The role of the copA copper efflux system in acinetobacter baumannii virulence

Acinetobacter baumannii has emerged as one of the leading causative agents of nosocomial infections. Due to its high level of intrinsic and adapted antibiotic resistance, treatment failure rates are high, which allows this opportunistic pathogen to thrive during infection in immune-compromised patients. A. baumannii can cause infections within a broad range of host niches, with pneumonia and bacteraemia being associated with the greatest levels of morbidity and mortality. Although its resistance to antibiotics is widely studied, our understanding of the mechanisms required for dealing with environmental stresses related to virulence and hospital persistence, such as copper toxicity, is limited. Here, we performed an in silico analysis of the A. baumannii copper resistome, examining its regulation under copper stress. Using comparative analyses of bacterial P-type ATPases, we propose that A. baumannii encodes a member of a novel subgroup of P1B-1 ATPases. Analyses of three putative inner membrane copper efflux systems identified the P1B-1 ATPase CopA as the primary mediator of cytoplasmic copper resistance in A. baumannii. Using a murine model of A. baumannii pneumonia, we reveal that CopA contributes to the virulence of A. baumannii. Collectively, this study advances our understanding of how A. baumannii deals with environmental copper toxicity, and it provides novel insights into how A. baumannii combats adversities encountered as part of the host immune defence.Saleh F. Alquethamy, Marjan Khorvash , Victoria G. Pederick, Jonathan J. Whittall, James C. Paton, Ian T. Paulsen, Karl A. Hassan, Christopher A. McDevitt and Bart A. Eijkelkam

Identification of novel Acinetobacter baumannii host fatty acid stress adaptation strategies

Free fatty acids hold important immune-modulatory roles during infection. However, the host's long-chain polyunsaturated fatty acids, not commonly found in the membranes of bacterial pathogens, also have significant broad-spectrum antibacterial potential. Of these, the omega-6 fatty acid arachidonic acid (AA) and the omega-3 fatty acid decosahexaenoic acid (DHA) are highly abundant; hence, we investigated their effects on the multidrug-resistant human pathogen Acinetobacter baumannii Our analyses reveal that AA and DHA incorporate into the A. baumannii bacterial membrane and impact bacterial fitness and membrane integrity, with DHA having a more pronounced effect. Through transcriptional profiling and mutant analyses, we show that the A. baumannii β-oxidation pathway plays a protective role against AA and DHA, by limiting their incorporation into the phospholipids of the bacterial membrane. Furthermore, our study identified a second bacterial membrane protection system mediated by the AdeIJK efflux system, which modulates the lipid content of the membrane via direct efflux of lipids other than AA and DHA, thereby providing a novel function for this major efflux system in A. baumannii This is the first study to examine the antimicrobial effects of host fatty acids on A. baumannii and highlights the potential of AA and DHA to protect against A. baumannii infections.IMPORTANCE A shift in the Western diet since the industrial revolution has resulted in a dramatic increase in the consumption of omega-6 fatty acids, with a concurrent decrease in the consumption of omega-3 fatty acids. This decrease in omega-3 fatty acid consumption has been associated with significant disease burden, including increased susceptibility to infectious diseases. Here we provide evidence that DHA, an omega-3 fatty acid, has superior antimicrobial effects upon the highly drug-resistant pathogen Acinetobacter baumannii, thereby providing insights into one of the potential health benefits of omega-3 fatty acids. The identification and characterization of two novel bacterial membrane protective mechanisms against host fatty acids provide important insights into A. baumannii adaptation during disease. Furthermore, we describe a novel role for the major multidrug efflux system AdeIJK in A. baumannii membrane maintenance and lipid transport. This core function, beyond drug efflux, increases the appeal of AdeIJK as a therapeutic target.Jhih-Hang Jiang, Karl A. Hassan, Stephanie L. Begg, Thusitha W. T. Rupasinghe, Varsha Naidu, Victoria G. Pederick, Marjan Khorvash, Jonathan J. Whittall, James C. Paton, Ian T. Paulsen, Christopher A. McDevitt, Anton Y. Peleg, Bart A. Eijkelkam

On twisted Fourier analysis and convergence of Fourier series on discrete groups

We study norm convergence and summability of Fourier series in the setting of reduced twisted group $C^*$-algebras of discrete groups. For amenable groups, F{\o}lner nets give the key to Fej\'er summation. We show that Abel-Poisson summation holds for a large class of groups, including e.g. all Coxeter groups and all Gromov hyperbolic groups. As a tool in our presentation, we introduce notions of polynomial and subexponential H-growth for countable groups w.r.t. proper scale functions, usually chosen as length functions. These coincide with the classical notions of growth in the case of amenable groups.Comment: 35 pages; abridged, revised and update

Characterization of temperature-dependent echo-shifts and backscattered energy induced by thermal ultrasound

Existence of accurate temporal-spatial temperature models, which would enable non-invasive estimates, will promote ultrasound-based thermal therapy applications. These models should reflect the tissue temperature with a maximum absolute error of 0.5 ºC within 1 cm3. In-vitro experiments have been developed to evaluate the temperature variations induced by standard ultrasound therapeutic device emitting continuously on gel-based phantom and on pork meat tissue using three different emitting intensities (1, 1.5 and 2 W/cm3). Temperature estimates were performed based on raw RF data collected using a second ultrasound transducer (imaging transducer). This second transducer worked in pulse-echo mode, and was placed perpendicularly to the therapeutic transducer. In order to access the quality of the estimates, temperatures were acquired by five and by two thermocouples placed in the gel-based phantom and on the porcine sample, respectively. At every 10 seconds the temperature and one RF-line is stored in a PC for future processing. The possibility to estimate temperature was assessed by considering two RFline features: temporal echo-shifts produced by changes in speed-of-sound and medium expansion/contraction and by changes on the backscattered energy originated by medium inhomogeneities. On one hand, results prove that echo-shifts correlated with temperature in both types of medium (phantom and ex-vivo porcine muscle). On the other hand, analyzing the backscattered energies one may conclude that this measures correlates with temperature in the porcine sample and not on the phantom. This led us to conclude that the developed phantom is not appropriate for studying changes on backscattered energy with temperature. Energy analysis of the porcine sample confirms the non-uniform temperature variation due to the existence of a heterogeneous media with different sound propagation velocities