Host-Detrimental Role of Esx-1-Mediated Inflammasome Activation in Mycobacterial Infection

The Esx-1 (type VII) secretion system is a major virulence determinant of pathogenic mycobacteria, including Mycobacterium marinum. However, the molecular events and host-pathogen interactions underlying Esx-1-mediated virulence in vivo remain unclear. Here we address this problem in a non-lethal mouse model of M. marinum infection that allows detailed quantitative analysis of disease progression. M. marinum established local infection in mouse tails, with Esx-1-dependent formation of caseating granulomas similar to those formed in human tuberculosis, and bone deterioration reminiscent of skeletal tuberculosis. Analysis of tails infected with wild type or Esx-1-deficient bacteria showed that Esx-1 enhanced generation of proinflammatory cytokines, including the secreted form of IL-1β, suggesting that Esx-1 promotes inflammasome activation in vivo. In vitro experiments indicated that Esx-1-dependent inflammasome activation required the host NLRP3 and ASC proteins. Infection of wild type and ASC-deficient mice demonstrated that Esx-1-dependent inflammasome activation exacerbated disease without restricting bacterial growth, indicating a host-detrimental role of this inflammatory pathway in mycobacterial infection. These findings define an immunoregulatory role for Esx-1 in a specific host-pathogen interaction in vivo, and indicate that the Esx-1 secretion system promotes disease and inflammation through its ability to activate the inflammasome

The impact of reduced worktime on sleep and perceived stress: A group randomized intervention study using diary data

Objective: Insufficient time for recovery between workdays may cause fatigue and disturbed sleep. This study evaluated the impact of an intervention that reduced weekly working hours by 25% on sleep, sleepiness and perceived stress for employees within the public sector. Method: Participating workplaces (N=33) were randomized into intervention and control groups. Participants (N=580, 76% women) worked full-time at baseline. The intervention group (N=354) reduced worktime to 75% with preserved salary during 18 months. Data were collected at baseline and after 9 and 18 months follow-up. Sleep quality, sleep duration, sleepiness, perceived stress,and worries and stress at bedtime were measured with diary during one week per data collection. Result: A multilevel mixed model showed that compared with the control group, at the 18-month follow-up, the intervention group had improved sleep quality and sleep duration (+23 minutes) and displayed reduced levels of sleepiness, perceived stress, and worries and stress at bedtime on workdays (P<0.002). The same effects were shown for days off (P<0.006), except for sleep length. Effect sizes were small (Cohen’s f2<0.08). Adding gender, age, having children living at home, and baseline values of sleep quality and worries and stress at bedtime as additional between-group factors did not influence the results. Conclusion: A 25% reduction of weekly work hours with retained salary resulted in beneficial effects on sleep, sleepiness and perceived stress both on workdays and days off. These effects were maintained over an 18-month period. This randomized intervention thus indicates that reduced worktime may improve recovery and perceived stress