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David Artis, Ph.D.
Assistant Professor, Department of Pathobiology
Office Address:
School of Veterinary Medicine
Department of Pathobiology (Rosenthal 207)
University of Pennsylvania
3800 Spruce Street
Philadelphia PA 19104-6008
(office) 215.898.7920
(laboratory) 215.898.6268
(fax) 215.573.7023
dartis@vet.upenn.edu
RESEARCH SUMMARY
The goals of the lab are to gain a better understanding of the immuno-regulatory
mechanisms that govern the initiation, regulation, and development of immune
effector responses following infection with pathogens of the gastrointestinal
tract. The gut is a unique immunologic niche, simultaneously maintaining
tolerance to food antigens and billions of enteric bacterial symbionts, while
retaining the ability to recognize and respond to potentially dangerous pathogens.
We are particularly interested in gut-dwelling helminth parasites. An estimated
two billion people world-wide are infected with soil transmitted helminth parasites,
with 300 million people suffering severe infections. In addition, this group
of pathogens represents a significant economic burden to the livestock industry.
Despite their ubiquitous distribution and evolutionary success, many of the
pathogen factors that promote parasitism and the host factors that mediate
resistance to these infections remain poorly defined.
Trichuris muris is one of the model systems we use to investigate the cellular
and molecular mechanisms that govern immunity and inflammation following infection.
T. muris is a natural gastrointestinal parasite of mice and provides an immunologically
well-defined model of human and veterinary infections. Previous studies have
shown that CD4+ T helper type 1 (Th1) responses promote chronic infection,
while CD4+ Th2 responses are required for host protective immunity. However,
the cellular and molecular mechanisms that control how Trichuris is recognized
by the innate immune system, how CD4+ T helper cell differentiation is regulated
in the gut, and what the immune effector mechanisms are that mediate expulsion
of these infections are unknown.
There are four key research areas in the lab:
1. How do intestinal epithelial cells (iEC) and intestinal dendritic cells
(iDC) regulate innate responses to Trichuris and other enteric pathogens? Using
a combination of cell lineage-specific knockout mice and adoptive transfers
of highly purified antigen presenting cell populations, we are defining how
innate responses against enteric pathogens such as Trichuris and other gut
pathogens are initiated.
2. What unique regulatory pathways control CD4+ T helper cell differentiation
and the development of T cell memory following infection in the gastrointestinal
tract? Many factors are known to influence CD4+ T helper cell fate in lymphoid
tissues, including the type of antigen presenting cell, costimulatory molecules,
and the cytokine environment. Using new tools, we are defining how pathogen-specific
CD4+ T cell responses develop and are maintained in the gut microenvironment.
3. What are the immune effector mechanisms elicited by CD4+ Th2 cells that
mediate host protective immunity in the gut? The effector mechanisms that mediate
expulsion of GI helminth parasites remain unknown. Using a combination of global
gene profiling and proteomic analysis we have identified a number of novel
gut-specific immune effector molecules against parasites and are now testing
their functions and potential for development as anti-microbial agents.
4. How have helminth parasites evolved to subvert the mammalian immune defenses?
Helminth parasites have evolved elaborate physical, biochemical, and molecular
adaptations to promote their survival. We are defining molecular mechanisms
that helminth parasites utilize to inhibit inflammation and protective immune
responses in the gut microenvironment. Understanding these pathways will be
useful in the design of therapeutics to target helminth infection and other
pathologies associated with chronic intestinal inflammation.
RECENT PUBLICATIONS
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