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MBio. 2017 Sep 26;8(5). pii: e00845-17. doi: 10.1128/mBio.00845-17.

Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm.

Author information

1
Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, USA.
2
Galveston National Laboratory, The University of Texas Medical Branch, Galveston, Texas, USA.
3
The University of Texas Medical Branch, Galveston, Texas, USA.
4
Department of Microbiology, University of Washington, Seattle, Washington, USA.
5
Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
6
Washington National Primate Research Center, Seattle, Washington, USA.
7
Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, USA alexander.bukreyev@utmb.edu.
8
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, Texas, USA.

Abstract

Ebola virus (EBOV) disease (EVD) results from an exacerbated immunological response that is highlighted by a burst in the production of inflammatory mediators known as a "cytokine storm." Previous reports have suggested that nonspecific activation of T lymphocytes may play a central role in this phenomenon. T-cell immunoglobulin and mucin domain-containing protein 1 (Tim-1) has recently been shown to interact with virion-associated phosphatidylserine to promote infection. Here, we demonstrate the central role of Tim-1 in EBOV pathogenesis, as Tim-1-/- mice exhibited increased survival rates and reduced disease severity; surprisingly, only a limited decrease in viremia was detected. Tim-1-/- mice exhibited a modified inflammatory response as evidenced by changes in serum cytokines and activation of T helper subsets. A series of in vitro assays based on the Tim-1 expression profile on T cells demonstrated that despite the apparent absence of detectable viral replication in T lymphocytes, EBOV directly binds to isolated T lymphocytes in a phosphatidylserine-Tim-1-dependent manner. Exposure to EBOV resulted in the rapid development of a CD4Hi CD3Low population, non-antigen-specific activation, and cytokine production. Transcriptome and Western blot analysis of EBOV-stimulated CD4+ T cells confirmed the induction of the Tim-1 signaling pathway. Furthermore, comparative analysis of transcriptome data and cytokine/chemokine analysis of supernatants highlight the similarities associated with EBOV-stimulated T cells and the onset of a cytokine storm. Flow cytometry revealed virtually exclusive binding and activation of central memory CD4+ T cells. These findings provide evidence for the role of Tim-1 in the induction of a cytokine storm phenomenon and the pathogenesis of EVD.IMPORTANCE Ebola virus infection is characterized by a massive release of inflammatory mediators, which has come to be known as a cytokine storm. The severity of the cytokine storm is consistently linked with fatal disease outcome. Previous findings have demonstrated that specific T-cell subsets are key contributors to the onset of a cytokine storm. In this study, we investigated the role of Tim-1, a T-cell-receptor-independent trigger of T-cell activation. We first demonstrated that Tim-1-knockout (KO) mice survive lethal Ebola virus challenge. We then used a series of in vitro assays to demonstrate that Ebola virus directly binds primary T cells in a Tim-1-phosphatidylserine-dependent manner. We noted that binding induces a cytokine storm-like phenomenon and that blocking Tim-1-phosphatidylserine interactions reduces viral binding, T-cell activation, and cytokine production. These findings highlight a previously unknown role of Tim-1 in the development of a cytokine storm and "immune paralysis."

KEYWORDS:

Ebola virus; T lymphocytes; cytokine storm; cytokines; transcriptome; viral pathogenesis

PMID:
28951472
PMCID:
PMC5615193
DOI:
10.1128/mBio.00845-17
[Indexed for MEDLINE]
Free PMC Article

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