Microbiology, Virology, and Parasitology

Address

318 Hill Pavilion
380 S. University Avenue
Philadelphia, PA 19104-4539

Office tel.: 215 573-3493
Lab tel.:
Fax: 215 746-2295
E-mail: ejpearce@mail.med.upenn.edu

Link(s)



Education

University of Wales, Aberystwyth, UK, BSc.

National Institute for Medical Research/Brunel University, London, UK, PhD.

National Institutes of Health, Bethesda, USA: Postdoctoral Research.

Research Interests

• The biology of parasites, with emphasis on helminths
• Immune responses during infection
• The biology of dendritic cells.

Key words: Helminth parasite; Th1/Th2; cytokines; dendritic cells; gene regulation; protein kinases/phosphatases

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Description of Research

Our research is focused on the biology of the helminth Schistosoma mansoni, and on the immune response of the host to this parasite during infection.

Schistosomes are complex metazoan pathogens that belong to an early diverging branch of the Bilateria, the Lophotrochozoans. They infect hundreds of millions of people in developing countries, causing the neglected disease schistosomiasis. Disease develops by virtue of the fact that the eggs that schistosomes produce, which are intended for release from the host in order to allow transmission of infection, become trapped in target organs such as the liver, where they induce immune-mediated pathologic changes.

The laboratory is engaged in three lines of research:

The molecular cell biology of schistosomes.
Little is known of the molecular basis of cell to cell communication in schistosomes, but targeted studies and genome sequencing efforts have revealed that, not surprisingly, these organisms contain some of the intercellular signaling systems that are found in higher order metazoa. Amongst these, we are particularly interested in the transforming growth factor β (TGFβ) pathways. In1998 we discovered that S. masoni expresses a type 1 TGFβ receptor (SmRK1; SmTβR1), and since that time we and others have identified in schistosomes many of the core components of the consensus TGFβ signaling pathway. However, the role of TGFβ signaling in schistosomes remains to be defined and elucidating the role(s) of the pathway in schistosome biology is a major goal of the laboratory. Central to our view of what the TGFβ pathway might be doing in schistosomes has been our failure to identify a gene for a TGFβ ligand in these organisms, which led us to hypothesize that the TGFβ signaling pathway in schistosomes evolved to receive signals from host TGFβ ligands, a concept that was given credence by findings that schistosome TGFβ receptors can respond to human TGFβ ligands. Recently however, we made a breakthrough by identifying a schistosome TGFβ family members, SmInAct,

We have found that the protein encoded by SmInAct is made only when females are paired with males in an immunologically competent setting. This is intriguing because egg production by female schistosomes is critically dependent on the presence of male parasites, without which females never fully develop, and (counterintuitively) on the contribution of signals from the host’s immune system.

Using recently developed RNAi tools that allow gene function to be inhibited in schistosomes, we have been able to show that SmInAct plays a crucial role in egg development. We are currently examining how the expression of this gene is controlled since understanding this process has the potential to provide insight into the molecular nature of the interactions between male and female parasites and their hosts. Moreover, the pivotal role of this gene in the egg makes it a potential target for blocking transmission and disease development.

The regulation of immune responses during chronic infection:
Schistosomes are long lived, causing chronic infections in their natural human and experimental mouse hosts. As with other helminth infections, schistosomiasis is associated with the development of a strong Th2 response, which serves a crucial host-protective function as illustrated by the fact that IL-4 is required for mice to survive the acute phase of infection. Ironically, the serious pathologic changes that develop during chronic infection are also due to the Th2 response, being primarily the result of the profibrotic properties of the Th2 cytokine IL-13. It has been long-recognized that during schistosomiasis the parasite-induced Th cell response, as measured by in vitro antigen-stimulated T cell proliferation or cytokine secretion assays, peaks early and then declines despite ongoing infection, a process that is referred to as immunomodulation. The size of granulomatous lesions around parasite eggs trapped in host tissues mirrors the rise and fall of the Th response. Immunomodulation in schistosomiasis appears to play a vital role in minimizing immunopathology in a setting where the immune system is incapable of eliminating the pathogen. We are engaged in studies to explore the underlying basis and functional significance of the diminished Th2 responses that characterize chronic schistosomiasis. We hypothesize that chronic schistosome infection leads to a state of Th2 cell dysfunction. We are investigating this using 4get IL-4 reporter mice, in which cells which can make IL-4 make GFP and thus can be monitored using flow cytometry and fluorescence microscopy. These mice allow the detailed tracking of Th2 cells throughout infection. We are interested in whether Th2 cells from chronically infected mice are irreversibly dysfunctional or whether ongoing environmental signals are required to maintain them in this state. We are hopeful that these studies will generate new insights into the processes that allow the regulation of Th2 responses during chronic schistosomiasis. We believe that our work has the potential to identify targets for intervention in important diseases of the developed world, such as asthma, allergy and ulcerative colitis, that are mediated by chronic, poorly controlled Th2 responses.

The role of dendritic cells in the recognition of pathogens and the induction of the adaptive immune response.
It has become clear over the past decade that dendritic cells (DCs) play a pivotal role in providing the cues that determine the effector function bias of CD4 T cell responses. The crucial element that shapes DC plasticity in this regard is now recognized to be the nature of the ‘conditioning’ information imparted by the particular pathogen that the DCs encounter. The molecular basis of conditioning is best understood from studies of the maturation of DCs exposed to defined Toll like receptor (TLR) ligands, such as LPS, or CpG, which are components of organisms that usually induce Th1-like immune responses. The Th1-biased nature of the data that has been used to construct the current model of DC maturation raised the obvious question of whether DCs are activated and function in a similar way in Th2-dominated settings. Experimental work using the mouse model of schistosomiasis has revealed that it is the egg stage of the parasite that is responsible for inducing the Th2 response that dominates during infection. Knowing this, we have focused on the interaction of egg molecules (“SEA” – soluble egg antigens) with DCs, and, as a counterpoint, compared the responses of DCs to Th1-inducing pathogens with known TLR-stimulatory properties (for example, the Gram+ bacterium Propionebacterium acnes (Pa)), or to molecules from these pathogens (for example LPS or CpG). We have made several significant findings: 1) SEA does not, in any conventional sense, stimulate DC maturation; 2) SEA-pulsed DCs are able to induce Th responses when injected into mice, and these responses are highly Th2-polarized; 3) SEA contains a potent inhibitor of TLR-initiated DC maturation; 4) DCs stimulated by TLRs inhibit Th2 cell development.

In ongoing research in this project we are particularly interested in: 1) why SEA is such a strong Th2 antigen, and 2) how different types of pathogens regulate expression of Notch ligands by DCs, and the effects of these events on DC biology and subsequent immune response development.

The long-term goal of our studies is to elucidate how DCs interpret pathogen-inherent signals to promote different types of effector Th cell response development, with a particular emphasis on understanding how schistosomiasis leads to the development of a Th2 response. We believe that our work has distinct medical relevance, with the potential to facilitate the discovery of: 1) new schistosome-derived anti-inflammatory molecules; 2) methods to regulate Th2-mediated immunopathologies, and 3) rational prophylactic and therapeutic vaccine-relevant methods for deliberately polarizing Th responses in particular directions.

Lab personnel:

Connie Krawczyk, PhD
Tori Freitas, PhD
Fraser Marshall, PhD
Justin Taylor, Immunology Graduate Group Student
EuiHye Jung, Technical Support