Cell death of gamma interferon-stimulated human fibroblasts upon Toxoplasma gondii infection induces early parasite egress and limits parasite replication
Open accessAbstract
The intracellular protozoan parasite Toxoplasma gondii is a major food-borne illness and opportunistic infection for the immunosuppressed. Resistance to Toxoplasma is dependent on gamma interferon (IFN-γ) activation of both hematopoietic and nonhematopoietic cells. Although IFN-γ-induced innate immunity in nonhematopoietic cells has been extensively studied in mice, it remains unclear what resistance mechanisms are relied on in nonhematopoietic human cells. Here, we report an IFN-γ-induced mechanism of resistance to Toxoplasma in primary human foreskin fibroblasts (HFFs) that does not depend on the deprivation of tryptophan or iron. In addition, infection is still controlled in HFFs deficient in the p65 guanylate binding proteins GBP1 or GBP2 and the autophagic protein ATG5. Resistance is coincident with host cell death that is not dependent on the necroptosis mediator RIPK3 or caspases and is correlated with early egress of the parasite before replication. This IFN-γ-induced cell death and early egress limits replication in HFFs and could promote clearance of the parasite by immune cells.
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IFN-γ induces apoptosis in epithelial cells and fibroblasts and can enhance cell-mediated cytotoxicity.
“Since IFN-γ induces apoptosis in epithelial cells and fibroblasts and can enhance cell-mediated cytotoxicity [21–23], we examined if the increased production of IFN-γ in C. auris-infected mice might promote increased cell death and enhance fungal burden.”
From The Emerging Fungal Pathogen Candida auris Induces IFNγ to Colonize the Skin (2025) · cites this paper as [23]
IFN-γ drives apoptosis of epithelial cells and fibroblasts and disrupts barrier integrity.
“Secondly, IFN-γ drives apoptosis of epithelial cells and fibroblasts and disrupts barrier integrity [117–119].”
From Host–Candida auris interactions in the skin (2026) · cites this paper as [119]
Cites
A Family of IFN-γ–Inducible 65-kD GTPases Protects Against Bacterial Infection
Kim, B.-H., Shenoy, A. R., Kumar, P., Das, R., Tiwari, S., & MacMicking, J. D. (2011) · Science · doi:10.1126/science.1201711 · Cited by 494 · see citing works
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The Emerging Fungal Pathogen Candida auris Induces IFNγ to Colonize the Skin
Das, D., Ganesh, S. M., Mishra, A., Netea, M. G., & Thangamani, S. (2025) · PLOS Pathogens · doi:10.1371/journal.ppat.1013114 · Cited by 18 · see citing works
Host–Candida auris interactions in the skin
Thangamani, S., Balakumar, A., Datta, A., Bryak, G., & Lionakis, M. S. (2026) · PLOS Pathogens · doi:10.1371/journal.ppat.1014075 · Cited by 3 · see citing works
- Authors
- Niedelman, W., Sprokholt, J. K., Clough, B., Frickel, E.-M., & Saeij, J. P. J.
- Affiliations
- Massachusetts Institute of Technology (US)
- Amsterdam UMC Location University of Amsterdam (NL)
- National Institute for Medical Research (GB)
- Venue
- Infection and Immunity
- Publisher
- American Society for Microbiology
- Published
- 2013-12
- Volume
- 81
- Issue
- 12
- Pages
- 4341-4349
- ISSN
- 0019-9567 (ISSN-L)
- 1098-5522
- PMC
- PMC3837980
- OpenAlex
- W2113137195
- Cited by
- 81
- References
- 1
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 7 · 2022: 8 · 2021: 9 · 2020: 10 · 2019: 5 · 2018: 7 · 2017: 7 · 2016: 7 · 2015: 6 · 2014: 2
- FWCI
- 4.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Infection and Immunity (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Massachusetts Institute of Technology
- Wellcome Trust
- National Institutes of Health
- Directorate for Biological Sciences
- National Institute of General Medical Sciences (5-T32-GM007287-33, T32GM007287)
- National Institute of Allergy and Infectious Diseases (R01AI080621)
- Topics
- Life Sciences › Immunology and Microbiology › Parasitology › Toxoplasma gondii Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Health Sciences › Medicine › Epidemiology › Cytomegalovirus and herpesvirus research
- Keywords
- Toxoplasma gondii, interferon-gamma, host cell death, human foreskin fibroblasts, parasite egress, parasite replication, GBP1, GBP2, ATG5, autophagy, tryptophan depletion, iron starvation, RIPK3, caspases, host-parasite interactions
- MeSH terms
- Autophagy-Related Protein 5, Cells, Cultured, Fibroblasts, Humans, Interferon-gamma, Iron, Microtubule-Associated Proteins, Toxoplasma, Toxoplasmosis, Tryptophan, Apoptosis, GTP-Binding Proteins, RNA Interference, RNA, Small Interfering, Receptor-Interacting Protein Serine-Threonine Kinases
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