RESUMEN
Co-opting host cell protein synthesis is a hallmark of many virus infections. In response, certain host defense proteins limit mRNA translation globally, albeit at the cost of the host cell's own protein synthesis. Here, we describe an interferon-stimulated helicase, DDX60, that decreases translation from viral internal ribosome entry sites (IRESs). DDX60 acts selectively on type II IRESs of encephalomyocarditis virus (EMCV) and foot and mouth disease virus (FMDV), but not by other IRES types or by 5' cap. Correspondingly, DDX60 reduces EMCV and FMDV (type II IRES) replication, but not that of poliovirus or bovine enterovirus 1 (BEV-1; type I IRES). Furthermore, replacing the IRES of poliovirus with a type II IRES is sufficient for DDX60 to inhibit viral replication. Finally, DDX60 selectively modulates the amount of translating ribosomes on viral and in vitro transcribed type II IRES mRNAs, but not 5' capped mRNA. Our study identifies a novel facet in the repertoire of interferon-stimulated effector genes, the selective downregulation of translation from viral type II IRES elements.
Asunto(s)
Interferones , Sitios Internos de Entrada al RibosomaRESUMEN
Induction of vast transcriptional programs is a central event of innate host responses to viral infections. Here we report a transcriptional program with potent antiviral activity, driven by E74-like ETS transcription factor 1 (ELF1). Using microscopy to quantify viral infection over time, we found that ELF1 inhibits eight diverse RNA and DNA viruses after multi-cycle replication. Elf1 deficiency results in enhanced susceptibility to influenza A virus infections in mice. ELF1 does not feed-forward to induce interferons, and ELF1's antiviral effect is not abolished by the absence of STAT1 or by inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by RNA-seq revealed that the ELF1 transcriptional program is distinct from interferon signatures. Thus, ELF1 provides an additional layer of the innate host response, independent from the action of type I interferons.
Asunto(s)
Antivirales/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Virus de la Influenza A/inmunología , Interferón Tipo I/farmacología , Proteínas Nucleares/metabolismo , Infecciones por Orthomyxoviridae/inmunología , Factores de Transcripción/metabolismo , Replicación Viral/inmunología , Células A549 , Animales , Femenino , Humanos , Inmunidad Innata , Virus de la Influenza A/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , FN-kappa B/metabolismo , Proteínas Nucleares/genética , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/virología , Fosforilación , Factor de Transcripción STAT1 , Transducción de Señal , Factores de Transcripción/genética , Replicación Viral/efectos de los fármacosRESUMEN
Listeriosis has more than a 50% mortality when the central nervous system is involved, necessitating rapid diagnosis and treatment. We present four patients with brain abscesses in the setting of diagnosed neurolisteriosis, all of which demonstrated an odd presentation of multiple small, contiguous tubular lesions with rim enhancement on magnetic resonance imaging. Our review of published cases of neurolisteriosis suggests that this may be a useful pattern to identify neurolisteriosis abscesses, allowing earlier detection and therapy.