Pseudomonas aeruginosa Adaptation to Lungs of Cystic Fibrosis Patients Leads to Lowered Resistance to Phage and Protist Enemies

Pathogenic life styles can lead to highly specialized interactions with host species, potentially resulting in fitness trade-offs in other ecological contexts. Here we studied how adaptation of the environmentally transmitted bacterial pathogen, Pseudomonas aeruginosa, to cystic fibrosis (CF) patients affects its survival in the presence of natural phage (14/1, ΦKZ, PNM and PT7) and protist (Tetrahymena thermophila and Acanthamoebae polyphaga) enemies. We found that most of the bacteria isolated from relatively recently intermittently colonised patients (1-25 months), were innately phage-resistant and highly toxic for protists. In contrast, bacteria isolated from long time chronically infected patients (2-23 years), were less efficient in both resisting phages and killing protists. Moreover, chronic isolates showed reduced killing of wax moth larvae (Galleria mellonella) probably due to weaker in vitro growth and protease expression. These results suggest that P. aeruginosa long-term adaptation to CF-lungs could trade off with its survival in aquatic environmental reservoirs in the presence of microbial enemies, while lowered virulence could reduce pathogen opportunities to infect insect vectors; factors that are both likely to result in poorer environmental transmission. From an applied perspective, phage therapy could be useful against chronic P. aeruginosa lung infections that are often characterized by multidrug resistance: chronic isolates were least resistant to phages and their poor growth will likely slow down the emergence of beneficial resistance mutations

Repetitive Exposure to Bacteriophage Cocktails against Pseudomonas aeruginosa or Escherichia coli Provokes Marginal Humoral Immunity in Naïve Mice

Phage therapy of ventilator-associated pneumonia (VAP) is of great interest due to the rising incidence of multidrug-resistant bacterial pathogens. However, natural or therapy-induced immunity against therapeutic phages remains a potential concern. In this study, we investigated the innate and adaptive immune responses to two different phage cocktails targeting either Pseudomonas aeruginosa or Escherichia coli—two VAP-associated pathogens—in naïve mice without the confounding effects of a bacterial infection. Active or UV-inactivated phage cocktails or buffers were injected intraperitoneally daily for 7 days in C57BL/6J wild-type mice. Blood cell analysis, flow cytometry analysis, assessment of phage distribution and histopathological analysis of spleens were performed at 6 h, 10 days and 21 days after treatment start. Phages reached the lungs and although the phage cocktails were slightly immunogenic, phage injections were well tolerated without obvious adverse effects. No signs of activation of innate or adaptive immune cells were observed; however, both active phage cocktails elicited a minimal humoral response with secretion of phage-specific antibodies. Our findings show that even repetitive injections lead only to a minimal innate and adaptive immune response in naïve mice and suggest that systemic phage treatment is thus potentially suitable for treating bacterial lung infections

International multicentre observational study to assess the efficacy and safety of a 0·5 mg kg−1 per day starting dose of oral corticosteroids to treat bullous pemphigoid

BackgroundEuropean guidelines propose a 0 center dot 5 mg kg(-1) per day dose of oral prednisone as initial treatment for bullous pemphigoid (BP). We assessed the safety and efficacy of this regimen depending on BP extent and general condition of the patients.MethodsIn a prospective international study, we consecutively included all patients diagnosed with BP. Patients received a 0 center dot 5 mg kg(-1) per day dose of prednisone, which was then gradually tapered 15 days after disease control, with the aim of stopping prednisone or maintaining minimal treatment (0 center dot 1 mg kg(-1) per day) within 6 months after the start of treatment. The two coprimary endpoints were control of disease activity at day 21 and 1-year overall survival. Disease severity was assessed according to the Bullous Pemphigoid Disease Area Index (BPDAI) score.ResultsIn total, 198 patients were included between 2015 and 2017. The final analysis comprised 190 patients with a mean age of 80 center dot 9 (SD 9 center dot 1) years. Control of disease activity was achieved at day 21 in 119 patients [62 center dot 6%, 95% confidence interval (CI) 55 center dot 3-69.5]; 18 of 24 patients (75%, 95% CI 53 center dot 3-90 center dot 2), 75 of 110 patients (68 center dot 8%, 95% CI 59 center dot 2-77 center dot 3) and 26 of 56 patients (46.4%, 95% CI 33 center dot 0-60 center dot 3) had mild, moderate and severe BP, respectively (P = 0 center dot 0218). A total of 30 patients died during the study. The overall Kaplan-Meier 1-year survival was 82 center dot 6% (95% CI 76 center dot 3-87 center dot 4) corresponding to 90 center dot 9%, 83 center dot 0% and 80 center dot 0% rates in patients with mild, moderate and severe BP, respectively (P = 0 center dot 5). Thresholds of 49 points for BPDAI score and 70 points for Karnofsky score yielded maximal Youden index values with respect to disease control at day 21 and 1-year survival, respectively.ConclusionsA 0 center dot 5 mg kg(-1) per day dose of prednisone is a valuable therapeutic option in patients with mild or moderate BP whose general condition allows them to be autonomous.</p

The phage therapy paradigm: prêt-à-porter or sur-mesure?

The present opinion is the result of discussions on the future of phage therapy (personalized or large-scale uniform therapy?) during the first International Congress on Viruses of Microbes, held at the Institut Pasteur in Paris on June 21–25, 2010

ATP-Dependent Infra-Slow (<0.1 Hz) Oscillations in Thalamic Networks

An increasing number of EEG and resting state fMRI studies in both humans and animals indicate that spontaneous low frequency fluctuations in cerebral activity at <0.1 Hz (infra-slow oscillations, ISOs) represent a fundamental component of brain functioning, being known to correlate with faster neuronal ensemble oscillations, regulate behavioural performance and influence seizure susceptibility. Although these oscillations have been commonly indicated to involve the thalamus their basic cellular mechanisms remain poorly understood. Here we show that various nuclei in the dorsal thalamus in vitro can express a robust ISO at ∼0.005–0.1 Hz that is greatly facilitated by activating metabotropic glutamate receptors (mGluRs) and/or Ach receptors (AchRs). This ISO is a neuronal population phenomenon which modulates faster gap junction (GJ)-dependent network oscillations, and can underlie epileptic activity when AchRs or mGluRs are stimulated excessively. In individual thalamocortical neurons the ISO is primarily shaped by rhythmic, long-lasting hyperpolarizing potentials which reflect the activation of A1 receptors, by ATP-derived adenosine, and subsequent opening of Ba2+-sensitive K+ channels. We argue that this ISO has a likely non-neuronal origin and may contribute to shaping ISOs in the intact brain

Back to the future: environmental security in nineteenth century global politics

Environmental security is generally held to be a contemporary or even futuristic concern. However, as with many facets of security thought, this overlooks how the unparalleled technological, economic and social changes of the 19th Century forged much of the international political landscape we now inhabit. The tendency for ecological political enquiry to focus on the rise of ecocentric policy serves to obscure how many aspects of national and human security relating to environmental change were apparent in the 19th century. Human insecurity in the face of pollution and resource depletion was a part of the emergence of ecological science in response to the industrialization of Europe and North America. In addition, this was the era when European imperialism reached its apex and European nationalisms fully emerged; both of which contributed to the national securitization of the environment around much of the world in contrasting ways as the desire to both conquer and preserve nature became more evident. Environmental questions of national, human and ecological security are not peculiar to the present age and were very much apparent in 19th Century global politics

An intrinsic vasopressin system in the olfactory bulb is involved in social recognition

Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain where they play fundamentally important roles in social behaviours1. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader-Willi syndrome, affective disorders, and obsessive-compulsive disorder, and polymorphisms of the vasopressin V1a receptor have been linked to autism2,3. Here we report that the rat olfactory bulb contains a large population of interneurones which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats, and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurones. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system