Alphaviruses represent a highly important group of human and animal pathogens,

Alphaviruses represent a highly important group of human and animal pathogens, which are transmitted by mosquito vectors between vertebrate hosts. the spectrum of WAY-100635 WAY-100635 genes activated during noncytopathic virus clearance. By applying microarray-based technology and bioinformatic analysis, we identified a number of IFN-stimulated genes (ISGs) specifically activated during VEEV clearance. One of these gene products, the long isoform of PARP12 (PARP12L), exhibited an inhibitory effect on the replication of VEEV, as well as other alphaviruses and several different types of other RNA viruses. Additionally, overexpression of two other members of the PARP gene superfamily was also shown to be capable of inhibiting VEEV replication. INTRODUCTION The genus is usually a group of arthropod-borne viruses in the family, many of which are important human and animal pathogens (54). In nature, these viruses are transmitted by mosquito vectors between vertebrate hosts (45). While mosquitoes remain mostly unaffected by alphavirus Rabbit Polyclonal to B-RAF. contamination, vertebrates develop diseases of various severities. The hallmark of alphavirus replication in vertebrates is an induction of a high-titer viremia, which is required for further transmission of contamination to feeding mosquitoes, thus perpetuating the cycle (24, 54). Alphaviruses are capable of reaching high titers due to highly efficient viral RNA replication and rapid production of viral nonstructural and structural proteins. However, the development of viremia is also strongly dependent on the virus’ ability to interfere with the development of antiviral responses at the cellular level and in the organism as a whole (52, 53). Similar to the case for many other viruses, alphaviruses have developed a complex system of countermeasures, which promote their replication in the presence of cellular molecular pattern recognition receptors (PRRs) (17C19). These viruses downregulate induction of the antiviral response and/or become at least partially resistant to its activation. The ability of the alphaviruses to interact with host responses is usually a multicomponent process, with some of the constituents being specific to each member WAY-100635 of the genus. However, some mechanisms appear to be common for several different members of the genus. First, all characterized alphaviruses isolate their double-stranded RNA (dsRNA) replication intermediates from the cytoplasm into plasma and endosome membrane invaginations (spherules), in order to prevent these dsRNA molecules from being efficiently recognized by such known PRRs as RIG-I, MDA5, and protein kinase R (PKR) or Toll-like receptor 3 (TLR3) (14, 15, 23). These membrane spherules are connected to the cytosol by very narrow openings, which are associated with viral nsPs. The dsRNAs are sufficiently isolated to prevent their recognition by dsRNA-specific antibodies unless the spherule membrane is usually permeabilized by nonionic detergents (14). However, such dsRNA compartmentalization is likely to be incomplete, because cells release cytokines in response to replication of alphavirus mutants that are incapable of inhibiting cellular transcription (5, 13, 21). Second, in cells of vertebrate origin, alphavirus replication induces transcriptional and translational shutoff (10, 20, 22). Previously, it was thought that inhibition of translation downregulates virus replication and represents a mechanism of host defense. However, an accumulating amount of data demonstrates that, at least in the case of Sindbis virus (SINV) and Semliki Forest virus (SFV), translational shutoff not only is mostly impartial of PKR (22, 50) but also is highly beneficial for translation of viral structural proteins (11, 12, 44). These viruses have developed translational enhancers in the 5 termini of their subgenomic RNAs (G-C-rich RNA sequences folded into stem-loops), which function only during virus-induced translational shutoff. The presence of these enhancers strongly increases expression of structural proteins by modified cellular translational machinery. Inhibition of cellular transcription has been unambiguously exhibited in cells of vertebrate origin infected by evolutionarily distinct alphaviruses, such as SINV, Venezuelan equine encephalitis virus (VEEV), and eastern equine encephalitis virus (EEEV) (2C4, 18). Each of these viruses uses different virus-specific proteins to achieve the same goal: to downregulate activation of antiviral genes. Cellular transcription inhibition is an efficient means of promoting virus replication but has some limitations. Both the SINV-specific nsP2 and the VEEV- and EEEV-specific capsid proteins, which demonstrate transcription-inhibitory activities, function in stoichiometric rather than catalytic, protease-dependent modes. This is likely to make them less efficient inhibitors during virus replication in less permissive cells, in which viral structural and nonstructural proteins.

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