RESUMEN
A rich body of theory on the evolution of virulence (disease severity) attempts to predict the conditions that cause parasites to harm their hosts, and a central assumption to many of these models is that the relative virulence of pathogen strains is stable across a range of host types. In contrast, a largely nonoverlapping body of theory on coevolution assumes that the fitness effects of parasites on hosts is not stable across host genotype, but instead depends on host genotype by parasite genotype interactions. If such genetic interactions largely determine virulence, it becomes difficult to predict the strength and direction of selection on virulence. In this study, we tested for host-by-parasite interactions in a medically relevant vertebrate disease model: the rodent malaria parasite Plasmodium chabaudi in laboratory mice. We found that parasite and particularly host main effects explained most of the variance in virulence (anaemia and weight loss), resistance (parasite burden) and transmission potential. Host-by-parasite interactions were of limited influence, but nevertheless had significant effects. This raises the possibility that host heterogeneity may affect the rate of any parasite response to selection on virulence. This study of rodent malaria is one of the first tests for host-by-parasite interactions in any vertebrate disease; host-by-parasite interactions typical of those assumed in coevolutionary models were present, but were by no means pervasive.
Asunto(s)
Evolución Biológica , Interacciones Huésped-Parásitos/genética , Malaria/parasitología , Plasmodium chabaudi/patogenicidad , Animales , Modelos Animales de Enfermedad , Femenino , Genotipo , Interacciones Huésped-Parásitos/inmunología , Inmunidad Innata/genética , Malaria/genética , Malaria/inmunología , Ratones , Ratones Endogámicos , Plasmodium chabaudi/genética , Plasmodium chabaudi/fisiología , VirulenciaRESUMEN
Multidrug resistance-associated protein (MRP) causes multidrug resistance (MDR) involving the anthracyclines and epipodophyllotoxins. Many studies show modulation of anthracycline levels and cytotoxicity in MRP-overexpressing cells, but there is limited data on the modulation of etoposide levels and cytotoxicity in MRP-overexpressing or in P-glycoprotein-expressing cells. Etoposide accumulation was 50% reduced in both the CEM/E1000 MRP-overexpressing subline and the CEM/VLB100 P-glycoprotein-expressing subline compared to the parental CEM cells, correlating with similar resistance to etoposide (200-fold) of the two sublines. For the CEM/VLB100 subline, the P-glycoprotein inhibitor SDZ PSC 833, but not verapamil, was able to increase etoposide accumulation and cytotoxicity. For the CEM/E1000 subline, neither SDZ PSC 833 nor verapamil had any effect on etoposide accumulation. However, verapamil caused a 4-fold sensitization to etoposide in this subline, along with an 80% decrease in cellular glutathione (P < 0.05). Buthionine sulfoximine (BSO), which depletes glutathione, also caused a 2.5-fold sensitization to etoposide with no effect on accumulation in the CEM/E1000 subline. In contrast, SDZ PSC 833 was able to increase daunorubicin accumulation in the CEM/E1000 subline (P < 0.05), but had no effect on daunorubicin cytotoxicity, or cellular glutathione. These results show that modulation of etoposide cytotoxicity in MRP-overexpressing cells may be through changes in glutathione metabolism rather than changes in accumulation and confirm that changes in drug accumulation are not related to drug resistance in MRP-overexpressing cells.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Glutatión/metabolismo , Transportadoras de Casetes de Unión a ATP/biosíntesis , Antineoplásicos/farmacología , Butionina Sulfoximina/farmacología , División Celular/efectos de los fármacos , Daunorrubicina/farmacología , Resistencia a Múltiples Medicamentos/genética , Resistencia a Múltiples Medicamentos/fisiología , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/fisiología , Etopósido/farmacología , Regulación Neoplásica de la Expresión Génica , Genes MDR , Humanos , Leucemia , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Células Tumorales CultivadasRESUMEN
A rare case of a patient with Laurence-Moon-Biedl syndrome associated with hypothalamic hamartoma is described. The English-language literature contains no cases of patients with this association. The clinical manifestations of this syndrome, those of hypothalamic hamartomas, and the appearance of the tumors on magnetic resonance images are discussed.