Julie Dyall

National Institutes of Health

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Peter B. Jahrling

National Institute of Allergy and Infectious Diseases

Lisa E. Hensley

Southern Illinois University School of Medicine

Michael R. Holbrook

National Institute of Allergy and Infectious Diseases

Gene G. Olinger

The University of Texas Medical Branch at Galveston

Huanying Zhou

National Institute of Allergy and Infectious Diseases

Elena Postnikova

National Institute of Allergy and Infectious Diseases

Reed F. Johnson

National Institutes of Health

Lisa Evans DeWald

National Institute of Allergy and Infectious Diseases

Brit J. Hart

National Institute of Allergy and Infectious Diseases

Janie Liang

National Institute of Allergy and Infectious Diseases

Cooperative Institutions

National Institutes of Health

National Institute of Allergy and Infectious Diseases

United States Army Medical Research Institute of Infectious Diseases

National Cancer Institute

National Center for Advancing Translational Sciences

University of Maryland, Baltimore

Frederick National Laboratory for Cancer Research

SRI International

Harvard University

The University of Texas Medical Branch at Galveston

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Inhibition of Ebola Virus by a Molecularly Engineered Banana Lectin

PLoS neglected tropical diseases (2019)

Evelyn Covés-Datson Julie Dyall Lisa Evans DeWald Steven R. King Derek Dube

Ebolaviruses cause an often rapidly fatal syndrome known as Ebola virus disease (EVD), with average case fatality rates of ~50%. There is no licensed vaccine or treatment for EVD, underscoring the urgent need to develop new anti-ebolavirus agents, especially in the face of an ongoing outbreak in the Democratic Republic of the Congo and the largest ever outbreak in Western Africa in 2013–2016. Lectins have been investigated as potential antiviral agents as they bind glycans present on viral surface glycoproteins, but clinical use of them has been slowed by concerns regarding their mitogenicity, i.e. ability to cause immune cell proliferation. We previously engineered a banana lectin (BanLec), a carbohydrate-binding protein, such that it retained antiviral activity but lost mitogenicity by mutating a single amino acid, yielding H84T BanLec (H84T). H84T shows activity against viruses containing high-mannose N-glycans, including influenza A and B, HIV-1 and -2, and hepatitis C virus. Since ebolavirus surface glycoproteins also contain many high-mannose N-glycans, we assessed whether H84T could inhibit ebolavirus replication. H84T inhibited Ebola virus (EBOV) replication in cell cultures. In cells, H84T inhibited both virus-like particle (VLP) entry and transcription/replication of the EBOV mini-genome at high micromolar concentrations, while inhibiting infection by transcription- and replication-competent VLPs, which measures the full viral life cycle, in the low micromolar range. H84T did not inhibit assembly, budding, or release of VLPs. These findings suggest that H84T may exert its anti-ebolavirus effect(s) by blocking both entry and transcription/replication. In a mouse model, H84T partially (maximally, ~50–80%) protected mice from an otherwise lethal mouse-adapted EBOV infection. Interestingly, a single dose of H84T pre-exposure to EBOV protected ~80% of mice. Thus, H84T shows promise as a new anti-ebolavirus agent with potential to be used in combination with vaccination or other agents in a prophylactic or therapeutic regimen.

Ebolavirus

10.1371/journal.pntd.0007595

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Citations (58)

Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome: Current Therapeutic Options and Potential Targets for Novel Therapies

Drugs (2017)

Julie Dyall Robin Gross Jason Kindrachuk Reed F. Johnson Gene G. Olinger

No specific antivirals are currently available for two emerging infectious diseases, Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). A literature search was performed covering pathogenesis, clinical features and therapeutics, clinically developed drugs for repurposing and novel drug targets. This review presents current knowledge on the epidemiology, pathogenesis and clinical features of the SARS and MERS coronaviruses. The rationale for and outcomes with treatments used for SARS and MERS is discussed. The main focus of the review is on drug development and the potential that drugs approved for other indications provide for repurposing. The drugs we discuss belong to a wide range of different drug classes, such as cancer therapeutics, antipsychotics, and antimalarials. In addition to their activity against MERS and SARS coronaviruses, many of these approved drugs have broad-spectrum potential and have already been in clinical use for treating other viral infections. A wealth of knowledge is available for these drugs. However, the information in this review is not meant to guide clinical decisions, and any therapeutic described here should only be used in context of a clinical trial. Potential targets for novel antivirals and antibodies are discussed as well as lessons learned from treatment development for other RNA viruses. The article concludes with a discussion of the gaps in our knowledge and areas for future research on emerging coronaviruses.

Drug repositioning

Repurposing

Drug Development

Coronavirus

10.1007/s40265-017-0830-1

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Citations (202)

The effect of volume of interest definition on quantification of lymph node immune response to a monkeypox virus infection assessed by 18F-FDG-PET

EJNMMI Research (2014)

Svetlana I. Chefer Richard C. Reba Christopher Leyson Jürgen Seidel Reed F. Johnson

2-deoxy-2-[(18)F]fluoro-D-glucose-positron emission tomography ((18)F-FDG-PET) is applied in the clinic for infection assessment and is under consideration for investigating the inflammatory/immune response in lymphoid tissue in animal models of viral infection. Assessing changes in (18)F-FDG uptake of lymph nodes (LNs), primary lymphoid tissues targeted during viral infection, requires suitable methods for image analysis. Similar to tumor evaluation, reliable quantitation of the LN function via multiple (18)F-FDG-PET sessions will depend how the volume of interest is defined. Volume of interest definition has a direct effect on statistical outcome. The current study objective is to compare for the first time agreement between conventional and modified VOI metrics to determine which method(s) provide(s) reproducible standardized uptake values (SUVs) for (18)F-FDG uptake in the LN of rhesus macaques.

Monkeypox

Standardized uptake value

Partial volume

Cardiac Imaging

10.1186/s13550-014-0049-z

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Citations (2)

Comparative Analysis of Monkeypox Virus Infection of Cynomolgus Macaques by the Intravenous or Intrabronchial Inoculation Route

Journal of Virology (2010)

Reed F. Johnson Julie Dyall Dan R. Ragland Louis Huzella Russell Byrum

Monkeypox virus (MPXV) infection has recently expanded in geographic distribution and can be fatal in up to 10% of cases. The intravenous (i.v.) inoculation of nonhuman primates (NHPs) results in an accelerated fulminant disease course compared to that of naturally occurring MPXV infection in humans. Alternative routes of inoculation are being investigated to define an NHP model of infection that more closely resembles natural disease progression. Our goal was to determine if the intrabronchial (i.b.) exposure of NHPs to MPXV results in a systemic disease that better resembles the progression of human MPXV infection. Here, we compared the disease course following an i.v. or i.b. inoculation of NHPs with 10-fold serial doses of MPXV Zaire. Classical pox-like disease was observed in NHPs administered a high virus dose by either route. Several key events were delayed in the highest doses tested of the i.b. model compared to the timing of the i.v. model, including the onset of fever, lesion appearance, peak viremia, viral shedding in nasal and oral swabs, peak cytokine levels, and time to reach endpoint criteria. Virus distribution across 19 tissues was largely unaffected by the inoculation route at the highest doses tested. The NHPs inoculated by the i.b. route developed a viral pneumonia that likely exacerbated disease progression. Based on the observations of the delayed onset of clinical and virological parameters and endpoint criteria that may more closely resemble those of human MPXV infection, the i.b. MPXV model should be considered for the further investigation of viral pathogenesis and countermeasures.

Viremia

Monkeypox

Viral Shedding

Viral Pneumonia

10.1128/jvi.01931-10

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Citations (77)

Repurposing of Clinically Developed Drugs for Treatment of Middle East Respiratory Syndrome Coronavirus Infection

Antimicrobial Agents and Chemotherapy (2014)

Julie Dyall Christopher M. Coleman Brit J. Hart Thiagarajan Venkataraman Michael R. Holbrook

Outbreaks of emerging infections present health professionals with the unique challenge of trying to select appropriate pharmacologic treatments in the clinic with little time available for drug testing and development. Typically, clinicians are left with general supportive care and often untested convalescent-phase plasma as available treatment options. Repurposing of approved pharmaceutical drugs for new indications presents an attractive alternative to clinicians, researchers, public health agencies, drug developers, and funding agencies. Given the development times and manufacturing requirements for new products, repurposing of existing drugs is likely the only solution for outbreaks due to emerging viruses. In the studies described here, a library of 290 compounds was screened for antiviral activity against Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Selection of compounds for inclusion in the library was dependent on current or previous FDA approval or advanced clinical development. Some drugs that had a well-defined cellular pathway as target were included. In total, 27 compounds with activity against both MERS-CoV and SARS-CoV were identified. The compounds belong to 13 different classes of pharmaceuticals, including inhibitors of estrogen receptors used for cancer treatment and inhibitors of dopamine receptor used as antipsychotics. The drugs identified in these screens provide new targets for in vivo studies as well as incorporation into ongoing clinical studies.

Repurposing

Drug repositioning

Drug Development

Coronavirus

10.1128/aac.03036-14

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Citations (680)

[¹⁸F]-Fluorodeoxyglucose Uptake in Lymphoid Tissue Serves as a Predictor of Disease Outcome in the Nonhuman Primate Model of Monkeypox Virus Infection

Journal of Virology (2017)

Julie Dyall Reed F. Johnson Svetlana I. Chefer Christopher Leyson David Thomasson

Real-time bioimaging of infectious disease processes may aid countermeasure development and lead to an improved understanding of pathogenesis. However, few studies have identified biomarkers for monitoring infections using

Monkeypox

Non human primate

Pathogenesis

10.1128/jvi.00897-17

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Citations (12)

A Novel Ebola Virus VP40 Matrix Protein-Based Screening for Identification of Novel Candidate Medical Countermeasures

Viruses (2020)

Ryan P. Bennett Courtney L. Finch Elena Postnikova Ryan A. Stewart Yíngyún Caì

Filoviruses, such as Ebola virus and Marburg virus, are of significant human health concern. From 2013 to 2016, Ebola virus caused 11,323 fatalities in Western Africa. Since 2018, two Ebola virus disease outbreaks in the Democratic Republic of the Congo resulted in 2354 fatalities. Although there is progress in medical countermeasure (MCM) development (in particular, vaccines and antibody-based therapeutics), the need for efficacious small-molecule therapeutics remains unmet. Here we describe a novel high-throughput screening assay to identify inhibitors of Ebola virus VP40 matrix protein association with viral particle assembly sites on the interior of the host cell plasma membrane. Using this assay, we screened nearly 3000 small molecules and identified several molecules with the desired inhibitory properties. In secondary assays, one identified compound, sangivamycin, inhibited not only Ebola viral infectivity but also that of other viruses. This finding indicates that it is possible for this new VP40-based screening method to identify highly potent MCMs against Ebola virus and its relatives.

VP40

Ebolavirus

Filoviridae

Marburg virus

10.3390/v13010052

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Citations (18)

Poxvirus Antigen Staining of Immune Cells as a Biomarker to Predict Disease Outcome in Monkeypox and Cowpox Virus Infection in Non-Human Primates

PLoS ONE (2013)

Haifeng Song Krisztina Janosko Reed F. Johnson Jing Qin Nicole Josleyn

Infection of non-human primates (NHPs) such as rhesus and cynomolgus macaques with monkeypox virus (MPXV) or cowpox virus (CPXV) serve as models to study poxvirus pathogenesis and to evaluate vaccines and anti-orthopox therapeutics. Intravenous inoculation of macaques with high dose of MPXV (>1–2×107 PFU) or CPXV (>102 PFU) results in 80% to 100% mortality and 66 to 100% mortality respectively. Here we report that NHPs with positive detection of poxvirus antigens in immune cells by flow cytometric staining, especially in monocytes and granulocytes succumbed to virus infection and that early positive pox staining is a strong predictor for lethality. Samples from four independent studies were analyzed. Eighteen NHPs from three different experiments were inoculated with two different MPXV strains at lethal doses. Ten NHPs displayed positive pox-staining and all 10 NHPs reached moribund endpoint. In contrast, none of the three NHPs that survived anticipated lethal virus dose showed apparent virus staining in the monocytes and granulocytes. In addition, three NHPs that were challenged with a lethal dose of MPXV and received cidofovir treatment were pox-antigen negative and all three NHPs survived. Furthermore, data from a CPXV study also demonstrated that 6/9 NHPs were pox-antigen staining positive and all 6 NHPs reached euthanasia endpoint, while the three survivors were pox-antigen staining negative. Thus, we conclude that monitoring pox-antigen staining in immune cells can be used as a biomarker to predict the prognosis of virus infection. Future studies should focus on the mechanisms and implications of the pox-infection of immune cells and the correlation between pox-antigen detection in immune cells and disease progression in human poxviral infection.

Cowpox virus

Cowpox

Monkeypox

Poxviridae

Orthopoxvirus

10.1371/journal.pone.0060533

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Citations (28)

The lipid moiety of brincidofovir is required for in vitro antiviral activity against Ebola virus

Antiviral Research (2015)

Laura K. McMullan Mike Flint Julie Dyall César G. Albariño Gene G. Olinger

Cidofovir

10.1016/j.antiviral.2015.10.010

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Citations (46)

Testing therapeutics in cell-based assays: Factors that influence the apparent potency of drugs

PLoS ONE (2018)

Elena Postnikova Yu Cong Lisa Evans DeWald Julie Dyall Shuĭqìng Yú

Identifying effective antivirals for treating Ebola virus disease (EVD) and minimizing transmission of such disease is critical. A variety of cell-based assays have been developed for evaluating compounds for activity against Ebola virus. However, very few reports discuss the variable assay conditions that can affect the results obtained from these drug screens. Here, we describe variable conditions tested during the development of our cell-based drug screen assays designed to identify compounds with anti-Ebola virus activity using established cell lines and human primary cells. The effect of multiple assay readouts and variable assay conditions, including virus input, time of infection, and the cell passage number, were compared, and the impact on the effective concentration for 50% and/ or 90% inhibition (EC50, EC90) was evaluated using the FDA-approved compound, toremifene citrate. In these studies, we show that altering cell-based assay conditions can have an impact on apparent drug potency as measured by the EC50. These results further support the importance of developing standard operating procedures for generating reliable and reproducible in vitro data sets for potential antivirals.

EC50

In vitro toxicology

10.1371/journal.pone.0194880

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Citations (44)