Multi-platform ’Omics Analysis of Human Ebola Virus Disease Pathogenesis

Abstract

SUMMARY The pathogenesis of Human Ebola virus disease (EVD) is complex. EVD is characterized by high levels of virus replication and dissemination, dysregulated immune responses, extensive virus- and host-mediated tissue damage, and disordered coagulation. To clarify how host responses contribute to EVD pathophysiology, we performed multi-platform ‘omics analysis of peripheral blood mononuclear cells and plasma from EVD patients. Our results indicate that EVD molecular signatures overlap with those of sepsis, imply that pancreatic enzymes contribute to tissue damage in fatal EVD, and suggest that EBOV infection may induce aberrant neutrophils whose activity could explain hallmarks of fatal EVD. Moreover, integrated biomarker prediction identified putative biomarkers from different data platforms that differentiated survivors and fatalities early after infection. This work reveals insight into EVD pathogenesis, suggests an effective approach for biomarker identification, and provides an important community resource for further analysis of human EVD severity.

Single-cell profiling of Ebola virus infectionin vivoreveals viral and host transcriptional dynamics

“…In addition to IARS , several gene sets associated with depletion of amino acids were significantly up-regulated such as KRIGE_RESPONSE_TO_TOSEDOSTAT_24HR_UP (Tosedostat is an aminopeptidase inhibitor), KRIGE_AMINO_ACID_DEPRIVATION and PENG_LEUCINE_DEPRIVATION_UP ( q = 2.3x10 -6 , q = 0.0030, q = 0.0040, respectively, Fisher's exact test, Table S6 ), suggesting that viral replication exhausts cellular amino acid stores. This hypothesis is consistent with prior observations of depleted amino acids in the plasma of fatal human EVD cases (Eisfeld et al, 2017) .…”

“…Viral transcription and translation can also deplete tRNAs and free amino acids; as a result, viruses have evolved mechanisms to maintain translational capacity (Albers and Czech, 2016) . The tRNA synthetase IARS could be up-regulated in response to this depleted host environment, also reflected in fatal EVD cases (Eisfeld et al, 2017) . By computationally staging cells by their phase in the infection cycle, we nominated several putative pro-viral genes for further study, highlighting the utility of single-cell profiling to study host-virus interactions.…”

“…Though neutrophils are typically removed during density-based PBMC isolations, immature neutrophils ( i.e. , band cells) -which are less dense than mature polymorphonuclear neutrophils -can be released from the bone marrow and co-isolate with PBMCs in infectious and autoimmune inflammatory conditions (Carmona-Rivera and Kaplan, 2013;Darcy et al, 2014;Deng et al, 2016) , including during EVD (Eisfeld et al, 2017) . Neutrophils were almost entirely absent from baseline samples in our data but constituted a high proportion of cells in late EVD samples (scRNA-Seq: 0.2% of baseline cells compared to 65.1% of late EVD cells; CyTOF: 9.3% of baseline compared to 49.8% of late EVD; Figures S5A and S5B ), which supports the hypothesis that band cells are released into the periphery from the bone marrow in response to cytokines elicited during EVD.…”

A global lipid map defines a network essential for Zika virus replication

“…Indeed, the role of sphingolipid signaling in regulating cell death, including during neural development, has been extensively described 91–93 . Further work is needed to validate lipidomic trends during ZIKV infection in clinical samples, as has recently been shown for Ebola virus 94,95 . A variety of nontoxic pharmacological modulators of sphingolipid metabolism exist, including one that is FDA-approved, raising the possibility that sphingolipid metabolism could be targeted as part of a host-directed therapeutic strategy in infected patients 96,97 .…”

When Dendritic Cells Go Viral: The Role of Siglec-1 in Host Defense and Dissemination of Enveloped Viruses

“…Intriguingly, the protective role of type I IFN responses is controversial, since the apparent antiviral function during the earliest stages of infection may, in turn, fuel pathogenesis during the later stages of viral disease. That seems to be the case not only for HIV-1 [43], but also for EBOV [76], where clinical data collected during human outbreaks have indicated that elevated levels of circulating IFNα, as well as upregulation of type I IFN-inducible genes, correlates with fatal disease outcome [64,[77][78][79]. Thus, HIV-1 and EBOV infections trigger an immune activation state that upregulates Siglec-1 expression on DCs, a situation that might favor early viral dissemination events in an otherwise antiviral environment [80].…”