Ewald, Sarah

Sarah Ewald

Sarah E Ewald

Primary Appointment

Assistant Professor, Microbiology, Immunology, and Cancer Biology


  • BA, Biology, University of Massachusetts, Amherst
  • PhD, Molecular and Cell Biology, University of California, Berkeley

Contact Information

Carter Immunology Center
Box 801386 MR6 #3706
Charlottesville, Virginia 22908
Telephone: 434-924-1925
Fax: 434-924-1221
Email: se2s@virginia.edu

Research Interests

Innate immunity, chronic disease, host-parasite interactions

Research Description

OVERVIEW: How does the body recognize an infectious organism? During infection, how does it determine when to escalate inflammation for pathogen clearance versus dampen inflammation to prevent damage to self? What are the long term consequences of these 'immunological decisions' in the balance of health and chronic disease? In the Ewald lab we want to understand how the innate immune system participates in these processes. To ask these questions we are interested in harnessing new technologies to examine human disease. We also study how the immune system interacts with the protozoan parasite Toxoplasma gondii: a pathogen with a long evolutionary relationship with both rodents and humans. PROJECTS: How does the innate immune system sense Toxoplasma? Inflammasomes are innate immune sensors that survey the host cell cytosol for foreign components, triggering release of pro-inflammatory cytokines as well as a rapid, 'firey' cell death termed pyroptosis. This process restricts infection by destroying the vessel for intracellular pathogen growth and recruiting other immune cells to the region. As inflammasomes are emerging as important targets for adjuvants (alum) and points of intersection in a range of chronic (gout, atherosclerosis) and autoimmune diseases (psoriasis, type I diabetes) a thorough understanding of their function is essential to develop better therapeutics. Recently, we and others, have shown that the inflammasome sensor NLRP1 triggers a host-protective immune response to Toxoplasma - a surprising finding since this sensor was originally described in the response to Bacillus anthracis, the causative agent of anthrax. Interestingly, our data indicate that the NLRP1 response to Toxoplasma is protective and occurs via a fundamentally different mechanism than B. anthracis. Interestingly, this response to Toxoplasma is highly conserved across rodents and humans (although sensitivity to B. Anthracis is not). Polymorphisms in the same region of human NLRP1 are associated with acquisition of congenital Toxoplasmosis and susceptibility to autoimmune disease. Cumulatively these observations suggest that: 1) interactions with B. anthracis and Toxoplasma have shaped the evolution of NLRP1 across species at the potential cost of autoreactivity; and 2) until now, a major mechanism of activation has been overlooked that controls parasite sensing and that may be critical in autoimmunity. We are interested in combining tools in host and parasite genetics to work our way down from the level of the parasite and up from the side of NLRP1 to determine the molecular mechanism of the NLRP1 response to Toxoplasma. Spatially Targeted Optical MicroProteomics (STOMP) an unbiased approach to identifying novel components in sub-cellular structures. Spatially targeted optical microproteomics or STOMP is a novel technique that employs standard 2-photon immunofluorescence microscopy to define subcellular structures and selectively UV-cross link proteins in those structures to a modified biotin tag (UV-bio). Once samples are dissociated, labeled proteins are affinity purified and identified by LC-MS. Since the technique does not require genetic modification and overexpression of a label-targeting protein STOMP can be performed on any primary cell or clinical sample where reagents are available to identify the structure of interest. While a minimal inflammasome requires a sensor (NLRP or PyHIIN families), an adapter (ASC or NLRC4) and caspase-1 and/or caspase-11, very little is known about the molecular mechanisms of inflammasome activation or the cell types generating these responses in vivo during disease. We are using STOMP to address basic questions in inflammasome biology including: how does a single inflammasome sensor respond to diverse triggers? Are there differences in the formation of a common inflammasome between individuals suffering from auto-inflammatory or autoimmune diseases versus healthy donors? In the future, our broad goal is to use STOMP to understand inflammation and tissue pathology in the human body, where genetic tools and experimental manipulation are limited. How does the innate immune system participate in chronic infection and inflammation? 'Health' is a dynamic process mediated by interactions between the cells of our organ systems, our microbial ecosystems and environmental inputs. Major insults like change in diet, toxins and pathogen exposure can have profound impacts on homeostasis. Following oral infection (the natural route of infection) with Toxoplasma gondii some strains of mice exhibit severe acute sickness. Acute illness corresponds with systemic parasite dissemination, a dramatic decline in intestinal microbial diversity and approximately 20% reduction in body mass. Although these animals survive and regain normal behavioral activities (eating, grooming, reproduction) and inflammation in the gut resolves the mice are permanently 'wasted.' We are interested in understanding how the microbial ecosystem and the chronic Toxoplasma infection status of the mice influence this phenotype. Our ultimate goal is to use techniques in microbiota profiling and parasite genetics to understand the molecular underpinnings of this disease, which has many parallels in to human conditions like cachexia, and gastrointestinal pathogen-induced wasting in the developing world. POSITIONS: The Ewald Lab is currently accepting applications for post doctoral positions. For information contact se2s@virginia.edu The Ewald lab is accepting graduate trainees through The University of Virginia Biomedical Sciences Graduate Program (BIMS) and Medical Scientist Training Program http://bims.virginia.edu/ https://mstp.med.virginia.edu/

Selected Publications