Contact

Location: 436.5D - MED

Department

Biochemistry/Pathology

LoVerde, Phillip, Ph.D.

Professor

Personal Statement:

Dr. LoVerde’s research involves studies of host-parasite interactions of Schistosoma mansoni and its hosts. He has more than 40 years of experience in field and bench research with schistosomiasis. The strengths of the lab are in molecular parasitology, immunoparasitology and genetics. They have contributed continuously to the molecular and genetic studies on Schistosoma.

Dr. Loverde trained 30 Ph.D. Students as a major and co-major professor. In addition He has trained 17 postdoctoral fellows and nine visiting postdoctoral fellows from other US laboratories and foreign institutions. Of the postdoctoral fellows trained, five are now full professors, one started her own company, three are at various Cancer Research Institutes, two are in industry, two are Research Associates and one is in a private practice as a physician.

Of the visiting scholars/postdoctorals, eight are professors at their institutions and all of the visiting scholars became heads of departments after being mentored in his lab. In addition, a majority of his graduate students are in academics as Professors, Department Heads and Associate Deans. Others have gone into industry, government and law as biotech lawyers.


Education

Ph.D., Epidemiologic Science at the University of Michigan, Ann Arbor

Research

Keywords: Schistosomiasis Mansoni

Research interests:
Schistosomiasis is a major cause of morbidity in 76 countries of the world where it afflicts more than 200 million people. Dr. LoVerde’s Lab 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 they 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, they 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. The labs research has shown that adult worms 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 they have demonstrated that forms of superoxide dismutase and glutathione peroxidase will consistently provide significant protection against schistosome infection.

The lab has demonstrated for the first time that adult worms and not just the larval stages of the parasite can be a target for immune elimination. This has resulted in a major advance in schistosome vaccinology as previous studies have always focused on the larval stage as an immune target. Currently, we are evaluating the efficacy of filamin, SOD and GPX in baboons as a prelude to human clinical trials.

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.

They 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, they are studying the signal pathways that the male stimulus might follow to regulate female-specific gene expression. In this regard they have been studying nuclear receptors (NR) and the TGF-beta signaling pathway. We have identified 21 NR in S. mansoni.

Of these they 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, th lab is also elucidating the TGF-beta signaling pathway. They have isolated and characterized two BMP-like ligands, Type II and I TGF-beta receptor, SmSmads 1,2,4 and 8.

They have been able to demonstrate by RNAi knockdown that human TGF-beta will bind to 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, 4, and 8 in the vitelline cells suggests an important role for the TGF-beta pathway in female reproductive development.

Their 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. Their results to date have provided them with information on potential signaling pathways in the male-female interaction and in host-parasite interactions. As regards the latter, they are interested in what host molecules the parasite utilizes to transduce signals to regulate development, site finding behavior, immune evasion, reproductive activity, etc.

In addition to the above major projects, they also have a number of other collaborative projects. One long standing collaboration is with The Institute for Genomic Research (TIGR) and the Wellcome Trust-Sanger Institute to sequence the S. mansoni genome and contribute towards the development of a linkage and physical map.

They have produced more than 8X coverage of the S. mansoni genome and are currently assembling and annotating the genome. As regards the genetic map, in a collaboration with Tim Anderson at the SFBR, they have developed over 300 microsatellite markers that they have mapped across the genome by mapping them to BAC clones that have been physically mapped to the various schistosome chromosomes. The lab has performed the genetic crosses and generated a 5cM map that will allow the schistosome community to identify genes responsible for various phenotypes such as drug resistance and virulence factors.

The overall focus in the lab is to understand the role genes and gene products play in schistosome-host interactions.

Publications

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