Transcriptional Correlates of Tolerance and Lethality in Mice Predict Ebola Virus Disease Patient Outcomes

Price, Adam; Okumura, Atsushi; Haddock, Elaine; Feldmann, Friederike; Meade-White, Kimberly; Sharma, Pryanka; Artami, Methinee; Lipkin, W. Ian; Threadgill, David W.; Feldmann, Heinz; Rasmussen, Angela L.

doi:10.1016/j.celrep.2020.01.026

Cited by 42 publications

(20 citation statements)

References 87 publications

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“…Mice transplanted with human immune cells or human immune system (HIS) mice, have been widely used to study human-specific viral infections 24,25 and the combination of HIS and ACE2 expression could help to further explore the efficacy of vaccines and therapies, in particular those that modulate human immune cells. Similarly, previous studies using the CC model of genetic diversity, a panel of recombinant inbred mice with expanded susceptibility to viruses that normally do not cause disease in laboratory mice can be used to enhance virus disease susceptibility, however, infection remains heavily dependent on a functional entry receptor 26,27 . CC mice were previously used with mouse-adapted SARS-CoV to identify mechanisms of pathogenesis and genetic loci that determine susceptibility 28 .…”

Section: Other Mouse Models and Approachesmentioning

confidence: 99%

Animal models for COVID-19

Muñoz‐Fontela

Dowling

Funnell

et al. 2020

Nature

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This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

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Section: Other Mouse Models and Approachesmentioning

confidence: 99%

Animal models for COVID-19

Muñoz‐Fontela

Dowling

Funnell

et al. 2020

Nature

Self Cite

777

810

View full text Add to dashboard Cite

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“…Both host effects [ 5 , 6 , 31 ] and the presence of other infections [ 9 ] will undoubtedly contribute to the outcome in EVD. The host response to EBOV infection is a major determinant of disease severity in EVD [ 5 ], as well as the timing and magnitude of transcriptional regulatory networks, where early induction of inflammatory gene expression is associated with an asymptomatic course of the disease [ 32 ]. The host response at the acute stage in many of the patients covered in this study was investigated previously [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

Variation around the dominant viral genome sequence contributes to viral load and outcome in patients with Ebola virus disease

et al. 2020

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Background Viral load is a major contributor to outcome in patients with Ebola virus disease (EVD), with high values leading to a fatal outcome. Evidence from the 2013–2016 Ebola virus (EBOV) outbreak indicated that different genotypes of the virus can have different phenotypes in patients. Additionally, due to the error-prone nature of viral RNA synthesis in an individual patient, the EBOV genome exists around a dominant viral genome sequence. The minor variants within a patient may contribute to the overall phenotype in terms of viral protein function. To investigate the effects of these minor variants, blood samples from patients with acute EVD were deeply sequenced. Results We examine the minor variant frequency between patients with acute EVD who survived infection with those who died. Non-synonymous differences in viral proteins were identified that have implications for viral protein function. The greatest frequency of substitution was identified at three codon sites in the L gene—which encodes the viral RNA-dependent RNA polymerase (RdRp). Recapitulating this in an assay for virus replication, these substitutions result in aberrant viral RNA synthesis and correlate with patient outcome. Conclusions Together, these findings support the notion that in patients who survived EVD, in some cases, the genetic variability of the virus resulted in deleterious mutations that affected viral protein function, leading to reduced viral load. Such mutations may also lead to persistent strains of the virus and be associated with recrudescent infections.

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“…A retrospective study of COVID-19 patients found that early administration of IFN-α2b treatment following hospital admission drastically improved outcomes, while late administration increased mortality rates compared to untreated patients [17]. Furthermore, studies investigating the prognosis in Ebola virus (EBOV) infection found that a potent and early type I IFN signature and its subsequent immune activation is indicative of greater survival outcomes in humans [18][19][20]. Viruses can also inhibit elements of the IFN signaling pathway in order to promote their replication and survival.…”

Section: The Paradoxical Role Of Type I Ifns In Inflammation and Disease Tolerancementioning

confidence: 99%

Aging and Interferons: Impacts on Inflammation and Viral Disease Outcomes

Feng

Balint

Poznanski

et al. 2021

Cells

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As highlighted by the COVID-19 global pandemic, elderly individuals comprise the majority of cases of severe viral infection outcomes and death. A combined inability to control viral replication and exacerbated inflammatory immune activation in elderly patients causes irreparable immune-mediated tissue pathology in response to infection. Key to these responses are type I, II, and III interferons (IFNs), which are involved in inducing an antiviral response, as well as controlling and suppressing inflammation and immunopathology. IFNs support monocyte/macrophage-stimulated immune responses that clear infection and promote their immunosuppressive functions that prevent excess inflammation and immune-mediated pathology. The timing and magnitude of IFN responses to infection are critical towards their immunoregulatory functions and ability to prevent immunopathology. Aging is associated with multiple defects in the ability of macrophages and dendritic cells to produce IFNs in response to viral infection, leading to a dysregulation of inflammatory immune responses. Understanding the implications of aging on IFN-regulated inflammation will give critical insights on how to treat and prevent severe infection in vulnerable individuals. In this review, we describe the causes of impaired IFN production in aging, and the evidence to suggest that these impairments impact the regulation of the innate and adaptive immune response to infection, thereby causing disease pathology.

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Transcriptional Correlates of Tolerance and Lethality in Mice Predict Ebola Virus Disease Patient Outcomes

Cited by 42 publications

References 87 publications

Animal models for COVID-19

Animal models for COVID-19

Variation around the dominant viral genome sequence contributes to viral load and outcome in patients with Ebola virus disease

Aging and Interferons: Impacts on Inflammation and Viral Disease Outcomes

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