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1.
Nature ; 615(7953): 678-686, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36922586

RESUMEN

Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million1 with annually around 10,000 deaths2. However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3. Here we present JNJ-1802-a highly potent DENV inhibitor that blocks the NS3-NS4B interaction within the viral replication complex. JNJ-1802 exerts picomolar to low nanomolar in vitro antiviral activity, a high barrier to resistance and potent in vivo efficacy in mice against infection with any of the four DENV serotypes. Finally, we demonstrate that the small-molecule inhibitor JNJ-1802 is highly effective against viral infection with DENV-1 or DENV-2 in non-human primates. JNJ-1802 has successfully completed a phase I first-in-human clinical study in healthy volunteers and was found to be safe and well tolerated4. These findings support the further clinical development of JNJ-1802, a first-in-class antiviral agent against dengue, which is now progressing in clinical studies for the prevention and treatment of dengue.


Asunto(s)
Antivirales , Virus del Dengue , Dengue , Primates , Proteínas no Estructurales Virales , Animales , Humanos , Ratones , Antivirales/efectos adversos , Antivirales/farmacología , Antivirales/uso terapéutico , Ensayos Clínicos Fase I como Asunto , Dengue/tratamiento farmacológico , Dengue/prevención & control , Dengue/virología , Virus del Dengue/clasificación , Virus del Dengue/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral , Técnicas In Vitro , Terapia Molecular Dirigida , Primates/virología , Unión Proteica/efectos de los fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/metabolismo , Replicación Viral
2.
Antimicrob Agents Chemother ; 68(7): e0011224, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38888319

RESUMEN

Inhalation anthrax is the most severe form of Bacillus anthracis infection, often progressing to fatal conditions if left untreated. While recommended antibiotics can effectively treat anthrax when promptly administered, strains engineered for antibiotic resistance could render these drugs ineffective. Telavancin, a semisynthetic lipoglycopeptide antibiotic, was evaluated in this study as a novel therapeutic against anthrax disease. Specifically, the aims were to (i) assess in vitro potency of telavancin against 17 B. anthracis isolates by minimum inhibitory concentration (MIC) testing and (ii) evaluate protective efficacy in rabbits infected with a lethal dose of aerosolized anthrax spores and treated with human-equivalent intravenous telavancin doses (30 mg/kg every 12 hours) for 5 days post-antigen detection versus a humanized dose of levofloxacin and vehicle control. Blood samples were collected at various times post-infection to assess the level of bacteremia and antibody production, and tissues were collected to determine bacterial load. The animals' body temperatures were also recorded. Telavancin demonstrated potent bactericidal activity against all strains tested (MICs 0.06-0.125 µg/mL). Further, telavancin conveyed 100% survival in this model and cleared B. anthracis from the bloodstream and organ tissues more effectively than a humanized dose of levofloxacin. Collectively, the low MICs against all strains tested and rapid bactericidal in vivo activity demonstrate that telavancin has the potential to be an effective alternative for the treatment or prophylaxis of anthrax infection.


Asunto(s)
Aminoglicósidos , Carbunco , Antibacterianos , Bacillus anthracis , Lipoglucopéptidos , Pruebas de Sensibilidad Microbiana , Infecciones del Sistema Respiratorio , Animales , Lipoglucopéptidos/farmacología , Conejos , Carbunco/tratamiento farmacológico , Carbunco/microbiología , Carbunco/mortalidad , Bacillus anthracis/efectos de los fármacos , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Aminoglicósidos/farmacología , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Infecciones del Sistema Respiratorio/microbiología , Modelos Animales de Enfermedad , Levofloxacino/farmacología , Femenino
3.
J Virol ; 97(5): e0188822, 2023 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-36975793

RESUMEN

Zaïre ebolavirus (EBOV) causes Ebola virus disease (EVD), a devastating viral hemorrhagic fever in humans. Nonhuman primate (NHP) models of EVD traditionally use intramuscular infection with higher case fatality rates and reduced mean time-to-death compared to contact transmission typical of human cases of EVD. A cynomolgus macaque model of oral and conjunctival EBOV was used to further characterize the more clinically relevant contact transmission of EVD. NHPs challenged via the oral route had an overall 50% survival rate. NHPs challenged with a target dose of 1 × 102 PFU or 1 × 104 PFU of EBOV via the conjunctival route had 40% and 100% mortality, respectively. Classic signs of lethal EVD-like disease were observed in all NHPs that succumbed to EBOV infection including viremia, hematological abnormalities, clinical chemistries indicative of hepatic and renal disease, and histopathological findings. Evidence of EBOV viral persistence in the eye was observed in NHPs challenged via the conjunctival route. IMPORTANCE This study is the first to examine the Kikwit strain of EBOV, the most commonly used strain, in the gold-standard macaque model of infection. Additionally, this is the first description of the detection of virus in the vitreous fluid, an immune privileged site that has been proposed as a viral reservoir, following conjunctival challenge. The oral and conjunctival macaque challenge model of EVD described here more faithfully recapitulates the prodrome that has been reported for human EVD. This work paves the way for more advanced studies to model contact transmission of EVD, including early events in mucosal infection and immunity, as well as the establishment of persistent viral infection and the emergence from these reservoirs.


Asunto(s)
Ebolavirus , Fiebre Hemorrágica Ebola , Animales , Humanos , Ebolavirus/fisiología , Fiebre Hemorrágica Ebola/transmisión , Macaca fascicularis , Modelos Animales de Enfermedad , Conjuntiva/virología , Transmisión de Enfermedad Infecciosa
4.
J Gen Virol ; 104(7)2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37432877

RESUMEN

The 2',5'- oligoadenylate synthetase (OAS) - ribonuclease L (RNAseL) - phosphodiesterase 12 (PDE12) pathway is an essential interferon-induced effector mechanism against RNA virus infection. Inhibition of PDE12 leads to selective amplification of RNAseL activity in infected cells. We aimed to investigate PDE12 as a potential pan-RNA virus antiviral drug target and develop PDE12 inhibitors that elicit antiviral activity against a range of viruses. A library of 18 000 small molecules was screened for PDE12 inhibitor activity using a fluorescent probe specific for PDE12. The lead compounds (CO-17 or CO-63) were tested in cell-based antiviral assays using encephalomyocarditis virus (EMCV), hepatitis C virus (HCV), dengue virus (DENV), West Nile virus (WNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in vitro. Cross reactivity of PDE12 inhibitors with other PDEs and in vivo toxicity were measured. In EMCV assays, CO-17 potentiated the effect of IFNα by 3 log10. The compounds were selective for PDE12 when tested against a panel of other PDEs and non-toxic at up to 42 mg kg-1 in rats in vivo. Thus, we have identified PDE12 inhibitors (CO-17 and CO-63), and established the principle that inhibitors of PDE12 have antiviral properties. Early studies suggest these PDE12 inhibitors are well tolerated at the therapeutic range, and reduce viral load in studies of DENV, HCV, WNV and SARS-CoV-2 in human cells and WNV in a mouse model.


Asunto(s)
COVID-19 , Virus ARN , Humanos , Ratones , Animales , Ratas , Antivirales/farmacología , SARS-CoV-2 , Interferón-alfa , Virus de la Encefalomiocarditis , Hidrolasas Diéster Fosfóricas
6.
J Virol ; 90(9): 4757-4770, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26912625

RESUMEN

UNLABELLED: Flaviviruses are positive-sense, single-stranded RNA viruses responsible for millions of human infections annually. The envelope (E) protein of flaviviruses comprises three structural domains, of which domain III (EIII) represents a discrete subunit. The EIII gene sequence typically encodes epitopes recognized by virus-specific, potently neutralizing antibodies, and EIII is believed to play a major role in receptor binding. In order to assess potential interactions between EIII and the remainder of the E protein and to assess the effects of EIII sequence substitutions on the antigenicity, growth, and virulence of a representative flavivirus, chimeric viruses were generated using the West Nile virus (WNV) infectious clone, into which EIIIs from nine flaviviruses with various levels of genetic diversity from WNV were substituted. Of the constructs tested, chimeras containing EIIIs from Koutango virus (KOUV), Japanese encephalitis virus (JEV), St. Louis encephalitis virus (SLEV), and Bagaza virus (BAGV) were successfully recovered. Characterization of the chimeras in vitro and in vivo revealed differences in growth and virulence between the viruses, within vivo pathogenesis often not being correlated within vitro growth. Taken together, the data demonstrate that substitutions of EIII can allow the generation of viable chimeric viruses with significantly altered antigenicity and virulence. IMPORTANCE: The envelope (E) glycoprotein is the major protein present on the surface of flavivirus virions and is responsible for mediating virus binding and entry into target cells. Several viable West Nile virus (WNV) variants with chimeric E proteins in which the putative receptor-binding domain (EIII) sequences of other mosquito-borne flaviviruses were substituted in place of the WNV EIII were recovered, although the substitution of several more divergent EIII sequences was not tolerated. The differences in virulence and tissue tropism observed with the chimeric viruses indicate a significant role for this sequence in determining the pathogenesis of the virus within the mammalian host. Our studies demonstrate that these chimeras are viable and suggest that such recombinant viruses may be useful for investigation of domain-specific antibody responses and the more extensive definition of the contributions of EIII to the tropism and pathogenesis of WNV or other flaviviruses.


Asunto(s)
Antígenos Virales/inmunología , Dominios y Motivos de Interacción de Proteínas/inmunología , Proteínas del Envoltorio Viral/inmunología , Virus del Nilo Occidental/inmunología , Secuencia de Aminoácidos , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Antígenos Virales/química , Antígenos Virales/genética , Línea Celular , Modelos Animales de Enfermedad , Epítopos/química , Epítopos/genética , Epítopos/inmunología , Femenino , Ratones , Viabilidad Microbiana/inmunología , Datos de Secuencia Molecular , Pruebas de Neutralización , Dominios y Motivos de Interacción de Proteínas/genética , Alineación de Secuencia , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/genética , Carga Viral , Ensayo de Placa Viral , Virulencia , Replicación Viral , Fiebre del Nilo Occidental/inmunología , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/genética , Virus del Nilo Occidental/patogenicidad
7.
Proc Natl Acad Sci U S A ; 111(29): 10708-13, 2014 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-25002490

RESUMEN

Since the development of infectious cDNA clones of viral RNA genomes and the means of delivery of the in vitro-synthesized RNA into cells, alphaviruses have become an attractive system for expression of heterologous genetic information. Alphaviruses replicate exclusively in the cytoplasm, and their genetic material cannot recombine with cellular DNA. Alphavirus genome-based, self-replicating RNAs (replicons) are widely used vectors for expression of heterologous proteins. Their current design relies on replacement of structural genes, encoded by subgenomic RNAs (SG RNA), with heterologous sequences of interest. The SG RNA is transcribed from a promoter located in the alphavirus-specific RNA replication intermediate and is not further amplified. In this study, we have applied the accumulated knowledge of the mechanism of alphavirus replication and promoter structures, in particular, to increase the expression level of heterologous proteins from Venezuelan equine encephalitis virus (VEEV)-based replicons. During VEEV infection, replication enzymes are produced in excess to RNA replication intermediates, and a large fraction of them are not involved in RNA synthesis. The newly designed constructs encode SG RNAs, which are not only transcribed from the SG promoter, but are additionally amplified by the previously underused VEEV replication enzymes. These replicons produce SG RNAs and encoded proteins of interest 10- to 50-fold more efficiently than those using a traditional design. A modified replicon encoding West Nile virus (WNV) premembrane and envelope proteins efficiently produced subviral particles and, after a single immunization, elicited high titers of neutralizing antibodies, which protected mice from lethal challenge with WNV.


Asunto(s)
Alphavirus/genética , Genoma Viral/genética , ARN Viral/metabolismo , Replicón/genética , Proteínas Virales/metabolismo , Replicación Viral/genética , Alphavirus/efectos de los fármacos , Animales , Anticuerpos Neutralizantes/farmacología , Virus de la Encefalitis Equina Venezolana/efectos de los fármacos , Virus de la Encefalitis Equina Venezolana/fisiología , Expresión Génica , Vectores Genéticos , Proteínas Fluorescentes Verdes/metabolismo , Interferón beta/farmacología , Espacio Intracelular/metabolismo , Ratones , Biosíntesis de Proteínas/efectos de los fármacos , Interferencia de ARN/efectos de los fármacos , ARN Viral/genética , Proteínas Virales/ultraestructura , Replicación Viral/efectos de los fármacos , Virus del Nilo Occidental/efectos de los fármacos , Virus del Nilo Occidental/fisiología
8.
J Am Chem Soc ; 136(29): 10315-24, 2014 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-24950171

RESUMEN

Mutations in the epitopes of antigenic proteins can confer viral resistance to antibody-mediated neutralization. However, the fundamental properties that characterize epitope residues and how mutations affect antibody binding to alter virus susceptibility to neutralization remain largely unknown. To address these questions, we used an ensemble-based algorithm to characterize the effects of mutations on the thermodynamics of protein conformational fluctuations. We applied this method to the envelope protein domain III (ED3) of two medically important flaviviruses: West Nile and dengue 2. We determined an intimate relationship between the susceptibility of a residue to thermodynamic perturbations and epitope location. This relationship allows the successful identification of the primary epitopes in each ED3, despite their high sequence and structural similarity. Mutations that allow the ED3 to evade detection by the antibody either increase or decrease conformational fluctuations of the epitopes through local effects or long-range interactions. Spatially distant interactions originate in the redistribution of conformations of the ED3 ensembles, not through a mechanically connected array of contiguous amino acids. These results reconcile previous observations of evasion of neutralization by mutations at a distance from the epitopes. Finally, we established a quantitative correlation between subtle changes in the conformational fluctuations of the epitope and large defects in antibody binding affinity. This correlation suggests that mutations that allow viral growth, while reducing neutralization, do not generate significant structural changes and underscores the importance of protein fluctuations and long-range interactions in the mechanism of antibody-mediated neutralization resistance.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Virus del Dengue/metabolismo , Proteínas del Envoltorio Viral , Virus del Nilo Occidental/metabolismo , Algoritmos , Secuencia de Aminoácidos , Anticuerpos Monoclonales/inmunología , Anticuerpos Antivirales/inmunología , Sitios de Unión de Anticuerpos , Simulación por Computador , Virus del Dengue/genética , Virus del Dengue/inmunología , Mapeo Epitopo , Datos de Secuencia Molecular , Mutación , Pruebas de Neutralización , Conformación Proteica , Termodinámica , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Virus del Nilo Occidental/genética , Virus del Nilo Occidental/inmunología
9.
Emerg Infect Dis ; 20(2): 272-5, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24447818

RESUMEN

Molecular analysis of West Nile virus (WNV) isolates obtained during a 2010 outbreak in Maricopa County, Arizona, USA, demonstrated co-circulation of 3 distinct genetic variants, including strains with novel envelope protein mutations. These results highlight the continuing evolution of WNV in North America and the current complexity of WNV dispersal and transmission.


Asunto(s)
Culex/virología , Brotes de Enfermedades , Insectos Vectores/virología , Proteínas del Envoltorio Viral/genética , Fiebre del Nilo Occidental/epidemiología , Virus del Nilo Occidental/genética , Animales , Arizona/epidemiología , Evolución Biológica , Análisis por Conglomerados , Variación Genética , Filogenia , Proteínas del Envoltorio Viral/clasificación , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/clasificación , Virus del Nilo Occidental/aislamiento & purificación
10.
Viruses ; 16(7)2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-39066263

RESUMEN

Favipiravir is a ribonucleoside analogue that has been explored as a therapeutic for the treatment of Ebola Virus Disease (EVD). Promising data from rodent models has informed nonhuman primate trials, as well as evaluation in patients during the 2013-2016 West African EVD outbreak of favipiravir treatment. However, mixed results from these studies hindered regulatory approval of favipiravir for the indication of EVD. This study examined the influence of route of administration, duration of treatment, and treatment schedule of favipiravir in immune competent mouse and guinea pig models using rodent-adapted Zaire ebolavirus (EBOV). A dose of 300 mg/kg/day of favipiravir with an 8-day treatment was found to be fully effective at preventing lethal EVD-like disease in BALB/c mice regardless of route of administration (oral, intraperitoneal, or subcutaneous) or whether it was provided as a once-daily dose or a twice-daily split dose. Preclinical data generated in guinea pigs demonstrates that an 8-day treatment of 300 mg/kg/day of favipiravir reduces mortality following EBOV challenge regardless of route of treatment or duration of treatments for 8, 11, or 15 days. This work supports the future translational development of favipiravir as an EVD therapeutic.


Asunto(s)
Amidas , Antivirales , Modelos Animales de Enfermedad , Ebolavirus , Fiebre Hemorrágica Ebola , Ratones Endogámicos BALB C , Pirazinas , Animales , Amidas/uso terapéutico , Amidas/administración & dosificación , Amidas/farmacología , Cobayas , Pirazinas/administración & dosificación , Pirazinas/uso terapéutico , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Ratones , Ebolavirus/efectos de los fármacos , Antivirales/administración & dosificación , Antivirales/uso terapéutico , Femenino , Vías de Administración de Medicamentos , Esquema de Medicación
11.
Vaccine ; 42(19S1): S9-S24, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-38407992

RESUMEN

Chikungunya virus (CHIKV) a mosquito-borne alphavirus is the causative agent of Chikungunya (CHIK), a disease with low mortality but high acute and chronic morbidity resulting in a high overall burden of disease. After the acute disease phase, chronic disease including persistent arthralgia is very common, and can cause fatigue and pain that is severe enough to limit normal activities. On average, around 40% of people infected with CHIKV will develop chronic arthritis, which may last for months or years. Recommendations for protection from CHIKV focus on infection control through preventing mosquito proliferation. There is currently no licensed antiviral drug or vaccine against CHIKV. Therefore, one of the most important public health impacts of vaccination would be to decrease burden of disease and economic losses in areas impacted by the virus, and prevent or reduce chronic morbidity associated with CHIK. This benefit would particularly be seen in Low and Middle Income Countries (LMIC) and socio-economically deprived areas, as they are more likely to have more infections and more severe outcomes. This 'Vaccine Value Profile' (VVP) for CHIK is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of vaccines in the development pipeline and vaccine-like products.This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships, and multi-lateral organizations. All contributors have extensive expertise on various elements of the CHIK VVP and collectively aimed to identify current research and knowledge gaps.The VVP was developed using only existing and publicly available information.


Asunto(s)
Fiebre Chikungunya , Virus Chikungunya , Vacunas Virales , Animales , Humanos , Fiebre Chikungunya/prevención & control , Fiebre Chikungunya/epidemiología , Virus Chikungunya/inmunología , Salud Pública , Vacunación , Vacunas Virales/inmunología , Vacunas Virales/administración & dosificación
12.
J Gen Virol ; 94(Pt 2): 318-325, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23136360

RESUMEN

Since the 1990s West Nile virus (WNV) has become an increasingly important public health problem and the cause of outbreaks of neurological disease. Genetic analyses have identified multiple lineages with many studies focusing on lineage 1 due to its emergence in New York in 1999 and its neuroinvasive phenotype. Until recently, viruses in lineage 2 were not thought to be of public health importance due to few outbreaks of disease being associated with viruses in this lineage. However, recent epidemics of lineage 2 in Europe (Greece and Italy) and Russia have shown the increasing importance of this lineage. There are very few genetic studies examining isolates belonging to lineage 2. We have sequenced the full-length genomes of four older lineage 2 WNV isolates, compared them to 12 previously published genomic sequences and examined the evolution of this lineage. Our studies show that this lineage has evolved over the past 300-400 years and appears to correlate with a change from mouse attenuated to virulent phenotype based on previous studies by our group. This evolution mirrors that which is seen in lineage 1 isolates, which have also evolved to a virulent phenotype over the same period of time.


Asunto(s)
Evolución Molecular , ARN Viral/genética , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/genética , Animales , Análisis por Conglomerados , Grecia/epidemiología , Humanos , Italia/epidemiología , Ratones , Datos de Secuencia Molecular , Filogenia , Federación de Rusia/epidemiología , Análisis de Secuencia de ADN , Virulencia , Fiebre del Nilo Occidental/epidemiología , Virus del Nilo Occidental/aislamiento & purificación , Virus del Nilo Occidental/patogenicidad
13.
Microbiol Resour Announc ; 12(11): e0042323, 2023 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-37846978

RESUMEN

Koutango virus (KOUV), a close relative of West Nile virus, is highly neuroinvasive in animal models and has been associated with human disease. The complete genome of the KOUV prototype strain DakAnD5443 is reported here and may facilitate development of infectious clones for further characterization of this novel flavivirus.

14.
Antiviral Res ; 209: 105492, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36535309

RESUMEN

Molnupiravir (EIDD-2801) is a prodrug of a ribonucleoside analogue that is currently being used under a US FDA emergency use authorization for the treatment of mild to moderate COVID-19. We evaluated molnupiravir for efficacy as an oral treatment in the rhesus macaque model of SARS-CoV-2 infection. Twenty non-human primates (NHPs) were challenged with SARS-CoV-2 and treated with 75 mg/kg (n = 8) or 250 mg/kg (n = 8) of molnupiravir twice daily by oral gavage for 7 days. The NHPs were observed for 14 days post-challenge and monitored for clinical signs of disease. After challenge, all groups showed a trend toward increased respiration rates. Treatment with molnupiravir significantly reduced viral RNA levels in bronchoalveolar lavage (BAL) samples at Days 7 and 10. Considering the mild to moderate nature of SARS-CoV-2 infection in the rhesus macaque model, this study highlights the importance of monitoring the viral load in the lung as an indicator of pharmaceutical efficacy for COVID-19 treatments. Additionally, this study provides evidence of the efficacy of molnupiravir which supplements the current ongoing clinical trials of this drug.


Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Macaca mulatta , Citidina/farmacología , Citidina/uso terapéutico
15.
NPJ Vaccines ; 7(1): 38, 2022 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-35301331

RESUMEN

Oropouche virus (OROV) is an arthropod-borne orthobunyavirus found in South America and causes Oropouche fever, a febrile infection similar to dengue. It is the second most prevalent arthropod-borne viral disease in South America after dengue. Over 500,000 cases have been diagnosed since the virus was first discovered in 1955; however, this is likely a significant underestimate given the limited availability of diagnostics. No fatalities have been reported to date, however, up to 60% of cases have a recurrent phase of disease within one month of recovery from the primary disease course. The main arthropod vector is the biting midge Culicoides paraensis, which has a geographic range as far north as the United States and demonstrates the potential for OROV to geographically expand. The transmission cycle is incompletely understood and vertebrate hosts include both non-human primates and birds further supporting the potential ability of the virus to spread. A number of candidate antivirals have been evaluated against OROV in vitro but none showed antiviral activity. Surprisingly, there is only one report in the literature on candidate vaccines. We suggest that OROV is an undervalued pathogen much like chikungunya, Schmallenberg, and Zika viruses were before they emerged. Overall, OROV is an important emerging disease that has been under-investigated and has the potential to cause large epidemics in the future. Further research, in particular candidate vaccines, is needed for this important pathogen.

16.
Viruses ; 14(10)2022 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-36298846

RESUMEN

The Biomedical Advanced Research and Development Authority, part of the Administration for Strategic Preparedness and Response within the U.S. Department of Health and Human Services, recognizes that the evaluation of medical countermeasures under the Animal Rule requires well-characterized and reproducible animal models that are likely to be predictive of clinical benefit. Marburg virus (MARV), one of two members of the genus Marburgvirus, is characterized by a hemorrhagic fever and a high case fatality rate for which there are no licensed vaccines or therapeutics available. This natural history study consisted of twelve cynomolgus macaques challenged with 1000 PFU of MARV Angola and observed for body weight, temperature, viremia, hematology, clinical chemistry, and coagulation at multiple time points. All animals succumbed to disease within 8 days and exhibited signs consistent with those observed in human cases, including viremia, fever, systemic inflammation, coagulopathy, and lymphocytolysis, among others. Additionally, this study determined the time from exposure to onset of disease manifestations and the time course, frequency, and magnitude of the manifestations. This study will be instrumental in the design and development of medical countermeasures to Marburg virus disease.


Asunto(s)
Enfermedad del Virus de Marburg , Marburgvirus , Contramedidas Médicas , Humanos , Animales , Marburgvirus/fisiología , Viremia , Macaca fascicularis
17.
J Gen Virol ; 92(Pt 12): 2810-2820, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21865445

RESUMEN

The hallmark attribute of North American West Nile virus (WNV) strains has been high pathogenicity in certain bird species. Surprisingly, this avian virulent WNV phenotype has not been observed during its geographical expansion into the Caribbean, Central America and South America. One WNV variant (TM171-03-pp1) isolated in Mexico has demonstrated an attenuated phenotype in two widely distributed North American bird species, American crows (AMCRs) and house sparrows (HOSPs). In order to identify genetic determinants associated with attenuated avian replication of the TM171-03-pp1 variant, chimeric viruses between the NY99 and Mexican strains were generated, and their replicative capacity was assessed in cell culture and in AMCR, HOSP and house finch avian hosts. The results demonstrated that mutations in both the pre-membrane (prM-I141T) and envelope (E-S156P) genes mediated the attenuation phenotype of the WNV TM171-03-pp1 variant in a chicken macrophage cell line and in all three avian species assayed. Inclusion of the prM-I141T and E-S156P TM171-03-pp1 mutations in the NY99 backbone was necessary to achieve the avian attenuation level of the Mexican virus. Furthermore, reciprocal incorporation of both prM-T141I and E-P156S substitutions into the Mexican virus genome was necessary to generate a virus that exhibited avian virulence equivalent to the NY99 virus. These structural changes may indicate the presence of new evolutionary pressures exerted on WNV populations circulating in Latin America or may signify a genetic bottleneck that has constrained their epiornitic potential in alternative geographical locations.


Asunto(s)
Cuervos/virología , Pinzones/virología , Gorriones/virología , Proteínas del Envoltorio Viral/metabolismo , Virus del Nilo Occidental/genética , Sustitución de Aminoácidos , Animales , Enfermedades de las Aves/virología , Línea Celular , Pollos , Clonación Molecular , ADN Complementario/genética , Proteínas de la Membrana/genética , México , Mutación , Fenotipo , Filogeografía , Plásmidos/genética , Análisis de Secuencia de ADN , Proteínas del Envoltorio Viral/genética , Carga Viral , Virulencia , Replicación Viral , Virus del Nilo Occidental/aislamiento & purificación , Virus del Nilo Occidental/patogenicidad
18.
J Infect Dis ; 201(1): 2-4, 2010 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-19961306

RESUMEN

West Nile virus (WNV) RNA was demonstrated in 5 (20%) of 25 urine samples collected from convalescent patients 573-2452 days (1.6-6.7 years) after WNV infection. Four of the 5 amplicons sequenced showed >99% homology to the WNV NY99 strain. These findings show that individuals with chronic symptoms after WNV infection may have persistent renal infection over several years.


Asunto(s)
ARN Viral/orina , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/aislamiento & purificación , Anciano , Progresión de la Enfermedad , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Virus del Nilo Occidental/genética
19.
ACS Infect Dis ; 7(8): 2176-2191, 2021 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-34218660

RESUMEN

Anthrax is caused by Bacillus anthracis and can result in nearly 100% mortality due in part to anthrax toxin. Antimalarial amodiaquine (AQ) acts as a host-oriented inhibitor of anthrax toxin endocytosis. Here, we determined the pharmacokinetics and safety of AQ in mice, rabbits, and humans as well as the efficacy in the fly, mouse, and rabbit models of anthrax infection. In the therapeutic-intervention studies, AQ nearly doubled the survival of mice infected subcutaneously with a B. anthracis dose lethal to 60% of the animals (LD60). In rabbits challenged with 200 LD50 of aerosolized B. anthracis, AQ as a monotherapy delayed death, doubled the survival rate of infected animals that received a suboptimal amount of antibacterial levofloxacin, and reduced bacteremia and toxemia in tissues. Surprisingly, the anthrax efficacy of AQ relies on an additional host macrophage-directed antibacterial mechanism, which was validated in the toxin-independent Drosophila model of Bacillus infection. Lastly, a systematic literature review of the safety and pharmacokinetics of AQ in humans from over 2 000 published articles revealed that AQ is likely safe when taken as prescribed, and its pharmacokinetics predicts anthrax efficacy in humans. Our results support the future examination of AQ as adjunctive therapy for the prophylactic anthrax treatment.


Asunto(s)
Carbunco , Bacillus anthracis , Amodiaquina , Animales , Carbunco/tratamiento farmacológico , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Levofloxacino , Ratones , Conejos , Revisiones Sistemáticas como Asunto
20.
NPJ Vaccines ; 5: 62, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32695479

RESUMEN

[This corrects the article DOI: 10.1038/s41541-020-0199-0.].

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