[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]
OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE
Ebola virus-mediated T-lymphocyte depletion is the result of an abortive infection
Patrick Younan , Rodrigo I. Santos , Palaniappan Ramanathan , Mathieu Iampietro, Andrew Nishida, Mukta Dutta, Tatiana Ammosova, Michelle Meyer, Michael G. Katze, Vsevolod L. Popov, Sergei Nekhai, Alexander Bukreyev
Published: October 24, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008068
Ebola virus (EBOV) infections are characterized by a pronounced lymphopenia that is highly correlative with fatalities. However, the mechanisms leading to T-cell depletion remain largely unknown. Here, we demonstrate that both viral mRNAs and antigens are detectable in CD4+ T cells despite the absence of productive infection. A protein phosphatase 1 inhibitor, 1E7-03, and siRNA-mediated suppression of viral antigens were used to demonstrate de novo synthesis of viral RNAs and antigens in CD4+ T cells, respectively. Cell-to-cell fusion of permissive Huh7 cells with non-permissive Jurkat T cells impaired productive EBOV infection suggesting the presence of a cellular restriction factor. We determined that viral transcription is partially impaired in the fusion T cells. Lastly, we demonstrate that exposure of T cells to EBOV resulted in autophagy through activation of ER-stress related pathways. These data indicate that exposure of T cells to EBOV results in an abortive infection, which likely contributes to the lymphopenia observed during EBOV infections.
Lymphopenia is a common characteristic of the disease caused by EBOV. We determined that despite the apparent lack of productive infection, EBOV is capable of entering T cells and producing both viral RNAs and proteins. Furthermore, we demonstrate that EBOV causes an abortive infection in T cells due to the presence of a cellular restriction factor. The abortive infection was associated with cell death following ER-stress induced autophagy. Collectively, these findings suggest that abortive infection in T cells is likely to contribute to lymphopenia during Ebola virus disease, which is uniformly linked with the severity of the disease. All EBOV vaccine candidates utilize GP as the sole antigen inducing a protective antibody response and in some clinical trials were shown to induce adverse side effects. The present study suggests that these effects can be associated with GP, which may lead to abortive infection of the vaccine construct in T cells contributing to the inflammatory response to the vaccines.
Citation: Younan P, Santos RI, Ramanathan P, Iampietro M, Nishida A, Dutta M, et al. (2019) Ebola virus-mediated T-lymphocyte depletion is the result of an abortive infection. PLoS Pathog 15(10): e1008068. https://doi.org/10.1371/journal.ppat.1008068
Editor: Yoshihiro Kawaoka, University of Wisconsin-Madison, UNITED STATES
Received: March 6, 2019; Accepted: September 3, 2019; Published: October 24, 2019
Copyright: © 2019 Younan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: This study was supported by the NIH grant U19 AI109945-01 Project 2 Molecular Basis for Ebola Virus Immune Paralysis (A.B.) and NIH grant 1R01AI102887-01A1 (A.B.). Sound Genomics, a service center of the Washington National Primate Research Center performed the mRNA sequencing and is supported by funds from the National Institutes of Health, the Office of the Director (Grant P51OD010425). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Keywords: Ebola; Immunopathology; Viral pathogenesis.