Análise da influência dos inibidores farmacológicos das vias celulares de MEK/ERK, JNK e PI3K/AKT no ciclo de replicação do vírus da febre amarela

Abstract

During the process of co-evolution with their hosts, the viruses acquired the capacity of intercept, mimic and usurp several cellular signaling pathways in a way to generate favorable conditions to the replication and dissemination. The flaviviruses are enveloped, with spherical form, and approximately 50 nm in size. Their capsid has icosahedral symmetry and their genetic material is composed by a molecule of single stranded, positive sense RNA. Inside this group we found the Yellow fever virus (YFV), an arbovirus causer of the disease that has the same name and is disseminated in the tropical regions of Africa and South America creating an zone of risk to approximate ly 900 million people and, in the past having being able to spread throughout several other regions in the world. In spite of the advances in the medicine, there is not an specific treatment to infected humans, and the maintenance of this virus in sylvatic cycles associated with intermittent campaigns of combat to the vector in the urban areas leads to the periodic outbreaks of his disease that can leads to death. The objective of this work is to effectuate analysis of the utilization of cellular pathways MEK/ERK, JNK and PI3K/AKT related to events of growth, survival, cellular differentiation, evasion of apoptosis and migration by this virus. The study demonstrated that the JNK and PI3K/AKT pathways, when inhibited by their specific pharmacological inhibitors, do not affect in a negative way the YFV multiplication in Vero cells and that the inhibition of PI3K/AKT leads to an subtle augment in the multiplication. On the other hand, the inhibition of the MEK/ERK pathway, by its inhibitor UO126, affected significantly the capacity of multiplication of the virus. Later, analyses of kinetic of activation of the last pathway, associated to analysis of scanning electron microscopy and visualization of the process of viral morphogenesis, leaded to the conclusio n that the period of replication of the genetic material is one of the critical period being strongly affected. This was concluded by the absence or the malformation of the viral replication complexes. In conclusion, the data encountered points that the ME K/ERK pathway not only is activated by the YFV, but this activation also leads to an accentuated diminution in the capacity of the replication of the virus.