Alan

L.

Scott

,

PhD

My laboratory is interested in understanding the immunobiology of host-parasite interactions. The specific focus of this interest is on the ability of certain helminth parasites to actively modify host immunity and control the Th1-Th2 axis of the immune response. In these studies the lab has taken on two lines of investigation that have a common theme of defining the molecular basis for control of Th2 responses. The first line of investigation concentrates on the use of a murine model of human asthma and allergy to define the genetic and molecular determinants that result in the disregulation of immune response to traditional allergens. In the second line of research we study filarial nematode infections with the goal of identifying the molecules released by the parasite that modify the immune responsiveness of the host and result in a highly polarized Th2 immunity and chronic infection. It is anticipated that an understanding of the mechanism of action of the parasite-derived molecules on the immune response will inform us of the molecular and cellular bases for the generation and regulation of asthma and allergy in humans. Likewise, understanding the regulation of Th2 immunity in asthma and allergy will provide us with a catalog of molecules and pathways that could be targeted for disruption by parasite-derived molecules. In addition to providing fundamental insight into regulation of Th2 immunity that can lead to control of disease, the work has implications for autoimmunity and transplantation biology.

Asthma/Allergy - Under the auspices of funding from NHBLI/NIH, I am the PI of a grant that employs genomic and proteomic approaches to define the molecules and pathways that are key in the regulation of pulmonary inflammation, repair and remodeling. Gene chip-based expression analysis is being used to define the genes that are regulated at the transcriptional level during inflammation in the lung. Studies are being carried out in murine models of major human diseases with particular emphasis on allergy/asthma. Genes identified as potentially important in inflammation/repair/remodeling are validated in the murine system. Once validated, the orthologous gene in humans is identified and studied for its relevance to human disease. In the context of the same project, we are also using proteomic approaches to identify genes/proteins important in the inflammation/repair/remodeling process that are not regulated at the transcriptional level. These studies utilize 2-dimensional gel analysis and liquid chromatography-mass spectroscopy to define changes in the proteome. As with the gene expression analyses, both mouse models and clinical samples are being utilized to define the proteins that are key to pulmonary inflammation/repair/remodeling. In association with this project, I am the director of a microarray/proteomics core facility.

Filarial Nematodes - The second major project in the lab focuses on the immunobiology of filarial nematode infections. Filarial nematodes establish long-term chronic infections that last for decades while causing little or no overt pathology in a majority of infected individuals. This maintenance of an asymptomatic status is made more remarkable by the fact that the adult filarial parasites take up residence within the lumen of efferent lymphatic vessels directly down stream from major lymph node clusters. We hypothesize that this tropism for the efferent lymphatics places the parasite in an ideal position to affect control of the immune response through the release of factors that actively modulate and selectively suppress the immune response of the host. One of the phenotypes of the parasite-mediated immune modulation is the generation of a highly polarized Th2 response. Th2 immunity strongly correlates with chronicity in this and many other infections. The goal of the work is to define the composition of the 300+ polypeptides released by the model filarial worm Brugia malayi and to identify the molecules that mediate immune modulation. The project is being carried out utilizing both proteomic and genomic approaches to define the protein factors released by the parasites. Whenever possible, orthologous genes in C. elegans are identified and studied. In a related project, I a member of the team centered at TIGR that is carrying out whole genome shotgun sequencing B. malayi.