ABSTRACT
Heartland virus (HRTV) is an emerging tick-borne bandavirus that causes a febrile illness of varying severity in humans, with cases reported in eastern and midwestern regions of the United States. No vaccines or approved therapies are available to prevent or treat HRTV disease. Here, we describe the genetic changes, natural history of disease, and pathogenesis of a mouse-adapted HRTV (MA-HRTV) that is uniformly lethal in 7- to 8-week-old AG129 mice at low challenge doses. We used this model to assess the efficacy of the ribonucleoside analog, 4'-fluorouridine (EIDD-2749), and showed that once-daily oral treatment with 3 mg/kg of drug, initiated after the onset of disease, protects mice against lethal MA-HRTV challenge and reduces viral loads in blood and tissues. Our findings provide insights into HRTV virulence and pathogenesis and support further development of EIDD-2749 as a therapeutic intervention for HRTV disease. IMPORTANCE: More than 60 cases of HRTV disease spanning 14 states have been reported to the United States Centers for Disease Control and Prevention. The expanding range of the Lone Star tick that transmits HRTV, the growing population of at-risk persons living in geographic areas where the tick is abundant, and the lack of antiviral treatments or vaccines raise significant public health concerns. Here, we report the development of a new small-animal model of lethal HRTV disease to gain insight into HRTV pathogenesis and the application of this model for the preclinical development of a promising new antiviral drug candidate, EIDD-2749. Our findings shed light on how the virus causes disease and support the continued development of EIDD-2749 as a therapeutic for severe cases of HRTV infection.
Subject(s)
Bunyaviridae Infections , Bunyaviridae , Uracil Nucleotides , Animals , Humans , Mice , Bunyaviridae Infections/drug therapy , Ticks , United States , Uracil Nucleotides/therapeutic useABSTRACT
Con el objeto de caracterizar el gen de la beta-lactoglobulina (BLG) en la raza Criollo Limonero, se utilizó la técnica PCR-RFLP en 163 animales puros de la estación local Carrasquero (Carrasquero-estado Zulia), los genotipos fueron determinados a través de electroforesis en geles de agarosa. Las frecuencias obtenidas del locus de la BLG fueron A (0,22) y B (0,78) y las frecuencias genotípicas fueron AA (0,07 ); AB (0,29) y BB (0,64), la población estudiada se encuentra en equilibrio de Hardy-Weinberg (P<0,05), los resultados indican que la frecuencia alélica del alelo B fue más alta que la de A, siendo esto importante, ya que se han determinado los efectos de esta variante alélica de la BLG sobre la cantidad de grasa y proteínas en la leche, la selección a favor del alelo B en la población conllevará a una mejora en la calidad y rendimiento en la producción de queso, estos resultados representan un valioso aporte al conocimiento de esta raza y de su importancia, ya que, representa una alternativa para sistemas dirigidos a la producción de queso.
In order to characterize the beta-lactoglobulina gene (BLG) in the Limonero Creole cattle through PCR-RFLP technique, 163 purebreed animals were used from the Carrasquero local station (Carrasquero-Zulia State), genotypes were determined through gel electroforesis in agarosa. Gene and genotypic frequencies obtained were A (0.22) and B (0.78) and AA (0.07), AB (0.24) and BB (0.64) respectively, the population is in equilibrium of Hardy-Weinberg with (P<0.05), the results indicate that the alelic frequency of was more high B but that A, being this important one, since the effects of the variants of the BLG on the amount of fat and proteins in milk have been determined, the selection in favor of allele B in the population will entail to an improvement in the quality and yield in the cheese production, these results represent a valuable contribution the knowledge of this race and its importance, since, represents an alternative for systems directed to the cheese production.
ABSTRACT
Con el objeto de estudiar el polimorfismo del gen CSN3 en la raza bovina Criollo Limonero, se extrajeron muestras séricas de 163 individuos (machos y hembras), los cuales fueron caracterizados mediante la técnica PCR-RFLP. Los resultados obtenidos indican que las frecuencias encontradas correspondieron a 0,11; 0,56 y 0,33 para los AA, AB y BB, respectivamente, correspondiendo a frecuencias alélicas de 0,39 para el alelo A y 0,61 para el B, respectivamente. Cabe destacar que a partir de esta información de la CSN3 y su relación con caracteres, tales como la producción de leche y rendimiento quesero, se pueden llevar a cabo planes de mejoramiento asistido por marcadores, garantizando el mantenimiento de la variabilidad genética de estas poblaciones locales que se caracterizan por censos reducidos y la amenaza constante por cruzamientos con razas mejoradoras o comerciales, que buscan incrementar el volumen de producción de leche en detrimento de la calidad del producto; así mismo, se indica la ventaja potencial que presenta la leche del ganado Criollo Limonero en la producción de quesos, por mostrar mayoritariamente alelos del tipo B de la CSN3.
In order to assess the polymorphism of CSN3 gen in Limonero Creole breed, blood samples were collected from 163 male and female individuals, with which characterization through RFLP-PCR was conducted. Results showed that genotypic frequencies were 0.11, 0.56 and 0.33 for AA, AB and BB, respectively. Allelic frequencies were 0.39 and 0.61 for allele A and B, accordingly. It is important to mention that with this information of CSN3 and its relationship with some traits such as milk production and cheese productivity, markers-assisted genetic improvement plans can be undertaken, which would maintain genetic variability of these local populations characterized by small numbers of animals and by the constant threat of crossbreeding with improved or commercial breeds, with the objective of increasing milk production over product quality; moreover, a potential advantage of Limonero Creole breed in milk production by its having mainly B-type alleles in CSN3 is shown.
