| Title: |
Gamma Interferon Mediates Experimental Cerebral Malaria by Signaling within Both the Hematopoietic and Nonhematopoietic Compartments |
| Authors: |
Villegas-Mendez, Ana; Strangward, Patrick; Shaw, Tovah N.; Rajkovic, Ivana; Tosevski, Vinko; Forman, Ruth; Muller, Werner; Couper, Kevin N. |
| Source: |
Villegas-Mendez, A, Strangward, P, Shaw, T N, Rajkovic, I, Tosevski, V, Forman, R, Muller, W & Couper, K N 2017, 'Gamma Interferon Mediates Experimental Cerebral Malaria by Signaling within Both the Hematopoietic and Nonhematopoietic Compartments', Infection and immunity, vol. 85, no. 11, pp. e01035-16. https://doi.org/10.1128/IAI.01035-16 |
| Publication Year: |
2017 |
| Collection: |
The University of Manchester: Research Explorer - Publications |
| Subject Terms: |
brain; cerebral malaria; IFN-γ; immunopathology; malaria; pathology |
| Description: |
Experimental cerebral malaria (ECM) is a gamma interferon (IFN-γ)-dependent syndrome. However, whether IFN-γ promotes ECM through direct and synergistic targeting of multiple cell populations or by acting primarily on a specific responsive cell type is currently unknown. Here, using a panel of cell- and compartment-specific IFN-γ receptor 2 (IFN-γR2)-deficient mice, we show that IFN-γ causes ECM by signaling within both the hematopoietic and nonhematopoietic compartments. Mechanistically, hematopoietic and nonhematopoietic compartment-specific IFN-γR signaling exerts additive effects in orchestrating intracerebral inflammation, leading to the development of ECM. Surprisingly, mice with specific deletion of IFN-γR2 expression on myeloid cells, T cells, or neurons were completely susceptible to terminal ECM. Utilizing a reductionist in vitro system, we show that synergistic IFN-γ and tumor necrosis factor (TNF) stimulation promotes strong activation of brain blood vessel endothelial cells. Combined, our data show that within the hematopoietic compartment, IFN-γ causes ECM by acting redundantly or by targeting non-T cell or non-myeloid cell populations. Within the nonhematopoietic compartment, brain endothelial cells, but not neurons, may be the major target of IFN-γ leading to ECM development. Collectively, our data provide information on how IFN-γ mediates the development of cerebral pathology during malaria infection. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
1098-5522 |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/28874445; info:eu-repo/semantics/altIdentifier/pissn/1098-5522; info:eu-repo/semantics/altIdentifier/eissn/1098-5522 |
| DOI: |
10.1128/IAI.01035-16 |
| Availability: |
https://research.manchester.ac.uk/en/publications/3ab9ec35-0b45-4dbc-9cfc-3726fc03a4b6; https://doi.org/10.1128/IAI.01035-16; https://www.scopus.com/pages/publications/85031894425 |
| Rights: |
info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.EBEF71CC |
| Database: |
BASE |