested in what host molecules the parasite utilizes to transduce signals to regulate development, site finding behavior, immune evasion, reproductive activity, etc. The overall focus in the lab is to understand the role genes and gene products play in schistosome-host interactions.

Affiliations

American Society of Parasitologists, 1970-present

American Society of Tropical Medicine and Hygiene, 1984-present

Publications

Charles D. Criscione, Claudia L. L. Valentim, Hirohisa Hirai, Philip T. LoVerde, & Timothy J. C. Anderson Genomic linkage map of the human blood fluke Schistosoma mansoni. Genom Biol, Jun 30;10(6):R71, 2009. Berriman, M., Haas, B.J., LoVerde, P.T., Wilson, R.A., Dillon, G.P. Cerqueira, G.C., Mashiyama, S.T., Al-Lazikani, B., Andrade, L.F., Ashton, P.D. Aslett, M.A., Bartholomeu, D.C., Blandin, G., Caffrey, C.R., Coghlan, A., Coulson, R., Day, T.A., Delcher, A., DeMarco, R., Djikeng, A., Eyre, T., Gamble, J.A., Ghedin, E., Gu, Y., Hertz-Fowler, C., Hirai, H., Hirai, Y., Houston, R., Ivens, A., Johnston, D.A., Lacerda, D., Macedo, C.A., McVeigh, P., Ning, Z., Oliveira, G., Overington, J.P., Parkhill, J., Pertea, M., Pierce, R.J., Protasio, A.V., Quail, M.A., Rajandream, M.A., Rogers, J., Sajid, M., Salzberg, S.L., Stanke, M., Tivey, A.R. White, O., Williams, D.L., Wortman, W., Wu, W., Zamanian, M., Zerlotini, A., Fraser-Liggett, C.M., Barrell, B.G. and El-Sayed, N.M.. The Genome of the blood fluke Schistosoma mansoni. Nature, 460:352-358, 2009. Structural and Functional Characterization of the Enantiomers of the Antischistosomal Drug Oxamniquine. Taylor AB, Pica-Mattoccia L, Polcaro CM, Donati E, Cao X, Basso A, Guidi A, Rugel AR, Holloway SP, Anderson TJ, Hart PJ, Cioli D, LoVerde PT PLoS Negl Trop Dis: 2015-10-01; 9(10); e0004132 Epub: 2015-10-20. PMID: 26485649 LINK: Protective potential of antioxidant enzymes as vaccines for schistosomiasis in a non-human primate model. Carvalho-Queiroz, C, Nyakundi, R, Ogongo, P, Rikoi, H, Egilmez,NK, Farah, IO, Kariuki, TK, LoVerde, PT. Frontiers in Immunology: 2015-06-02; 6(); 273 Epub: 2015-06-02. PMID: LINK: doi: 10.3389/fimmu.2015.00273. Efficient linkage mapping using exome capture and extreme QTL in schistosome parasites. Chevalier FD, Valentim CL, LoVerde PT, Anderson TJ BMC Genomics: 2014-07-21; 15(); 617 Epub: 2014-07-21. PMID: 25048426 LINK: Genetic and molecular basis of drug resistance and species-specific drug action in schistosome parasites. Valentim CL, Cioli D, Chevalier FD, Cao X, Taylor AB, Holloway SP, Pica-Mattoccia L, Guidi A, Basso A, Tsai IJ, Berriman M, Carvalho-Queiroz C, Almeida M, Aguilar H, Frantz DE, Hart PJ, LoVerde PT, Anderson TJ Science: 2013-12-13; 342(6164); 1385-9 Epub: 2013-11-21. PMID: 24263136 LINK: Nuclear hormone receptors in parasitic helminths. Wu W, LoVerde PT Mol Cell Endocrinol: 2011-03-01; 334(1-2); 56-66 Epub: 2010-06-26. PMID: 20600585 LINK: Taylor AB, Roberts KM, Cao X, Clark NE, Holloway SP, Donati E, Polcaro CM, Pica-Mattoccia L, Tarpley RS, McHardy SF, Cioli D, LoVerde PT, Fitzpatrick PF, Hart PJ. Structural and Enzymatic Insights into Species-specific Resistance to Schistosome Parasite Drug Therapy. J Biol Chem. 2017 May 23. pii: jbc.M116.766527. doi: 10.1074/jbc.M116.766527. PMID:28536265 Anastasia Rugel, Reid Tarpley, Ambrosio Lopez, Travis Menard, Meghan A. Guzman, Alexander B. Taylor, Xiaohang Cao, Frédéric D. Chevalier, Timothy J. C. Anderson, P. John Hart, Philip T LoVerde and Stanton F. McHardy. Design, Synthesis, and Characterization of Novel Small Molecules as Broad Range Anti-Schistosomal Agents. ACS Medicinal Chemistry Letters, in revision.