RESUMEN
BACKGROUND: Parasite evolution is hypothesized to select for levels of parasite virulence that maximise transmission success. When host population densities fluctuate, low levels of virulence with limited impact on the host are expected, as this should increase the likelihood of surviving periods of low host density. We examined the effects of Morogoro arenavirus on the survival and recapture probability of multimammate mice (Mastomys natalensis) using a seven-year capture-mark-recapture time series. Mastomys natalensis is the natural host of Morogoro virus and is known for its strong seasonal density fluctuations. RESULTS: Antibody presence was negatively correlated with survival probability (effect size: 5-8% per month depending on season) but positively with recapture probability (effect size: 8%). CONCLUSIONS: The small negative correlation between host survival probability and antibody presence suggests that either the virus has a negative effect on host condition, or that hosts with lower survival probability are more likely to obtain Morogoro virus infection, for example due to particular behavioural or immunological traits. The latter hypothesis is supported by the positive correlation between antibody status and recapture probability which suggests that risky behaviour might increase the probability of becoming infected.
Asunto(s)
Infecciones por Arenaviridae/veterinaria , Arenavirus/aislamiento & purificación , Murinae , Enfermedades de los Roedores/mortalidad , Animales , Anticuerpos Antivirales/sangre , Infecciones por Arenaviridae/mortalidad , Arenavirus/inmunología , Conducta Animal , Enfermedades de los Roedores/virología , Análisis de SupervivenciaRESUMEN
Several arenaviruses are responsible for causing viral hemorrhagic fevers (VHF) in humans. Lassa virus (LASV), the causative agent of Lassa fever, is a biosafety level 4 (BSL4) pathogen that requires handling in BSL4 facilities. In contrast, the Pichinde arenavirus (PICV) is a BSL2 pathogen that can cause hemorrhagic fever-like symptoms in guinea pigs that resemble those observed in human Lassa fever. Comparative sequence analysis of the avirulent P2 strain of PICV and the virulent P18 strain shows a high degree of sequence homology in the bisegmented genome between the two strains despite the polarized clinical outcomes noted for the infected animals. Using reverse genetics systems that we have recently developed, we have mapped the sequence changes in the large (L) segment of the PICV genome that are responsible for the heightened virulence phenotype of the P18 strain. By monitoring the degree of disease severity and lethality caused by the different mutant viruses, we have identified specific residues located within the viral L polymerase gene encoded on the L segment essential for mediating disease pathogenesis. Through quantitative reverse transcription-PCR (RT-PCR) analysis, we have confirmed that the same set of residues is responsible for the increased viral replicative potential of the P18 strain and its heightened disease severity in vivo. Our laboratory findings serve to reinforce field observations that a high level of viremia often correlates with severe disease outcomes in LASV-infected patients.
Asunto(s)
Infecciones por Arenaviridae/patología , ARN Polimerasas Dirigidas por ADN/genética , Genómica , Virus Pichinde/clasificación , Virus Pichinde/patogenicidad , Animales , Infecciones por Arenaviridae/mortalidad , Infecciones por Arenaviridae/virología , Chlorocebus aethiops , ARN Polimerasas Dirigidas por ADN/química , Cobayas , Humanos , Hígado/patología , Masculino , Virus Pichinde/genética , Mutación Puntual , ARN Viral/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Vero , Proteínas Virales/química , Proteínas Virales/genética , Virulencia/genética , Replicación ViralRESUMEN
Tacaribe virus (TCRV) was first isolated from 11 Artibeus species bats captured in Trinidad in the 1950s during a rabies virus surveillance program. Despite significant effort, no evidence of infection of other mammals, mostly rodents, was found, suggesting that no other vertebrates harbored TCRV. For this reason, it was hypothesized that TCRV was naturally hosted by artibeus bats. This is in stark contrast to other arenaviruses with known hosts, all of which are rodents. To examine this hypothesis, we conducted experimental infections of Jamaican fruit bats (Artibeus jamaicensis) to determine whether they could be persistently infected without substantial pathology. We subcutaneously or intranasally infected bats with TCRV strain TRVL-11573, the only remaining strain of TCRV, and found that low-dose (10(4) 50% tissue culture infective dose [TCID(50)]) inoculations resulted in asymptomatic and apathogenic infection and virus clearance, while high-dose (10(6) TCID(50)) inoculations caused substantial morbidity and mortality as early as 10 days postinfection. Uninoculated cage mates failed to seroconvert, and viral RNA was not detected in their tissues, suggesting that transmission did not occur. Together, these data suggest that A. jamaicensis bats may not be a reservoir host for TCRV.
Asunto(s)
Infecciones por Arenaviridae/veterinaria , Arenaviridae/patogenicidad , Quirópteros/virología , Reservorios de Enfermedades/virología , Animales , Arenaviridae/genética , Arenaviridae/aislamiento & purificación , Arenaviridae/fisiología , Infecciones por Arenaviridae/mortalidad , Infecciones por Arenaviridae/patología , Infecciones por Arenaviridae/virología , Quirópteros/crecimiento & desarrollo , Femenino , Masculino , Trinidad y Tobago , VirulenciaRESUMEN
Junin virus (JUNV) is the aetiological agent of Argentine haemorrhagic fever. The pathogenesis of the infection is not well understood, no licensed vaccines exist and no specific antiviral therapy is available. Previous studies have demonstrated the ability of ribavirin to delay and reduce JUNV disease and virus burden in guinea pigs without preventing death. Based on available data, we performed three different studies to determine the efficacy of ribavirin against JUNV in the guinea pig model with a focus on survival. Different doses and treatment schedules of ribavirin were tested in a lethal model of JUNV infection. Our results show that prolonged treatment with high doses of ribavirin significantly reduces the mortality in guinea pigs infected with JUNV. These results may be useful in future experimental studies or clinical testing.
Asunto(s)
Antivirales/uso terapéutico , Infecciones por Arenaviridae/tratamiento farmacológico , Virus Junin/efectos de los fármacos , Ribavirina/uso terapéutico , Animales , Infecciones por Arenaviridae/diagnóstico , Infecciones por Arenaviridae/mortalidad , Infecciones por Arenaviridae/virología , Chlorocebus aethiops , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Cobayas , Virus Junin/aislamiento & purificación , Estimación de Kaplan-Meier , Profilaxis Posexposición , Células VeroRESUMEN
The Arenaviridae are a diverse and globally distributed collection of viruses that are maintained primarily by rodent reservoirs. Junin virus (JUNV) and Lassa virus (LASV) can both cause significant outbreaks of severe and often fatal human disease throughout their respective areas of endemicity. In an effort to improve upon the existing live attenuated JUNV Candid1 vaccine, we generated a genetically homogenous stock of this virus from cDNA copies of the virus S and L segments by using a reverse genetics system. Further, these cDNAs were used in combination with LASV cDNAs to successfully generate two recombinant Candid1 JUNV/LASV chimeric viruses (via envelope glycoprotein [GPC] exchange). It was found that while the GPC extravirion domains were readily exchangeable, homologous stable signal peptide (SSP) and G2 transmembrane and cytoplasmic tail domains were essential for correct GPC maturation and production of infectious chimeric viruses. The switching of the JUNV and LASV G1/G2 ectodomains within the Candid1 vaccine background did not alter the attenuated phenotype of the vaccine strain in a lethal mouse model. These recombinant chimeric viruses shed light on the fundamental requirements of arenavirus GPC maturation and may serve as a strategy for the development of bivalent JUNV and LASV vaccine candidates.
Asunto(s)
Glicoproteínas/genética , Virus Junin/genética , Virus Lassa/genética , Recombinación Genética , Proteínas del Envoltorio Viral/genética , Vacunas Virales , Animales , Infecciones por Arenaviridae/mortalidad , Infecciones por Arenaviridae/prevención & control , Infecciones por Arenaviridae/virología , Chlorocebus aethiops , Glicoproteínas/química , Glicoproteínas/metabolismo , Humanos , Virus Junin/metabolismo , Virus Junin/patogenicidad , Virus Lassa/metabolismo , Virus Lassa/patogenicidad , Ratones , Señales de Clasificación de Proteína/genética , Señales de Clasificación de Proteína/fisiología , Estructura Terciaria de Proteína/genética , Estructura Terciaria de Proteína/fisiología , Células Vero , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/metabolismo , Vacunas Virales/administración & dosificación , Vacunas Virales/genéticaRESUMEN
BACKGROUND: A growing number of arenaviruses can cause a devastating viral hemorrhagic fever (VHF) syndrome. They pose a public health threat as emerging viruses and because of their potential use as bioterror agents. All of the highly pathogenic New World arenaviruses (NWA) phylogenetically segregate into clade B and require maximum biosafety containment facilities for their study. Tacaribe virus (TCRV) is a nonpathogenic member of clade B that is closely related to the VHF arenaviruses at the amino acid level. Despite this relatedness, TCRV lacks the ability to antagonize the host interferon (IFN) response, which likely contributes to its inability to cause disease in animals other than newborn mice. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe a new mouse model based on TCRV challenge of AG129 IFN-α/ß and -γ receptor-deficient mice. Titration of the virus by intraperitoneal (i.p.) challenge of AG129 mice resulted in an LD(50) of â¼100 fifty percent cell culture infectious doses. Virus replication was evident in the serum, liver, lung, spleen, and brain 4-8 days after inoculation. MY-24, an aristeromycin derivative active against TCRV in cell culture at 0.9 µM, administered i.p. once daily for 7 days, offered highly significant (P<0.001) protection against mortality in the AG129 mouse TCRV infection model, without appreciably reducing viral burden. In contrast, in a hamster model of arenaviral hemorrhagic fever based on challenge with clade A Pichinde arenavirus, MY-24 did not offer significant protection against mortality. CONCLUSIONS/SIGNIFICANCE: MY-24 is believed to act as an inhibitor of S-adenosyl-L-homocysteine hydrolase, but our findings suggest that it may ameliorate disease by blunting the effects of the host response that play a role in disease pathogenesis. The new AG129 mouse TCRV infection model provides a safe and cost-effective means to conduct early-stage pre-clinical evaluations of candidate antiviral therapies that target clade B arenaviruses.
Asunto(s)
Adenosina/análogos & derivados , Antivirales/administración & dosificación , Infecciones por Arenaviridae/tratamiento farmacológico , Arenavirus del Nuevo Mundo/fisiología , Modelos Animales de Enfermedad , Ratones , Adenosina/administración & dosificación , Adenosina/química , Animales , Antivirales/química , Infecciones por Arenaviridae/mortalidad , Infecciones por Arenaviridae/virología , Arenavirus del Nuevo Mundo/efectos de los fármacos , Chlorocebus aethiops , Cricetinae , Femenino , Humanos , Masculino , Mesocricetus , Ratones Noqueados , Células Vero , Replicación ViralRESUMEN
Lujo virus (LUJV), a new member of the family Arenaviridae and the first hemorrhagic fever-associated arenavirus from the Old World discovered in three decades, was isolated in South Africa during an outbreak of human disease characterized by nosocomial transmission and an unprecedented high case fatality rate of 80% (4/5 cases). Unbiased pyrosequencing of RNA extracts from serum and tissues of outbreak victims enabled identification and detailed phylogenetic characterization within 72 hours of sample receipt. Full genome analyses of LUJV showed it to be unique and branching off the ancestral node of the Old World arenaviruses. The virus G1 glycoprotein sequence was highly diverse and almost equidistant from that of other Old World and New World arenaviruses, consistent with a potential distinctive receptor tropism. LUJV is a novel, genetically distinct, highly pathogenic arenavirus.
Asunto(s)
Arenavirus del Viejo Mundo/genética , Arenavirus del Viejo Mundo/aislamiento & purificación , Especiación Genética , África Austral/epidemiología , Infecciones por Arenaviridae/mortalidad , Infecciones por Arenaviridae/transmisión , Infecciones por Arenaviridae/virología , Secuencia de Bases , Infección Hospitalaria , Genoma Viral , Humanos , Filogenia , ARN Viral/genética , Proteínas ViralesRESUMEN
On 12 September 2008, a tourist guide organising safari trips, residing in Lusaka, Zambia, was evacuated in a critical condition to Johannesburg, South Africa. She was admitted to a clinic where she died on 14 September about 10 days after the onset of symptoms. The symptoms included a prodromal phase with fever, myalgia, vomiting, diarrhoea, followed by rash, liver dysfunction and convulsions [1]. Cerebral oedema was detected on scan examination. No laboratory specimen was available for investigation.
Asunto(s)
Infecciones por Arenaviridae/diagnóstico , Infecciones por Arenaviridae/mortalidad , Infecciones por Arenaviridae/fisiopatología , Infecciones por Arenaviridae/transmisión , Femenino , Humanos , Masculino , Sudáfrica/epidemiologíaAsunto(s)
Ambulancias Aéreas , Infecciones por Arenaviridae/mortalidad , Infecciones por Arenaviridae/transmisión , Arenavirus , Causas de Muerte/tendencias , Brotes de Enfermedades/estadística & datos numéricos , Humanos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/estadística & datos numéricos , Sudáfrica/epidemiologíaRESUMEN
Several arenaviruses endemic to South America (Junin, Machupo, and Guanarito) and Africa (Lassa) are known to cause frequently fatal haemorrhagic fever. With the exception of ribavirin, which has demonstrated efficacy in cases of Lassa fever, there is no other effective therapeutic for the treatment of arenaviral haemorrhagic fever. We have recently reported that consensus interferon-a (IFN alfacon-1) can protect hamsters from lethal Pichinde virus (PCV) infection, which serves as a model for acute arenaviral disease in humans. Here we demonstrate highly effective therapy through the combined use of ribavirin with IFN alfacon-1 for the treatment of PCV infection in hamsters. Ribavirin was given orally, twice per day for 7 days, and IFN alfacon-1 was administered intraperitoneally once per day for 10 days. Treatments were initiated 1-5 days post-virus challenge using various dose combinations, many of which were less than optimal when the drugs were given independently. Combining suboptimal doses of ribavirin (5-10 mg/kg/day) with IFN alfacon-1 (5-10 microg/kg/day), we were able to demonstrate increased protection from mortality, reduced viral burden and liver disease, and greatly extended survival times as compared to treatments where drugs were administered alone. Our data indicate that combination therapy results in synergistic activity that may slow down the progression of the disease and decrease fatality rates associated with severe arenaviral infections in humans. Further, combination therapy reduces the effective dosage of ribavirin, which would serve to limit its toxicity.
Asunto(s)
Infecciones por Arenaviridae/tratamiento farmacológico , Interferón Tipo I/uso terapéutico , Ribavirina/uso terapéutico , Enfermedad Aguda/mortalidad , Administración Oral , Animales , Antivirales/uso terapéutico , Infecciones por Arenaviridae/mortalidad , Cricetinae , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Interferón Tipo I/administración & dosificación , Interferón-alfa , Placebos , Proteínas Recombinantes , Ribavirina/administración & dosificación , Análisis de Supervivencia , Factores de TiempoRESUMEN
The clinical laboratory, virologic, and pathologic changes occurring in hamsters after infection with Pirital virus (Arenaviridae) are described. Pirital virus infection in the hamsters was characterized by high titered viremia, leukocytosis, coagulopathy, pulmonary hemorrhage and edema, hepatocellular and splenic necrosis, and marked elevation of serum transaminase levels. All of the animals died within 9 days. The clinical and histopathological findings in the Pirital virus-infected hamsters were very similar to those reported in severe human cases of Lassa fever, suggesting that this new animal model could serve as a low-cost and relatively safe alternative for studying the pathogenesis and therapy of Lassa fever.
Asunto(s)
Infecciones por Arenaviridae/patología , Infecciones por Arenaviridae/virología , Arenavirus del Nuevo Mundo/patogenicidad , Modelos Animales de Enfermedad , Mesocricetus , Animales , Infecciones por Arenaviridae/sangre , Infecciones por Arenaviridae/mortalidad , Análisis Químico de la Sangre/métodos , Cricetinae , Femenino , Pruebas Hematológicas/métodos , Humanos , Inmunohistoquímica/métodos , Fiebre de Lassa/sangre , Fiebre de Lassa/mortalidad , Fiebre de Lassa/patología , Fiebre de Lassa/virología , Hígado/patología , Pulmón/patología , Microscopía Electrónica de Transmisión/métodos , Bazo/patología , Viremia/sangre , Viremia/virologíaRESUMEN
The expression of ubiquitin-like modifier ISG15 and its conjugation to target proteins are highly induced by interferon (IFN) stimulation and during viral and bacterial infections. However, the biological significance of this modification has not been clearly understood. To investigate the function of protein modification by ISG15, we generated a mouse model deficient in UBE1L, an ISG15-activating enzyme. Ube1L-/- mice did not produce ISG15 conjugates but expressed free ISG15 normally. ISGylation has been implicated in the reproduction and innate immunity. However, Ube1L-/- mice were fertile and exhibited normal antiviral responses against vesicular stomatitis virus and lymphocytic choriomeningitis virus infection. Our results indicate that UBE1L and protein ISGylation are not critical for IFN-alpha/beta signaling via JAK/STAT activation. Moreover, using Ube1L/Ubp43 double-deficient mice, we showed that lack of UBP43, but not the increase of protein ISGylation, is related to the increased IFN signaling in Ubp43-deficient mice.
Asunto(s)
Citocinas/metabolismo , Endopeptidasas/metabolismo , Interferón-alfa/fisiología , Interferón beta/fisiología , Enzimas Activadoras de Ubiquitina/metabolismo , Animales , Apoptosis , Infecciones por Arenaviridae/inmunología , Infecciones por Arenaviridae/metabolismo , Infecciones por Arenaviridae/mortalidad , Células Cultivadas , Citocinas/genética , Endopeptidasas/genética , Virus de la Coriomeningitis Linfocítica , Ratones , Ratones Noqueados , Mutación , Infecciones por Rhabdoviridae/inmunología , Infecciones por Rhabdoviridae/metabolismo , Transducción de Señal , Ubiquitina Tiolesterasa , Enzimas Activadoras de Ubiquitina/genética , Ubiquitinas/genética , Ubiquitinas/metabolismo , Virus de la Estomatitis Vesicular IndianaAsunto(s)
Infecciones por Arenaviridae/mortalidad , Arenavirus/genética , Adolescente , Adulto , Animales , Infecciones por Arenaviridae/complicaciones , Infecciones por Arenaviridae/transmisión , Arenavirus/aislamiento & purificación , California/epidemiología , Femenino , Hemorragia/etiología , Humanos , Fallo Hepático/etiología , Persona de Mediana Edad , ARN Viral/análisis , Síndrome de Dificultad Respiratoria/etiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Roedores/virologíaAsunto(s)
Infecciones por Arenaviridae/transmisión , Arenavirus/patogenicidad , Animales , Infecciones por Arenaviridae/mortalidad , Infecciones por Arenaviridae/virología , California , Femenino , Humanos , Enfermedades de los Roedores/transmisión , Enfermedades de los Roedores/virología , RoedoresRESUMEN
The California Department of Health Services (CDHS) and the University of Texas Medical Branch (UTMB) recently identified evidence of infection with an arenavirus in three patients hospitalized with similar fatal illnesses. This report summarizes the investigation of these cases.
Asunto(s)
Infecciones por Arenaviridae/mortalidad , Arenavirus/genética , Adolescente , Adulto , Animales , Infecciones por Arenaviridae/complicaciones , Infecciones por Arenaviridae/transmisión , Arenavirus/aislamiento & purificación , California/epidemiología , Femenino , Hemorragia/etiología , Humanos , Fallo Hepático/etiología , Persona de Mediana Edad , ARN Viral/análisis , Síndrome de Dificultad Respiratoria/etiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Roedores/virologíaRESUMEN
The clinical signs, hypoglycemia, and mortality of "spiking mortality syndrome" were experimentally reproduced. Seven groups of day-old male primary broiler breeder chicks were orally inoculated with tissue and/or fecal-urate homogenates taken from field broilers with spiking mortality syndrome and from field broilers with enteritis and/or runting-stunting syndrome. All homogenates used as inocula were shown by transmission electron microscopy and negative staining to contain arenavirus-like particles. Inocula produced from field broilers with spiking mortality syndrome contained the highest numbers of the arena-virus-like particles and produced the highest percentage of hypoglycemic chicks 13-15 days postinoculation after a 5-to-9-hour fast. These homogenates also produced the most significant differences in mean plasma growth hormone and insulin-like growth factor-1 levels. The significance of the arenavirus-like particles is unknown but is currently being investigated.
Asunto(s)
Infecciones por Arenaviridae/veterinaria , Arenavirus/aislamiento & purificación , Enteritis/veterinaria , Hipoglucemia/veterinaria , Enfermedades de las Aves de Corral , Reproducción , Animales , Antígenos Virales/análisis , Infecciones por Arenaviridae/epidemiología , Infecciones por Arenaviridae/mortalidad , Arenavirus/ultraestructura , Pollos , Enteritis/epidemiología , Enteritis/mortalidad , Heces/microbiología , Femenino , Georgia/epidemiología , Hipoglucemia/epidemiología , Hipoglucemia/mortalidad , Inmunohistoquímica , Islotes Pancreáticos/patología , Islotes Pancreáticos/ultraestructura , Islotes Pancreáticos/virología , Masculino , Microscopía Electrónica , Células de Purkinje/microbiología , Células de Purkinje/patología , Células de Purkinje/ultraestructura , SíndromeRESUMEN
The lethal events of Pichinide virus infections were studied in large (> 36-week-old), small (4- to 6-week-old), and uninfected strain 13 guinea pigs. Time to death was shorter and the rate of body weight loss greater for large than for small virus-infected guinea pigs. Severely ill large guinea pigs developed a life-threatening, nonlactate metabolic acidemia with an increased anion gap, hypokalemia, and renal failure. Small infected guinea pigs near death demonstrated a modest increase in blood and plasma volume indices and in lung and heart permeability to albumin. This group showed a severe hypoxemia, elevated blood lactate, and bicarbonate ion concentrations with a doubled respiratory rate. These findings are consistent with respiratory failure due to obstruction of small airways. Although virus-infected guinea pig endothelial cells showed a decrease in DNA and protein synthesis, no change in bradykinin-induced intracellular calcium signaling was noted.
Asunto(s)
Infecciones por Arenaviridae/mortalidad , Animales , Infecciones por Arenaviridae/metabolismo , Infecciones por Arenaviridae/patología , Análisis de los Gases de la Sangre , Volumen Sanguíneo , Peso Corporal , Permeabilidad Capilar , Línea Celular , Electrólitos/sangre , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Femenino , Cobayas , Pulmón/metabolismo , Masculino , Miocardio/metabolismo , Transducción de SeñalRESUMEN
The data presented in this paper suggest that the susceptible MHA hamster strain possesses a spleen target cell for Pichinde virus replication which is minimally expressed in the resistant strain. This target cell co-purifies with cells mediating NK activity, raising the possibility that the NK cell itself may be the additional target cell for Pichinde virus replication in the susceptible hamster strain. We hypothesize that early virus replication in the spleens of IP-inoculated hamsters leads to an overwhelming proliferation of virus. In contrast, a footpad inoculation of Pichinde virus retards virus spread into the spleen, and the host's immune response can effectively clear the relatively low amount of virus. In addition, data have been presented that show that a footpad inoculation of Pichinde virus elicits swelling in resistant hamster strains at eight days after infection, but fails to evoke a response in the susceptible MHA hamster strain. The response is controlled by a single autosomal dominant gene, and suggests that the MHA hamster strain has a defective delayed-type hypersensitivity response. The gene responsible for footpad swelling appears to be distinct from the single autosomal dominant gene that controls virus replication in the popliteal lymph nodes of footpad-injected hamsters. The phenotype of survival, then, may be the result of either limited virus replication early in infection, or an effective anti-viral cell-mediated immune response, or both.