About

Sarah Ewald is a faculty member in the Neuroscience Graduate Program at the University of Virginia. Her research specialty focuses on host-parasite interactions, immunity, and proteomics. She is involved in advancing understanding of neuroimmunology and related fields, contributing to the development of the nervous system and its disorders. As part of her academic role, she engages in research that explores the complex interactions between immune responses and neural processes, with particular attention to neurodegeneration, neurodevelopmental disorders, and CNS infections. Her work supports the broader mission of the Neuroscience Graduate Program, fostering research and education in neuroscience.

Research topics

• Immunology
• Biology
• Medicine
• Internal medicine
• Biochemistry
• Cell biology

Selected publications

• <i>Toxoplasma gondii</i> effector MAF1 blocks mouse AIM2 inflammasome activation by inhibiting mtDNA release

  The Journal of Immunology · 2026-02-01

  articleSenior author

  Toxoplasma gondii is an obligate intracellular pathogen that can infect most nucleated cell types in rodents and humans. Parasite infection is regulated by inflammasome activation, downstream of Toll-like receptors (TLRs) priming, and interferon γ (IFN-γ)-mediated activation of immunity inducible GTPases. In vivo, the activation of these pathways overlaps, however, the molecular mechanism of cooperation between IFN-γ signaling and inflammasome activation has not been rigorously explored during T. gondii infection. Here we show that IFN-γ is sufficient to prime T. gondii-induced inflammasome activation in murine myeloid cells. The cytosolic DNA sensor absent in melanoma 2 (AIM2) inflammasome plays a dominant role in IL-1β release through caspase-1/11 and ASC in cooperation with NLRP3. Unexpectedly, we found that AIM2 inflammasome activation was not dependent on parasite killing as iNOS-deficiency rescued T. gondii clearance but did not inhibit IL-1β release or cell death. Instead, we found that depleting host mitochondrial DNA (mtDNA) blocked IL-1β release, suggesting that host DNA is the ligand for AIM2. Moreover, we found that expressing mitochondrial association factor 1 (MAF1I) from the hyper-virulent type I strain in type II T. gondii significantly inhibited the release of mtDNA into the host cell cytosol and reduced inflammasome activation. These data indicate that T. gondii infection in the context of IFN-γ signaling leads to AIM2 inflammasome activation by host mtDNA, a process that is competitively inhibited by MAF1I-mediated mitochondrial recruitment to the parasitophorous vacuole.

  PublisherDOI

• Spatially-divergent metabolic impact of experimental toxoplasmosis: immunological and microbial correlates

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-13

  preprintOpen access

  Abstract Maladaptive host metabolic responses to infection are emerging as major determinants of infectious disease pathogenesis. However, the factors regulating these metabolic changes within tissues remain poorly understood. In this study, we used toxoplasmosis, as a prototypical example of a disease regulated by strong type I immune responses, to assess the relative roles of local parasite burden, local tissue inflammation and the microbiome in shaping local tissue metabolism during acute and chronic infection. Toxoplasmosis is a zoonotic disease caused by the parasite Toxoplasma gondii . This protozoan infects the small intestine and then disseminates to nearly every organ in the acute stage of infection, before establishing chronic infection in the skeletal muscle, cardiac muscle and brain. We compared metabolism in eleven sampling sites in C57BL/6 mice during the acute and chronic stage of T. gondii infection. Strikingly, significant metabolic changes were observed in the large intestine and colon during chronic infection, organs not associated with T. gondii persistence. Overall, major spatial mismatches were observed between metabolic perturbation and local parasite burden for both disease stages. In contrast, a stronger association with indicators of type I immune responses was observed, indicating a tighter relationship between metabolic perturbation and local immunity, than with local parasite burden. In addition, we observed significant changes in microbiota composition with infection, and candidate microbial origins for multiple metabolites impacted by infection. These findings highlight the metabolic consequences of toxoplasmosis across different organs, and their regulators. Importance Inflammation is a major driver of tissue perturbation. However, the signals driving these changes on a tissue-intrinsic and molecular level are poorly understood. This study evaluated tissue-specific metabolic perturbations across eleven sampling sites following systemic murine infection with the parasite Toxoplasma gondii . Results revealed relationships between differential metabolite enrichment and variables including inflammatory signals, pathogen burden and commensal microbial communities. These data will inform hypotheses about the signals driving specific metabolic adaptation in acute and chronic protozoan infection, with broader implications for infection and inflammation in general.

  PublisherOA PDFDOI

• Macrophage peroxisomes guide alveolar regeneration and limit SARS-CoV-2 tissue sequelae

  Science · 2025-03-06 · 39 citations

  articleOpen access

  Peroxisomes are vital but often overlooked metabolic organelles. We found that excessive interferon signaling remodeled macrophage peroxisomes. This loss of peroxisomes impaired inflammation resolution and lung repair during severe respiratory viral infections. Peroxisomes were found to modulate lipid metabolism and mitochondrial health in a macrophage type-specific manner and enhanced alveolar macrophage-mediated tissue repair and alveolar regeneration after viral infection. Peroxisomes also prevented excessive macrophage inflammasome activation and IL-1β release, limiting accumulation of KRT8 high dysplastic epithelial progenitors following viral injury. Pharmacologically enhancing peroxisome biogenesis mitigated both acute symptoms and post-acute sequelae of COVID-19 (PASC) in animal models. Thus, macrophage peroxisome dysfunction contributes to chronic lung pathology and fibrosis after severe acute respiratory syndrome coronavirus 2 infection.

  PublisherOA PDFDOI

• Spatially divergent metabolic impact of experimental toxoplasmosis: immunological and microbial correlates

  mSystems · 2025-11-06

  articleOpen access

  ABSTRACT Maladaptive host metabolic responses to infection are emerging as major determinants of infectious disease pathogenesis. However, the factors regulating these metabolic changes within tissues remain poorly understood. In this study, we used toxoplasmosis, as a prototypical example of a disease regulated by strong type I immune responses, to assess the relative roles of current local parasite burden, local tissue inflammation, and the microbiome in shaping local tissue metabolism during acute and chronic infections. Toxoplasmosis is a zoonotic disease caused by the parasite Toxoplasma gondii . This protozoan infects the small intestine and then disseminates broadly in the acute stage of infection, before establishing chronic infection in the skeletal muscle, cardiac muscle, and brain. We compared metabolism in 11 sampling sites in C57BL/6 mice during the acute and chronic stages of T. gondii infection. Strikingly, major spatial mismatches were observed between metabolic perturbation and local parasite burden at the time of sample collection for both disease stages. By contrast, a stronger association with indicators of active type I immune responses was observed, indicating a tighter relationship between metabolic perturbation and local immunity than with local parasite burden. Loss of signaling through the IL1 receptor in IL1R knockout mice was associated with reduced metabolic impact of infection. In addition, we observed significant changes in microbiota composition with infection and candidate microbial origins for multiple metabolites impacted by infection. These findings highlight the metabolic consequences of toxoplasmosis across different organs and potential regulators. IMPORTANCE Inflammation is a major driver of tissue perturbation. However, the signals driving these changes on a tissue-intrinsic and molecular level are poorly understood. This study evaluated tissue-specific metabolic perturbations across 11 sampling sites following systemic murine infection with the parasite Toxoplasma gondii . Results revealed relationships between differential metabolite enrichment and variables, including inflammatory signals, pathogen burden, and commensal microbial communities. These data will inform hypotheses about the signals driving specific metabolic adaptation in acute and chronic protozoan infection, with broader implications for infection and inflammation in general.

  PublisherDOI

• Toxoplasma gondii infection supports the infiltration of T cells into brain tumors

  Journal of Neuroimmunology · 2024-07-08 · 6 citations

  articleOpen access
  PublisherOA PDFDOI

• Poly I:C vaccination drives transient CXCL9 expression near B cell follicles in the lymph node through type-I and type-II interferon signaling

  Cytokine · 2024-08-20 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

• Toxoplasma Gondii Infection Supports the Infiltration of T Cells into Brain Tumors

  SSRN Electronic Journal · 2024-01-01

  preprintOpen access
  PublisherDOI

• Corrigendum to “Poly I:C vaccination drives transient CXCL9 expression near B cell follicles in the lymph node through type-I and type-II interferon signaling” [Cytokine 183 (2024) 156731]

  Cytokine · 2024-09-11

  erratumOpen access
  PublisherDOI

• Conjugation of IL‐33 to Microporous Annealed Particle Scaffolds Enhances Type 2‐Like Immune Responses In Vitro and In Vivo

  Advanced Healthcare Materials · 2024-04-22 · 9 citations

  articleOpen access

  The inflammatory foreign body response (FBR) is the main driver of biomaterial implant failure. Current strategies to mitigate the onset of a FBR include modification of the implant surface, release of anti-inflammatory drugs, and cell-scale implant porosity. The microporous annealed particle (MAP) scaffold platform is an injectable, porous biomaterial composed of individual microgels, which are annealed in situ to provide a structurally stable scaffold with cell-scale microporosity. MAP scaffold does not induce a discernible foreign body response in vivo and, therefore, can be used a "blank canvas" for biomaterial-mediated immunomodulation. Damage associated molecular patterns (DAMPs), such as IL-33, are potent regulators of type 2 immunity that play an important role in tissue repair. In this manuscript, IL-33 is conjugated to the microgel building-blocks of MAP scaffold to generate a bioactive material (IL33-MAP) capable of stimulating macrophages in vitro via a ST-2 receptor dependent pathway and modulating immune cell recruitment to the implant site in vivo, which indicates an upregulation of a type 2-like immune response and downregulation of a type 1-like immune response.

  PublisherOA PDFDOI

• The intersection of host <i>in vivo</i> metabolism and immune responses to infection with kinetoplastid and apicomplexan parasites

  Microbiology and Molecular Biology Reviews · 2024-02-01 · 7 citations

  reviewOpen access1st authorCorresponding

  SUMMARY Protozoan parasite infection dramatically alters host metabolism, driven by immunological demand and parasite manipulation strategies. Immunometabolic checkpoints are often exploited by kinetoplastid and protozoan parasites to establish chronic infection, which can significantly impair host metabolic homeostasis. The recent growth of tools to analyze metabolism is expanding our understanding of these questions. Here, we review and contrast host metabolic alterations that occur in vivo during infection with Leishmania , trypanosomes, Toxoplasma , Plasmodium, and Cryptosporidium . Although genetically divergent, there are commonalities among these pathogens in terms of metabolic needs, induction of the type I immune responses required for clearance, and the potential for sustained host metabolic dysbiosis. Comparing these pathogens provides an opportunity to explore how transmission strategy, nutritional demand, and host cell and tissue tropism drive similarities and unique aspects in host response and infection outcome and to design new strategies to treat disease.

  PublisherOA PDFDOI

Recent grants

• Innate Inflammatory Control of Cachexia

  NIH · $2.5M · 2020–2030

• Identification of the non-proteolytic mechanism of NLRP1 activation

  NIH · $269k · 2016–2018

• Proteomic interrogation of the parasite vacuole using autoSTOMP

  NIH · $444k · 2020–2023

Frequent coauthors

• Xiaoyu Zhao

  Carter Center

  27 shared

• Samantha L. Lempke

  Carter Center

  20 shared

• Bocheng Yin

  19 shared

• Nadia K. Holness

  University of Virginia

  17 shared

• Stephanie J. Melchor

  Silicon Valley University

  11 shared

• Emily C. McGowan

  University of Virginia

  10 shared

• Dana May

  Carter Center

  9 shared

• Jamison Smiley

  Carter Center

  8 shared