PHILIP T LoVERDE, Ph.D.
(University of Michigan, 1976)
Professor of Biochemistry, Professor of Pathology
Office 436½D, phone: 210-567-3772
Lab 431C, phone 210-567-3738
Molecular, Genetic and Immunological Investigation of Schistosomiasis
Schistosomiasis is a major cause of morbidity in 76 countries of the world where it afflicts more than 200 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. One area of research is to characterize genes that encode antigens and to assess the role these antigens play in schistosome-host interactions. In this regard we have identified a number of genes that encode antigens associated with the outer covering (tegument) of larval schistosomes, the targets of immune killing, and elucidated their role in schistosome immunity. Using naked DNA vaccination strategies, we have identified several vaccine candidates such as filamin. Larval schistosome parasites are eliminated by a cell mediated cytotoxic response in which host cells like macrophages and eosinophils produce cidal oxidants. Our research has shown that adults which are able to evade the host immune response, have the highest level of antioxidant activity in terms of transcription and specific activity and the activity localizes to the tegument (outer covering) of the adult stage but not the larval stage. Using naked DNA vaccines we have demonstrated that forms of superoxide dismutase and glutathione peroxidase will provide significant protection against schistosome infection. Current studies in a baboon model will lead to vaccine optimization and justify clinical trials in humans.
Pathogenesis is due to eggs (produced by female worms) that lodge in tissues and incite a granulomatous inflammatory reaction. It turns out that female schistosomes will not develop and become reproductively active without a direct stimulation by the male parasite. The male stimulus regulates the development of the vitelline tissue of the female that is required for eggshell precursors. We have characterized two small gene families that each encode a major eggshell protein. We have isolated a number of transacting factors (nuclear receptors) and signaling molecules (TGF) and demonstrated a role for them in male-female interactions. For example we have demonstrated that human TGF beta will bind to a schistosome receptor and transducer a signal that regulates the expression of a gene invoved in parasite mating. 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.
The S. mansoni genome has been sequenced to 8.8X coverage as part of a collaboration between The Institute for Genomic Research (TIGR), the Sanger Institute and the LoVerde Lab. The genome is undergoing annotation and should be published in 2008. As part of this collaboration a physical map was generated by FISH mapping BAC and YAC sequences to the genome. The available information allowed a collaboration with Dr. Tim Anderson to develop a 5cM genetic map. This will open the door for studies to identify schistosome genes involved in host-parasite interactions such as virulence and drug resistant genes.
The overall focus in the lab is to understand the role genes and gene products play in schistosome-host interaction. Students are exposed to molecular and immunological methods as a way to study questions of developmental regulation and gene expression of an important human pathogen. In addition, these methods are applied to an endemic population so the students are also exposed to epidemiologic and human genetic principles. Although each student focuses on a project, the breadth of the lab allows for broad training. This is important as future scientists, students will have to deal with emerging and re-emerging diseases.
(Publications selected from 152 refereed papers; 5 book chapters; co-editor 1 book)
Gazzinelli, A., Velasquez-Melendez, G., Crawford ,S.B., LoVerde, P.T., Correa-Oliveira, R. and Kloos, K. Socioeconomic determinants of schistosomiasis in a rural area in Brazil. Acta Tropica., 99: 260-271, 2006
Wu, W., Niles, E. G., El-Sayed, N., Berriman, M. and LoVerde, P. T. Schistosoma mansoni Nuclear Receptors: Sixteen New Members and a Novel Subfamily. Gene 366: 303-315, 2006.
Alves Oliveira, L.F., Moreno E.C., Gazzinelli, G., Martins-Filho, O.A., Silveira, A.M.S., Gazzinelli A., Malaquias. L.C.C., LoVerde P. T., Martins Leite P., and Correa-Oliveira, R. Cytokine Production Associated with Periportal Fibrosis during Chronic Schistosomiasis mansoni in humans. Infect Immun., 74:1215-21, 2006.
Lu, C., Wu, W., Niles, E.G., and LoVerde, P.T. Identification and characterization of a novel fushi tarazu factor 1 (FTZ-F1) nuclear receptor in Schistosoma mansoni. Mol Biochem Parasitol., 150: 25-36, 2006.
Hu, R., Wu, W., Niles, E.G., and LoVerde, P.T. Isolation and characterization of Schistosoma mansoni constitutive androstane receptor. Mol. Biochem. Parasitol., 148: 31-43, 2006.
Osman, A., Niles, E.G., Verjovski-Almeida, S., LoVerde, P.T. Schistosoma mansoni type II TGF-beta receptor mediates a signal that is involved in host ligand-induced regulation of a schistosome target gene. PloSPathogen, PLoS Pathog 2(6): e54, 2006. Provided picture for cover of June issue
Hu, R., Wu, W., Niles, E.G. and LoVerde, P.T. SmTR2/4, a Schistosoma mansoni homologue of TR2/TR4 orphan nuclear receptor. Int. J. Parasitol., 36:1113 - 1122, 2006.
Lu, C., Niles, E.G., and LoVerde, P.T. Characterization of the DNA-binding properties and the transactivation activity of Schistosoma mansoni nuclear receptor fushi tarazu-factor 1 (SmFTZ-F1)
Mol. Biochem. Parasitol., 150: 72-78, 2006. (provided figure for cover of volume 150).
Hu, R., Niles, E.G., and LoVerde, P.T. Schistosoma mansoni constitutive androstane receptor, a nuclear receptor that can bind its cognate response element as a monomer, and a heterodimer with RXR. Mol Biochem Parasitol., 150:174-185, 2006.
Gazzinelli, A., Hightower, A., LoVerde, P.T., Haddad, J.P., Pereira, W.R., Bethony, J., Correa-Oliveira, R. and Kloos, H. The spatial distribution of Schistosoma mansoni infection before and after chemotherapy in the Jequitinhonha Valley in Brazil. Mem Inst Oswaldo Cruz. 101:63-71, 2006.
Rodrigues, N.B., Minchella, D., Sorensen, R, LoVerde, P.T., Romanha, A.J., Oliveira, G. Microsatellite enriched genomic libraries as a source of polymorphic loci for Schistosoma mansoni. Mol Ecol Notes, 7: 263–265, 2007.
Deng, J., Gold, D., LoVerde, P.T., and Fishelson, Z. Mapping of the complement C9 binding domain in paramyosin of the blood fluke Schistosoma mansoni. Int J Parasitol, 37: 67-75, 2007.
Wu, W., Niles, E. G., Hirai, H., and LoVerde, P. T. Identification and characterization of a nuclear receptor subfamily I member in the Platyhelminth Schistosoma mansoni (SmNR1). FEBS Journal, 274:390-405, 2007.
Taguchi, T., Hirai, Y., LoVerde, P.T., Tominaga, A. and Hirai, H. DNA probes for identifying chromosomes 5, 6 and 7 of Schistosoma mansoni. J. Parasitol., 93: 724-726, 2007
Wu, W., Niles, E. G., Hirai, H., and LoVerde, P. T. Evolution of a Novel Family of Nuclear Receptors With Members That Contain Two DNA Binding Domains. BMC Evol Biol, 7:27 doi:10.1186/1471-2148-7-27, 2007.
Santos, D.N., Aguiar,P.H.N., Lobo, F.P., Tambor, J.H.M., Valadão, A.F., Vilas-Boas, A., Nóbrega,F.G., LoVerde, P.T., Macedo, A.M., Pena, S.J.D., Machado,C.R. and Franco, G. R. Heterologous complementation of a yeast null mutant by SmRbx, a Schistosoma mansoni protein similar to a RING box protein involved in the ubiquitination process. Exp Parasitol., 116: 440-449, 2007.
LoVerde, P.T., Osman, A. and Hinck, A.P. Schistosoma mansoni: TGF- Signaling Pathways, Exp. Parasitol., 117:304-317, 2007.
Carlo, J.M., Osman, A., Niles, E.G., Wu, W., Fantappie, M.R., Oliveira, F.M.B. and LoVerde, P.T. Identification and Characterization of a R-Smad orthologue (SmSmad1B) from Schistosoma mansoni. FEBS Journal, 274:4075-4093, 2007.
Haas, B.J., Berriman, M., Hirai, H., Cerqueira, G.G., LoVerde, P.T. and El-Sayed, N.M Schistosoma mansoni genome: Closing in on a final gene set. Exp. Parasitol, 117:225-228, 2007.
Wu, W., Niles, E.G. and LoVerde, P.T. Thyroid hormone receptor homologues from invertebrate species with emphasis on Schistosoma mansoni. BMC Evol. Biol., 7:150, doi:10.1186/1471-2148-7-150, 2007.
Cho, P.Y., Kim, T.Y., Yoo, W.K., Li, S., Kim, T.Y., Park, Y.S., Song, K-Y., Choi, M-H., Hong, S-T., Chung, Y.J., LoVerde, P.T., Osman, A., Kang, S-Y., Hong, S-J. Molecular cloning and partial characterization of an actin-interacting protein of Clonorchis sinensis, a WD40-repeat protein. Parasitol. Res., 102:53-56, 2007
Mohamed, M.R., Shalaby, K.A., LoVerde, P.T., Abd Allah, N.M. and Karim, A.M..
Cloning and characterization of a cDNA fragment encoding a Schistosoma mansoniI actin binding protein (Smfilamin). Parasitol. Res.in press, 2008.