Ebola virus binding to Tim-1 on T lymphocytes induces a cytokine storm

Patrick Younan, Mathieu Iampietro, Andrew Nishida, Palaniappan Ramanathan, Rodrigo I. Santos, Mukta Dutta, Ndongala Michel Lubaki, Richard A. Koup, Michael G. Katze, Alexander Bukreyev

Research output: Contribution to journalArticle

23 Scopus citations

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 non-specific 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 high- light a previously unknown role of Tim-1 in the development of a cytokine storm and “immune paralysis.”.

Original languageEnglish (US)
Article numbere00845-17
JournalmBio
Volume8
Issue number5
DOIs
StatePublished - Sep 1 2017

    Fingerprint

Keywords

  • Cytokine storm
  • Cytokines
  • Ebola virus
  • T lymphocytes
  • Transcriptome
  • Viral pathogenesis

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Younan, P., Iampietro, M., Nishida, A., Ramanathan, P., Santos, R. I., Dutta, M., Lubaki, N. M., Koup, R. A., Katze, M. G., & Bukreyev, A. (2017). Ebola virus binding to Tim-1 on T lymphocytes induces a cytokine storm. mBio, 8(5), [e00845-17]. https://doi.org/10.1128/mBio.00845-17