Activation of Human Eosinophils with Nanoparticles: a New Area of Research

International audienceIt is becoming increasingly clear that nanoparticles (NPs) possess many potential applications in both clinical medicine and research. Potential utilization of NPs in nanomedicine for the treatment of respiratory diseases where eosinophils exert pathogenic roles is gaining increasing attention. Even though several NPs were found to possess pro-inflammatory activities in in vivo models based on an increased number of eosinophils in rodent airways, it is not clear how NPs could directly activate eosinophils themselves and how they can alter their biology. In this review, we discuss the most recent data in this new area of research demonstrating that NPs could now be added as new eosinophils modulators. Indeed, activation of eosinophils with NPs could lead to modulation of spontaneous apoptosis, caspase activation, and cytoskeleton breakdown when apoptosis is induced; cytokine production, de novo protein synthesis, cellular adhesion onto a cell substratum, and cell signalling events such as activation of the phosphoinositide 3-kinase/Akt pathway and actin re-localization are involved in NP-induced adhesion. Therefore, future development of therapeutic strategies with NPs aiming at targeting diseases where eosinophils are involved should now consider the capacity of NPs to modulate human eosinophil biology

A mutation in UL24 abolishes expression of the newly identified UL24.5 protein of herpes simplex virus 1, and leads to an increase in pathogenicity in mice

International audienceHerpes simplex virus 1 (HSV-1) infects the host via epithelia and establishes latency in sensory neurons. ul24 is conserved throughout the Herpesviridae family, and the UL24 protein is important for efficient viral replication and pathogenesis. Multiple transcripts are expressed from the ul24 gene. The presence of a transcription initiation site inside the open reading frame of ul24 (ORF UL24) and an ATG start codon in the same open reading frame led us to suspect that another protein was expressed from the ul24 locus. To test our hypothesis, we constructed a recombinant virus that expresses a hemagglutin tag at the C-terminus of UL24. Western blot analysis revealed the expression of an 18 kDa protein that is not a degradation product of the full-length UL24, which we refer to as UL24.5. Ectopically expressed UL24.5 did not induce the dispersal of nucleolar proteins as seen for UL24. In order to characterize the role of UL24.5, we constructed a mutant virus encoding a substitution of the predicted initiation methionine to a valine. This substitution eliminated the expression of the 18 kDa polypeptide. Unlike the UL24-null mutant (UL24X), which exhibits reduced viral yields, the UL24.5-null mutant exhibited the same replication phenotype in cell culture as the parental strain. However, in a murine ocular infection model, we observed an increase in the incidence of neurological disorders with the UL24.5 mutant. Alignment of amino acid sequences for various herpesviruses revealed that the initiation site of UL24.5 is conserved among HSV-1 strains and is present in many herpesviruses.ImportanceWe discovered a new HSV-1 protein, UL24.5, which corresponds to the C-terminal portion of UL24. In contrast to the replication defects observed with HSV-1 strains that do not express full length UL24, the absence of UL24.5 did not affect viral replication in cell culture. Moreover, in mice, the absence of UL24.5 did not affect viral titers in epithelia or trigeminal ganglia during acute infection; however, it was associated with a prolonged persistence of signs of inflammation. Strikingly, the absence of UL24.5 also led to an increase in the incidence of severe neurological impairment compared to results for wild-type control viruses. This increase in pathogenecity is in stark contrast to the reduction in clinical signs associated with the absence of full length UL24. Bioinformatic analyses suggest that UL24.5 is conserved among all human α-herpesviruses and in some non-human α-herpesviruses. Thus, we have identified UL24.5 as a new HSV-1 determinant of pathogenesis