Search

RNA viruses are a major human health threat. The life cycles of many highly pathogenic RNA viruses like influenza A virus (IAV) and Lassa virus depends on host mRNA, because viral polymerases cleave 5'-m7G-capped host transcripts to prime viral mRNA synthesis ("cap-snatching"). We hypothesized that start codons within cap-snatched host transcripts could generate chimeric human-viral mRNAs with coding potential. We report the existence of this mechanism of gene origination, which we named "start-snatching." Depending on the reading frame, start-snatching allows the translation of host and viral "untranslated regions" (UTRs) to create N-terminally extended viral proteins or entirely novel polypeptides by genetic overprinting. We show that both types of chimeric proteins are made in IAV-infected cells, generate T cell responses, and contribute to virulence. Our results indicate that during infection with IAV, and likely a multitude of other human, animal and plant viruses, a host-dependent mechanism allows the genesis of hybrid genes.

While the centrality of posttranscriptional modifications to RNA biology has long been acknowledged, the function of the vast majority of modified sites remains to be discovered. Illustrative of this, there is not yet a discrete biological role assigned for one of the most highly conserved modifications, 5-methyluridine at position 54 in tRNAs (m5U54). Here, we uncover contributions of m5U54 to both tRNA maturation and protein synthesis. Our mass spectrometry analyses demonstrate that cells lacking the enzyme that installs m5U in the T-loop (TrmA in Escherichia coli, Trm2 in Saccharomyces cerevisiae) exhibit altered tRNA modification patterns. Furthermore, m5U54-deficient tRNAs are desensitized to small molecules that prevent translocation in vitro. This finding is consistent with our observations that relative to wild-type cells, trm2Δ cell growth and transcriptome-wide gene expression are less perturbed by translocation inhibitors. Together our data suggest a model in which m5U54 acts as an important modulator of tRNA maturation and translocation of the ribosome during protein synthesis. [ABSTRACT FROM AUTHOR]

New approaches to managing infections in cardiac and peripheral vascular surgery are required to reduce costs to patients and healthcare providers. Bacteriophage (phage) therapy is a promising antimicrobial approach that has been recommended for consideration in antibiotic refractory cases. We systematically reviewed the clinical evidence for phage therapy in vascular surgery to support the unlicensed use of phage therapy and inform future research. Three electronic databases were searched for articles that reported primary data about human phage therapy for infections in cardiac or peripheral vascular surgery. Fourteen reports were eligible for inclusion, representing 40 patients, among which an estimated 70.3% of patients (n = 26/37) achieved clinical resolution. A further 10.8% (n = 4/37) of patients showed improvement and 18.9% (n = 7/37) showed no improvement. Six of the twelve reports that commented on the safety of phage therapy did not report adverse effects. No adverse effects documented in the remaining six reports were directly linked to phages but reflected the presence of manufacturing contaminants or release of bacterial debris following bacterial lysis. The reports identified by this review suggest that appropriately purified phages represent a safe and efficacious treatment option for infections in cardiac and peripheral vascular surgery. [ABSTRACT FROM AUTHOR]

The treatment of diabetic foot infections (DFIs) represents a costly and growing challenge to the NHS. DFIs can be difficult to treat for a variety of reasons, including late presentation of advanced infection, and antibiotic tolerance or resistance. Bacteriophage (phage) are ubiquitous viruses that infect and kill bacteria in a species-, sometimes even strain-, specific manner. Phages have been used to treat bacterial infection since 1919, but their use in the geopolitical West ceased in the 1930s due to a variety of factors, including the mass production of antibiotics. The modern antibiotic resistance crisis has driven renewed interest in phage therapy and 2,241 patients with mostly with antibiotic refractory infections have been treated since 2000, 79% of whom improved. This includes at least 310 patients with chronic wound infections, among whom 86.1% achieved clinical resolution or improvement of infection. Reassuringly, the available evidence suggests that phage therapy is safe and without notable side effects. Some phages also possess enzymes capable of degrading the biofilms that afford antibiotic tolerance to bacteria and underpin many chronic infections. Phages also act independent of antibiotic resistance, allowing the treatment of even pan-resistant bacteria, and topical or local application to DFIs means antimicrobial activity is independent of a patient's peripheral perfusion. Presently only an option when antibiotics are not meeting a patient's clinical needs, future integration of phage therapy at all levels of DFI care will radically transform the outlook for DFIs in the UK. Reducing the number of serious infections and amputations will not only benefit patients but will deliver vast savings to the NHS and reduce the amount of antibiotics used, making phage therapy a tangible response to the antibiotic resistance crisis. [ABSTRACT FROM AUTHOR]

On October 4, 2001, we confirmed the first bioterrorism-related anthrax case identified in the United States in a resident of Palm Beach County, Florida. Epidemiologic investigation indicated that exposure occurred [...]