Viruses are leading causes of severe acute lower respiratory infections (LRIs). These infections evoke incomplete immunity, as individuals can be repeatedly reinfected throughout life. We report that acute viral LRI causes rapid pulmonary CD8 + cytotoxic T lymphocyte (T CD8 ) functional impairment via programmed death-1/ programmed death ligand-1 (PD-1/PD-L1) signaling, a pathway previously associated with prolonged antigenic stimulation during chronic infections and cancer. PD-1-mediated T CD8 impairment occurred acutely in mice following infection with human metapneumovirus or influenza virus. Viral antigen was sufficient for PD-1 upregulation, but induction of PD-L1 was required for impairment. During secondary viral infection or epitope-only challenge, memory T CD8 rapidly reexpressed PD-1 and exhibited severe functional impairment. Inhibition of PD-1 signaling using monoclonal antibody blockade prevented T CD8 impairment, reduced viral titers during primary infection, and enhanced protection of immunized mice against challenge infection. Additionally, PD-1 and PD-L1 were upregulated in the lungs of patients with 2009 H1N1 influenza virus, respiratory syncytial virus, or parainfluenza virus infection. These results indicate that PD-1 mediates T CD8 functional impairment during acute viral infection and may contribute to recurrent viral LRIs. Therefore, the PD-1/PD-L1 pathway may represent a therapeutic target in the treatment of respiratory viruses.
Paramyxoviruses use a specialized fusion protein to merge the viral envelope with cell membranes and initiate infection. Most paramyxoviruses require the interaction of two viral proteins to enter cells; an attachment protein binds cell surface receptors, leading to the activation of a fusion (F) protein that fuses the viral envelope and host cell plasma membrane. In contrast, human metapneumovirus (HMPV) expressing only the F protein is replication competent, suggesting a primary role for HMPV F in attachment and fusion. We previously identified an invariant arginine-glycine-aspartate (RGD) motif in the HMPV F protein and showed that the RGD-binding integrin ␣V1-promoted HMPV infection. Here we show that both HMPV F-mediated binding and virus entry depend upon multiple RGD Enveloped virus surface proteins attach to cell surface receptors and fuse viral membranes with cell membranes during entry. Several unrelated enveloped viruses, including influenza virus, human immunodeficiency virus (HIV), and paramyxoviruses, use class I viral fusion proteins to induce membrane fusion. Class I fusion proteins initiate fusion by springing open to insert a hydrophobic fusion peptide into the cell membrane, creating a molecular bridge between the viral and cellular membranes, which are merged by fusion protein refolding (8,19). Although all class I fusion proteins appear to use this spring-loaded mechanism, each virus family has adapted different strategies for triggering fusion. Paramyxoviruses encode two viral proteins, an attachment protein and a fusion protein, both of which are typically necessary for fusion. Paramyxovirus attachment and fusion are tightly connected events, such that attachment protein binding to cell surface receptors activates the fusion protein to induce fusion at the cell membrane (1,9,18,20,23,25,(28)(29)(30)36). This does not appear to be the mechanism used by the members of the Pneumovirinae subfamily of paramyxoviruses, which includes two important human respiratory viruses: human metapneumovirus (HMPV) and human respiratory syncytial virus (hRSV) (34). HMPV and hRSV encode a separate attachment (G) protein; however, viruses with only the fusion protein on the surface are replication competent in vitro and in vivo, although HMPV lacking G is attenuated in primates (4, 5, 17). Thus, the HMPV fusion (F) protein can mediate both attachment and membrane fusion, suggesting that F binds to specific cell surface receptors during attachment, drives fusion, and mediates virus entry in a manner that supports productive infection. In contrast to the current model of paramyxovirus fusion, where attachment protein binding is coupled to fusion activity of a separate fusion protein, the mechanism by which Pneumovirinae fusion proteins, including the HMPV F protein, bind to receptors and induce fusion is a mystery.We previously identified an invariant arginine-glycine-aspartate (RGD) motif that was unique to HMPV F among human paramyxoviruses. This discovery led us to hypothesize that integrins may serve as re...
Restraint use in the treatment of mental illness has long been a controversial practice. Regulatory agencies, licensing organizations, and professional and advocacy groups have called for reduction of restraint use. Responding to this call for action, the leadership team of a behavioral health unit in a private, nonprofit community hospital evaluated reducing restraint use. Following training through the National Executive Training Institute of the National Association of State Mental Health Program Directors, a restraint-reduction project team was formed. Instead of reducing restraint use, it was decided to eliminate restraint use. Vision guided, the team developed an action plan. Culture change focused on the Mental Health Recovery Model and principles of trauma-informed care. Emphasizing person-centered care, this unit has now been restraint free for nearly 2 years. A surprise finding was that restraint elimination accompanied a decrease in use of "as needed" sedative-hypnotic medications. Person-centered care delivered by frontline staff led to culture change, a restraint-free environment, and less medication.
While recognition for work has been positively related to nurses' job satisfaction in the research literature, specific types of recognition that would be most meaningful have not been identified. In this descriptive survey, 341 randomly selected staff nurses rated the extent of meaningfulness of 38 head nurse recognition behaviors. The most meaningful, in order of importance, were monetary rewards commensurate with performance, private verbal feedback, and written acknowledgment. Three other categories of recognition were identified as moderately meaningful: public acknowledgement, schedule adjustment, and opportunities for growth and development.
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