ABSTRACT
Filoviruses, amongst the most lethal of primate pathogens, have only been reported as natural infections in sub-Saharan Africa and the Philippines. Infections of bats with the ebolaviruses and marburgviruses do not appear to be associated with disease. Here we report identification in dead insectivorous bats of a genetically distinct filovirus, provisionally named Lloviu virus, after the site of detection, Cueva del Lloviu, in Spain.
Subject(s)
Chiroptera/virology , Disease Reservoirs , Ebolavirus/isolation & purification , Hemorrhagic Fever, Ebola/veterinary , Animals , Base Sequence , DNA, Viral/analysis , Disease Outbreaks , Ebolavirus/genetics , Genome , Hemorrhagic Fever, Ebola/pathology , Hemorrhagic Fever, Ebola/virology , Lung/pathology , Lung/virology , Molecular Sequence Data , Phylogeny , Spain , Spleen/pathology , Spleen/virologyABSTRACT
RATIONALE: Glutamate is a major signaling molecule that binds to glutamate receptors including the ionotropic glutamate receptors; kainate (KA) receptor (KAR), the N-methyl-d-aspartate receptor, and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Each is well characterized in the central nervous system, but glutamate has important signaling roles in peripheral tissues as well, including a role in regulating platelet function. OBJECTIVE: Our previous work has demonstrated that glutamate is released by platelets in high concentrations within a developing thrombus and increases platelet activation and thrombosis. We now show that platelets express a functional KAR that drives increased agonist induced platelet activation. METHODS AND RESULTS: KAR induced increase in platelet activation is in part the result of activation of platelet cyclooxygenase in a mitogen-activated protein kinase-dependent manner. Platelets derived from KAR subunit knockout mice (GluR6(-/-)) are resistant to KA effects and have a prolonged time to thrombosis in vivo. Importantly, we have also identified polymorphisms in KAR subunits that are associated with phenotypic changes in platelet function in a large group of whites and blacks. CONCLUSIONS: Our data demonstrate that glutamate regulation of platelet activation is in part cyclooxygenase-dependent and suggest that the KAR is a novel antithrombotic target.
Subject(s)
Blood Platelets/metabolism , Platelet Activation , Prostaglandin-Endoperoxide Synthases/metabolism , Receptors, Kainic Acid/metabolism , Thrombosis/metabolism , Animals , Excitatory Amino Acid Agonists/pharmacology , Humans , Kainic Acid/pharmacology , Mice , Mice, Knockout , Prostaglandin-Endoperoxide Synthases/genetics , Receptors, Kainic Acid/genetics , Thrombosis/genetics , GluK2 Kainate ReceptorABSTRACT
El objetivo de la investigación fue identificar en pacientes con diagnóstico presuntivo de MELAS la mutación A3243G, tradicionalmente asociada con ella. Se secuenciaron los fragmentos 533 pb del genoma mitocondrial correspondiente al tRNA-Leu y parte del gen NDI (posiciones 3162 a 3695) en 29 pacientes con diagnóstico presuntivo de MELAS y en cuatro personas sanas. Todos los pacientes fueron negativos para la mutación A3243G, tampoco se hallaron otras mutaciones descritas en MELAS. Se halló una transición (A3547G) en el gen NDI, hasta ahora no informada en la literatura, en 14 de las muestras secuenciadas. Esta transición, identificada en pacientes y controles, cambia el codón ATC(i) por GTC(V). Al realizar el genotipo del mtDNA de la PCR, se encontró que de las 14 muestras con G en la posición 3547 de NDI, 13 expresaban el haplotipo B. Teniendo en cuenta que la transición detectada se presentó tanto en pacientes como en controles y que I y V son aminoácidos de estructura química semejante, hidrofóbicos, que se localizan en un motivo altamente hidrofóbico de la proteína (LALTIALLL), es posible concluír que este cambio consiste en un polimorfismo. La presencia del Haplotipo B, propia de la población amerindia, indica la alta frecuencia de mitocondria de origen antioqueño. La transición 3547G podría ser un marcador de la población indoamericana con la cual se mezclaron los españoles para constituír la población antioqueña
