In vivo Ebola virus infection leads to a strong innate response in circulating immune cells

Abstract

BackgroundEbola virus is the causative agent of a severe syndrome in humans with a fatality rate that can approach 90 %. During infection, the host immune response is thought to become dysregulated, but the mechanisms through which this happens are not entirely understood. In this study, we analyze RNA sequencing data to determine the host response to Ebola virus infection in circulating immune cells.ResultsApproximately half of the 100 genes with the strongest early increases in expression were interferon-stimulated genes, such as ISG15, OAS1, IFIT2, HERC5, MX1 and DHX58. Other highly upregulated genes included cytokines CXCL11, CCL7, IL2RA, IL2R1, IL15RA, and CSF2RB, which have not been previously reported to change during Ebola virus infection. Comparing this response in two different models of exposure (intramuscular and aerosol) revealed a similar signature of infection. The strong innate response in the aerosol model was seen not only in circulating cells, but also in primary and secondary target tissues. Conversely, the innate immune response of vaccinated macaques was almost non-existent. This suggests that the innate response is a major aspect of the cellular response to Ebola virus infection in multiple tissues.ConclusionsEbola virus causes a severe infection in humans that is associated with high mortality. The host immune response to virus infection is thought to be an important aspect leading to severe pathology, but the components of this overactive response are not well characterized. Here, we analyzed how circulating immune cells respond to the virus and found that there is a strong innate response dependent on active virus replication. This finding is in stark contrast to in vitro evidence showing a suppression of innate immune signaling, and it suggests that the strong innate response we observe in infected animals may be an important contributor to pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3060-0) contains supplementary material, which is available to authorized users.

Decoding the enigma of antiviral crisis: Does one target molecule regulate all?

“…Significantly higher levels of pro-inflammatory cytokines and chemokines were detected in all fatal cases compared to non-fatal cases. Analysis of animal models revealed profound up-regulation of interferon-stimulated genes (ISGs) from the early stage of the infection [14,19]. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expressed by CD8 + T cells was detected at a markedly higher level in nonsurviving patients.…”

“…Analysis of both in vitro and in vivo models strongly suggests that EBOV, SARS-CoV and DENV are each able to evade type-1 IFNs responses in order to establish infection [37,[45][46][47][48]. Viral entry and infection are characterized by the expression of extremely high levels of pro-inflammatory cytokines and chemokines by T lymphocytes [14,19,21,25,39]. Their excessive provokes a cytokine storm that is responsible for plasma leakage, vascular permeability and disseminated intravascular coagulation (DIC) as well as defective adaptive immunity [37,49,50].…”

“…In spite of such acknowledged limitations, this type of computational modeling analysis could shape future antiviral research by narrowing down the targets through logical explanation and rational Cytokine 115 (2019) [13][14][15][16][17][18][19][20][21][22][23] hypothesis proposition. The outcomes of numerous research studies performed around the world are known but have not been analysed collectively.…”

The Role of Nucleic Acid Sensing in Controlling Microbial and Autoimmune Disorders

“…Further in vivo experiments have shown a more complex picture of EBOV infection than just the antagonizing properties of EBOV-VP35 (Caballero et al, 2016). Transcriptomics analysis of peripheral blood mononuclear cells from cynomolgus macaques infected with EBOV showed strong innate immune activation during viral infection.…”

“…Then, in neighboring cells, EBOV-VP35 might be inducing IRF3 nuclear translocation to facilitate induction of IFN signaling through an unknown mechanism. This hypothesis aims to explain why in isolated EBOV-VP35 experiments, the protein appears to decrease IFN signaling but then during in vivo EBOV infection, ISGs are upregulated (Caballero et al, 2016). This elevated pro-inflammatory response to EBOV has been described in other studies.…”