Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo

2018 ◽  
Vol 10 (468) ◽  
pp. eaat6420 ◽  
Author(s):  
Jose L. Garrido ◽  
Joseph Prescott ◽  
Mario Calvo ◽  
Felipe Bravo ◽  
Raymond Alvarez ◽  
...  
Keyword(s):  
Severe Disease ◽  
Gastrointestinal Symptoms ◽  
Specific Treatment ◽  
Case Fatality ◽  
Hantavirus Infection ◽  
Lethal Challenge ◽  
Hamster Model ◽  
Post Exposure ◽  
Andes Hantavirus

Andes hantavirus (ANDV) is an etiologic agent of hantavirus cardiopulmonary syndrome (HCPS), a severe disease characterized by fever, headache, and gastrointestinal symptoms that may progress to hypotension, pulmonary failure, and cardiac shock that results in a 25 to 40% case-fatality rate. Currently, there is no specific treatment or vaccine; however, several studies have shown that the generation of neutralizing antibody (Ab) responses strongly correlates with survival from HCPS in humans. In this study, we screened 27 ANDV convalescent HCPS patient sera for their capacity to bind and neutralize ANDV in vitro. One patient who showed high neutralizing titer was selected to isolate ANDV–glycoprotein (GP) Abs. ANDV-GP–specific memory B cells were single cell sorted, and recombinant immunoglobulin G antibodies were cloned and produced. Two monoclonal Abs (mAbs), JL16 and MIB22, potently recognized ANDV-GPs and neutralized ANDV. We examined the post-exposure efficacy of these two mAbs as a monotherapy or in combination therapy in a Syrian hamster model of ANDV-induced HCPS, and both mAbs protected 100% of animals from a lethal challenge dose. These data suggest that monotherapy with mAb JL16 or MIB22, or a cocktail of both, could be an effective post-exposure treatment for patients infected with ANDV-induced HCPS.

scholarly journals MBX-500, a Hybrid Antibiotic withIn VitroandIn VivoEfficacy against Toxigenic Clostridium difficile

2012 ◽  
Vol 56 (9) ◽  
pp. 4786-4792 ◽  
Author(s):  
Michelle M. Butler ◽  
Dean L. Shinabarger ◽  
Diane M. Citron ◽  
Ciarán P. Kelly ◽  
Sofya Dvoskin ◽  
...  
Keyword(s):  
Weight Gain ◽  
Clostridium Difficile ◽  
Severe Disease ◽  
Normal Weight ◽  
New Drugs ◽  
Hamster Model ◽  
Resistance Development ◽  
Content Type

ABSTRACTClostridium difficileinfection (CDI) causes moderate to severe disease, resulting in diarrhea and pseudomembranous colitis. CDI is difficult to treat due to production of inflammation-inducing toxins, resistance development, and high probability of recurrence. Only two antibiotics are approved for the treatment of CDI, and the pipeline for therapeutic agents contains few new drugs. MBX-500 is a hybrid antibacterial, composed of an anilinouracil DNA polymerase inhibitor linked to a fluoroquinolone DNA gyrase/topoisomerase inhibitor, with potential as a new therapeutic for CDI treatment. Since MBX-500 inhibits three bacterial targets, it has been previously shown to be minimally susceptible to resistance development. In the present study, thein vitroandin vivoefficacies of MBX-500 were explored against the Gram-positive anaerobe,C. difficile. MBX-500 displayed potency across nearly 50 isolates, including those of the fluoroquinolone-resistant, toxin-overproducing NAP1/027 ribotype, performing as well as comparator antibiotics vancomycin and metronidazole. Furthermore, MBX-500 was a narrow-spectrum agent, displaying poor activity against many other gut anaerobes. MBX-500 was active in acute and recurrent infections in a toxigenic hamster model of CDI, exhibiting full protection against acute infections and prevention of recurrence in 70% of the animals. Hamsters treated with MBX-500 displayed significantly greater weight gain than did those treated with vancomycin. Finally, MBX-500 was efficacious in a murine model of CDI, again demonstrating a fully protective effect and permitting near-normal weight gain in the treated animals. These selective anti-CDI features support the further development of MBX 500 for the treatment of CDI.

scholarly journals Differences in Viral RNA Synthesis but Not Budding or Entry Contribute to the In Vitro Attenuation of Reston Virus Compared to Ebola Virus

2020 ◽  
Vol 8 (8) ◽  
pp. 1215
Author(s):  
Bianca S. Bodmer ◽  
Josephin Greßler ◽  
Marie L. Schmidt ◽  
Julia Holzerland ◽  
Janine Brandt ◽  
...  
Keyword(s):  
Life Cycle ◽  
Rna Synthesis ◽  
Ebola Virus ◽  
Severe Disease ◽  
Case Fatality ◽  
Viral Rna ◽  
Pathogenic Potential ◽  
Rnp Complex ◽  
Reston Virus

Most filoviruses cause severe disease in humans. For example, Ebola virus (EBOV) is responsible for the two most extensive outbreaks of filovirus disease to date, with case fatality rates of 66% and 40%, respectively. In contrast, Reston virus (RESTV) is apparently apathogenic in humans, and while transmission of RESTV from domestic pigs to people results in seroconversion, no signs of disease have been reported in such cases. The determinants leading to these differences in pathogenicity are not well understood, but such information is needed in order to better evaluate the risks posed by the repeated spillover of RESTV into the human population and to perform risk assessments for newly emerging filoviruses with unknown pathogenic potential. Interestingly, RESTV and EBOV already show marked differences in their growth in vitro, with RESTV growing slower and reaching lower end titers. In order to understand the basis for this in vitro attenuation of RESTV, we used various life cycle modeling systems mimicking different aspects of the virus life cycle. Our results showed that viral RNA synthesis was markedly slower when using the ribonucleoprotein (RNP) components from RESTV, rather than those for EBOV. In contrast, the kinetics of budding and entry were indistinguishable between these two viruses. These data contribute to our understanding of the molecular basis for filovirus pathogenicity by showing that it is primarily differences in the robustness of RNA synthesis by the viral RNP complex that are responsible for the impaired growth of RESTV in tissue culture.

scholarly journals In vitro virucidal activity of Echinaforce®, an Echinacea purpurea preparation, against coronaviruses, including common cold coronavirus 229E and SARS-CoV-2

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Johanna Signer ◽  
Hulda R. Jonsdottir ◽  
Werner C. Albrich ◽  
Marc Strasser ◽  
Roland Züst ◽  
...  
Keyword(s):  
Cell Culture ◽  
Protective Effect ◽  
Common Cold ◽  
Natural Infection ◽  
Gastrointestinal Symptoms ◽  
Case Fatality ◽  
Echinacea Purpurea ◽  
Marginal Effect ◽  
Virucidal Activity

Abstract Background Coronaviruses (CoVs) were long thought to only cause mild respiratory and gastrointestinal symptoms in humans but outbreaks of Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV-1, and the recently identified SARS-CoV-2 have cemented their zoonotic potential and their capacity to cause serious morbidity and mortality, with case fatality rates ranging from 4 to 35%. Currently, no specific prophylaxis or treatment is available for CoV infections. Therefore we investigated the virucidal and antiviral potential of Echinacea purpurea (Echinaforce®) against human coronavirus (HCoV) 229E, highly pathogenic MERS- and SARS-CoVs, as well as the newly identified SARS-CoV-2, in vitro. Methods To evaluate the antiviral potential of the extract, we pre-treated virus particles and cells and evaluated remaining infectivity by limited dilution. Furthermore, we exposed cells to the extract after infection to further evaluate its potential as a prophylaxis and treatment against coronaviruses. We also determined the protective effect of Echinaforce® in re-constituted nasal epithelium. Results In the current study, we found that HCoV-229E was irreversibly inactivated when exposed to Echinaforce® at 3.2 μg/ml IC50. Pre-treatment of cell lines, however, did not inhibit infection with HCoV-229E and post-infection treatment had only a marginal effect on virus propagation at 50 μg/ml. However, we did observe a protective effect in an organotypic respiratory cell culture system by exposing pre-treated respiratory epithelium to droplets of HCoV-229E, imitating a natural infection. The observed virucidal activity of Echinaforce® was not restricted to common cold coronaviruses, as both SARS-CoV-1 and MERS-CoVs were inactivated at comparable concentrations. Finally, the causative agent of COVID-19, SARS-CoV-2 was also inactivated upon treatment with 50μg/ml Echinaforce®. Conclusions These results show that Echinaforce® is virucidal against HCoV-229E, upon direct contact and in an organotypic cell culture model. Furthermore, MERS-CoV and both SARS-CoV-1 and SARS-CoV-2 were inactivated at similar concentrations of the extract. Therefore we hypothesize that Echinacea purpurea preparations, such as Echinaforce®, could be effective as prophylactic treatment for all CoVs due to their structural similarities.

scholarly journals A Replication-Defective Influenza Virus Vaccine Confers Complete Protection against H7N9 Viral Infection in Mice

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 207 ◽  
Author(s):  
Shelby Landreth ◽  
Yao Lu ◽  
Kannupriya Pandey ◽  
Yan Zhou
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Cleavage Site ◽  
Case Fatality ◽  
Body Weight Loss ◽  
Wild Type Virus ◽  
Mouse Lung ◽  
H7n9 Virus ◽  
Lethal Challenge

Avian influenza H7N9 viruses continue to pose a great threat to public health, which is evident by their high case-fatality rates. Although H7N9 was first isolated in humans in China in 2013, to date, there is no commercial vaccine available against this particular strain. Our previous studies developed a replication-defective influenza virus through mutation of the hemagglutinin (HA) cleavage site from a trypsin-sensitive to an elastase-sensitive motif. In this study, we report the development of a reassortant mutant influenza virus derived from the human isolate A/British Columbia/01/2015 (H7N9) [BC15 (H7N9)], which is the QVT virus. The HA gene of this virus possesses three mutations at the cleavage site, Lys-Gly-Arg were mutated to Gln-Thr-Val at amino acid (aa) positions 337, 338, and 339, respectively. We report this virus to rely on elastase in vitro, possess unaltered replication abilities when elastase was provided compared to the wild type virus in vitro, and to be non-virulent and replication-defective in mice. In addition, we report this virus to induce significant levels of antibodies and IFN-γ and IL-5 secreting cells, and to protect mice against a lethal challenge of the BC15 (H7N9) virus. This protection is demonstrated through the lack of body weight loss, 100% survival rate, and the prevention of BC15 (H7N9) viral replication as well as the reduction of proinflammatory cytokines induced in the mouse lung associated with the influenza disease. Therefore, these results provide strong evidence for the use of this reassortant mutant H7N9 virus as a replication-defective virus vaccine candidate against H7N9 viruses.

scholarly journals Fabry Disease

2021 ◽  
Author(s):  
Ida Kåks ◽  
Peter Magnusson
Keyword(s):  
Fabry Disease ◽  
Severe Disease ◽  
Gastrointestinal Symptoms ◽  
Specific Treatment ◽  
Skin Lesions ◽  
Lysosomal Storage ◽  
Pharmacological Chaperone ◽  
Enzyme Replacement ◽  
Related Quality ◽  
Health Related

Fabry disease (FD) is a lysosomal storage disorder where deficient or completely absent activity of the enzyme α-galactosidas A leads to accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in lysosomes. The condition is rare, approximately 1:50,000, although underdiagnosis seems frequent. The condition can affect multiple organ systems, including the skin, nervous system, kidneys, and heart. Early manifestations include skin lesions (angiokeratoma), neuropathic pain, and gastrointestinal symptoms. Later on, FD can result in cardiomyopathy, kidney failure, and stroke. Both lifespan and health-related quality of life are affected negatively by FD. Patients are divided into a classical or a non-classical phenotype based on presentation, where the diagnosis of classical FD requires that a set of specific criteria are met. Patients with non-classical FD often have a less severe disease course, sometimes limited to one organ. The hereditary pattern is X-linked. Thus, men are in general more severely affected than women, although there is an overlap in symptomatic burden. Two types of specific treatment options are available: enzyme replacement therapy and pharmacological chaperone therapy. In addition to this, management of each organ manifestation with usual treatment is indicated.

scholarly journals Ifit2 Is a Restriction Factor in Rabies Virus Pathogenicity

2017 ◽  
Vol 91 (17) ◽  
Author(s):  
Benjamin M. Davis ◽  
Volker Fensterl ◽  
Tessa M. Lawrence ◽  
Andrew W. Hudacek ◽  
Ganes C. Sen ◽  
...  
Keyword(s):  
Viral Replication ◽  
Rabies Virus ◽  
Rna Binding ◽  
Binding Capacity ◽  
Severe Disease ◽  
Case Fatality ◽  
Brain Regions ◽  
Restriction Factor

ABSTRACT Understanding the interactions between rabies virus (RABV) and individual host cell proteins is critical for the development of targeted therapies. Here we report that interferon-induced protein with tetratricopeptide repeats 2 (Ifit2), an interferon-stimulated gene (ISG) with possible RNA-binding capacity, is an important restriction factor for rabies virus. When Ifit2 was depleted, RABV grew more quickly in mouse neuroblastoma cells in vitro. This effect was replicated in vivo, where Ifit2 knockout mice displayed a dramatically more severe disease phenotype than wild-type mice after intranasal inoculation of RABV. This increase in pathogenicity correlated to an increase in RABV mRNA and live viral load in the brain, as well as to an accelerated spread to brain regions normally affected by this RABV model. These results suggest that Ifit2 exerts its antiviral effect mainly at the level of viral replication, as opposed to functioning as a mechanism that restricts viral entry/egress or transports RABV particles through axons. IMPORTANCE Rabies is a fatal zoonotic disease with a nearly 100% case fatality rate. Although there are effective vaccines for rabies, this disease still takes the lives of about 50,000 people each year. Victims tend to be children living in regions without comprehensive medical infrastructure who present to health care workers too late for postexposure prophylaxis. The protein discussed in our report, Ifit2, is found to be an important restriction factor for rabies virus, acting directly or indirectly against viral replication. A more nuanced understanding of this interaction may reveal a step of a pathway or site at which the system could be exploited for the development of a targeted therapy.

scholarly journals The Cluster 1 Type VI Secretion System Is a Major Virulence Determinant inBurkholderia pseudomallei

2011 ◽  
Vol 79 (4) ◽  
pp. 1512-1525 ◽  
Author(s):  
Mary N. Burtnick ◽  
Paul J. Brett ◽  
Sarah V. Harding ◽  
Sarah A. Ngugi ◽  
Wilson J. Ribot ◽  
...  
Keyword(s):  
Growth Defect ◽  
Raw 264.7 ◽  
Type Vi Secretion System ◽  
Secretion Systems ◽  
Lethal Challenge ◽  
Hamster Model ◽  
Raw 264.7 Macrophages ◽  
Link Type ◽  
Type Vi Secretion

ABSTRACTTheBurkholderia pseudomalleiK96243genome encodes six type VI secretion systems (T6SSs), but little is known about the role of these systems in the biology ofB. pseudomallei. In this study, we purified recombinant Hcp proteins from each T6SS and tested them as vaccine candidates in the BALB/c mouse model of melioidosis. Recombinant Hcp2 protected 80% of mice against a lethal challenge withK96243, while recombinant Hcp1, Hcp3, and Hcp6 protected 50% of mice against challenge. Hcp6 was the only Hcp constitutively produced byB. pseudomallei in vitro; however, it was not exported to the extracellular milieu. Hcp1, on the other hand, was produced and exportedin vitrowhen the VirAG two-component regulatory system was overexpressed intrans. We also constructed sixhcpdeletion mutants (Δhcp1throughΔhcp6) and tested them for virulence in the Syrian hamster model of infection. The 50% lethal doses (LD50s) for theΔhcp2throughΔhcp6mutants were indistinguishable fromK96243(<10 bacteria), but the LD50for theΔhcp1mutant was >103bacteria. Thehcp1deletion mutant also exhibited a growth defect in RAW 264.7 macrophages and was unable to form multinucleated giant cells in this cell line. UnlikeK96243, theΔhcp1mutant was only weakly cytotoxic to RAW 264.7 macrophages 18 h after infection. The results suggest that the cluster 1 T6SS is essential for virulence and plays an important role in the intracellular lifestyle ofB. pseudomallei.

scholarly journals In vitro antiviral activity of Echinaforce®, an Echinacea purpurea preparation, against common cold coronavirus 229E and highly pathogenic MERS-CoV and SARS-CoV

2020 ◽  
Author(s):  
Johanna Signer ◽  
Hulda R. Jonsdottir ◽  
Werner C. Albrich ◽  
Marc Strasser ◽  
Roland Züst ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Common Cold ◽  
Natural Infection ◽  
Gastrointestinal Symptoms ◽  
Case Fatality ◽  
Echinacea Purpurea ◽  
Marginal Effect ◽  
Virus Propagation ◽  
Highly Pathogenic

Abstract Coronaviruses (CoVs) were long thought to only cause mild respiratory and gastrointestinal symptoms in humans but recent outbreaks of Middle Eastern Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV, and the newly identified SARS-CoV-2 have cemented their zoonotic potential and their capacity to cause serious morbidity and mortality, with case fatality rates ranging from 2 to 35%. Currently, no specific prophylaxis or treatment is available for CoV infections and therefore we investigated the antiviral potential of Echinacea purpurea (Echinaforce®) against human coronavirus (HCoV) 229E and the highly pathogenic MERS- and SARS-CoVs in vitro. We found that HCoV-229E was irreversibly inactivated when exposed to Echinaforce at 3.2µg/ml IC50. Pre-treatment of cell lines, however, did not inhibit infection with HCoV-229E and post-infection treatment had only a marginal effect on virus propagation at 50 µg/ml. However, we did observe a protective effect in an organotypic respiratory cell culture system by exposing pre-treated respiratory epithelium to droplets of HCoV-229E, imitating a natural infection. Finally, antiviral activity was not restricted to common cold coronaviruses, as the highly pathogenic SARS- and MERS-CoVs were inactivated at comparable concentrations. These results suggest that Echinacea purpurea preparations, such as Echinaforce, could be effective as prophylactic treatment for all CoVs, including newly occurring strains, such as SARS-CoV-2.

scholarly journals Gastrointestinal symptoms in COVID-19 could be associated with severe lung involvement and increased readmission rates

2021 ◽  
Vol 19 ◽  
pp. 205873922110482
Author(s):  
Hüseyin S Bozkurt ◽  
Ömer Bilen
Keyword(s):  
Gastrointestinal Symptom ◽  
Severe Disease ◽  
Gastrointestinal Symptoms ◽  
Specific Treatment ◽  
Lung Damage ◽  
Readmission Rates ◽  
Antibody Positivity ◽  
Bowel Disorders ◽  
Severity Of The Disease ◽  
Relationship Of

Introduction SARS-CoV-2 virus manifests itself with primary lung damage but also has intestinal involvement. In this study, we aimed to investigate the frequency of gastrointestinal symptoms (GIS) and the relationship of GIS with readmission to the hospital within 30 days in SARS-CoV-2 infected patients who were hospitalized in a specified pandemic hospital. Materials and Methods Symptomatic patients diagnosed with rapid antibody positivity with real-time polymerase chain reaction and typical thorax computed tomography findings were included in this retrospective cohort observational study. Demographic and clinical data were obtained from electronic medical records. Hospital-associated GIS were considered as experiencing at least one of the GIS such as gas, bloating, diarrhea, and constipation developing within72 h after hospital admission. Results The mean age of the patients was 58 ± 14.4 years and 60.7% were men. 82% of hospitalizations were a moderate and severe disease. 71.4% of patients without GIS had at least one of the GIS after hospitalization. As the severity of the disease increased, the frequency of the severity of gastrointestinal symptom increased. GIS bowel disorders were more prominent in patients with moderate and severe disease. Antibiotic and specific treatment (anti-Il-1, anti-Il-6) contributed to the occurrence of gastrointestinal symptom in SARS-CoV-2 inpatients. Conclusion According to our observations of the second wave of the pandemic, the presence, frequency, and severity of gastrointestinal symptom in inpatient is associated with severity of lung disease and increased readmission rate after discharge.

scholarly journals Screening of an FDA-Approved Drug Library with a Two-Tier System Identifies an Entry Inhibitor of Severe Fever with Thrombocytopenia Syndrome Virus

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 385 ◽  
Author(s):  
Shuofeng Yuan ◽  
Jasper Fuk-Woo Chan ◽  
Zi-Wei Ye ◽  
Lei Wen ◽  
Terance Gi-Wai Tsang ◽  
...  
Keyword(s):  
Severe Disease ◽  
Treatment Options ◽  
Case Fatality ◽  
Test System ◽  
Host Cells ◽  
Entry Inhibitor ◽  
Tier System ◽  
Drug Compounds ◽  
Severe Fever

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans with case-fatality rates of up to 30%. There are currently very limited treatment options for SFTSV infection. We conducted a drug repurposing program by establishing a two-tier test system to rapidly screen a Food and Drug Administration- (FDA)-approved drug library for drug compounds with anti-SFTSV activity in vitro. We identified five drug compounds that inhibited SFTSV replication at low micromolar concentrations, including hexachlorophene, triclosan, regorafenib, eltrombopag, and broxyquinoline. Among them, hexachlorophene was the most potent with an IC50 of 1.3 ± 0.3 µM and a selectivity index of 18.7. Mechanistic studies suggested that hexachlorophene was a virus entry inhibitor, which impaired SFTSV entry into host cells by interfering with cell membrane fusion. Molecular docking analysis predicted that the binding of hexachlorophene with the hydrophobic pocket between domain I and domain III of the SFTSV Gc glycoprotein was highly stable. The novel antiviral activity and mechanism of hexachlorophene in this study would facilitate the use of hexachlorophene as a lead compound to develop more entry inhibitors with higher anti-SFTSV potency and lower toxicity.

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