No abstract

Upon entry into stationary phase, bacteria dimerize 70S ribosomes into translationally inactive 100S particles by a process called ribosome hibernation. Previously, we reported that the hibernation-promoting factor (HPF) of Listeria monocytogenes is required for 100S particle formation and facilitates adaptation to a number of stresses. Here, we demonstrate that HPF is required for the high tolerance of stationary-phase cultures to aminoglycosides but not to beta-lactam or quinolone antibiotics. The sensitivity of a ⌬hpf mutant to gentamicin was suppressed by the bacteriostatic antibiotics chloramphenicol and rifampin, which inhibit translation and transcription, respectively. Disruption of the proton motive force by the ionophore carbonyl cyanide m-chlorophenylhydrazone or mutation of genes involved in respiration also suppressed the sensitivity of the ⌬hpf mutant. Accordingly, ⌬hpf mutants had aberrantly high levels of ATP and reducing equivalents during prolonged stationary phase. Analysis of bacterial uptake of fluorescently labeled gentamicin demonstrated that the ⌬hpf mutant harbored increased intracellular levels of the drug. Finally, deletion of the main ribosome hibernation factor of Escherichia coli, ribosome modulation factor (rmf), rendered these bacteria susceptible to gentamicin. Taken together, these data suggest that HPF-mediated ribosome hibernation results in repression of the metabolic activity that underlies aminoglycoside tolerance. HPF is conserved in nearly every bacterial pathogen, and the role of ribosome hibernation in antibiotic tolerance may have clinical implications. Listeria monocytogenes is a Gram-positive, facultative intracellular pathogen that poses serious medical risks for pregnant women, immunocompromised individuals, and infants (1, 2). The significance of L. monocytogenes as a foodborne pathogen was recently highlighted when contaminated cantaloupes caused the deadliest U.S. foodborne disease outbreak since 1924 (3). This bacterium is hardy and able to survive in a variety of environments, including soil, groundwater, and processed meats and cheeses, and within mammalian cells (2, 4-6). L. monocytogenes can also form biofilms that can persist for years in food processing plants, despite repeated exposure to disinfectants (7,8). Persistent L. monocytogenes contamination of food processing plants remains a significant source of foodborne illness (9-11). Understanding the molecular mechanisms that allow L. monocytogenes to survive and persist in harsh environments is crucial for developing strategies to ensure food safety.Ribosome dimerization is a highly conserved yet relatively underappreciated arm of the classic ribosome cycle. During stress, bacteria are able to dimerize 70S ribosomes into inactive hibernating 100S ribosome dimers. These dimers lack mRNA and tRNA and have been shown to be translationally silent in vitro (12, 13). Upon introduction of fresh nutrients, 100S ribosomes are immediately dissociated into 70S ribosomes and available for translation (14-16). Thus,...

Background The primary reported risk factors for herpes zoster (HZ) include increasing age and immunodeficiency, yet estimates of HZ risk by immunocompromising condition have not been well characterized. We undertook a systematic literature review to estimate the HZ risk in immunocompromised patients. Methods We systematically reviewed studies that examined the risk of HZ and associated complications in adult patients with hematopoietic cell transplants (HCT), cancer, human immunodeficiency virus (HIV), and solid organ transplant (SOT). We identified studies in PubMed, Embase, Medline, Cochrane, Scopus, and clinicaltrials.gov that presented original data from the United States and were published after 1992. We assessed the risk of bias with Cochrane or Grading of Recommendations Assessment, Development, and Evaluation methods. Results We identified and screened 3765 records and synthesized 34 studies with low or moderate risks of bias. Most studies that were included (32/34) reported at least 1 estimate of the HZ cumulative incidence (range, 0–41%). There were 12 studies that reported HZ incidences that varied widely within and between immunocompromised populations. Incidence estimates ranged from 9 to 92 HZ cases/1000 patient-years and were highest in HCT, followed by hematologic malignancies, SOT, and solid tumor malignancies, and were lowest in people living with HIV. Among 17 HCT studies, the absence of or use of antiviral prophylaxis at <1 year post-transplant was associated with a higher HZ incidence. Conclusions HZ was common among all immunocompromised populations studied, exceeding the expected HZ incidence among immunocompetent adults aged ≥60 years. Better evidence of the incidence of HZ complications and their severity in immunocompromised populations is needed to inform economic and HZ vaccine policies.