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Spreading Salmonella—hyper-replicating bacteria act as a reservoir for dissemination

New research reveals how Salmonella enterica spread in the gut and gallbladder—a subpopulation of Salmonella primed for invasion rapidly replicate in the host cell cytosol such that bacteria-laden cells are extruded out of the epithelial-cell layer releasing invasive Salmonella into the gastrointestinal and biliary lumen. Leigh Knodler and colleagues write that other mucosal-dwelling pathogens could use this “host cell process as an exit strategy”.

Salmonella species can cause a range of infections from typhoid fever to food poisoning. Ordinarily, the intracellular bacteria Salmonella enterica resides and replicates within a membrane-bound vacuole in epithelial cells. During its life cycle, the bacteria are adapted to survive within a wide range of environmental niches within the human host (including cells such as enterocytes and macrophages and organs such as the spleen and gastrointestinal tract).

Knodler et al. observed a subpopulation of Salmonella that were ‘hyper-replicating’; these bacteria were doubling in number at almost five times the rate of the overall population of bacteria in the epithelial cell. Not only that, these bacteria were rapidly proliferating not in the Salmonella-containing vacuole, but in the host cell cytosol (which is believed to be nutrient rich) and were ready to invade other cells (they expressed type III secretion system 1 components and flagella, virulence factors that are required for invasion). Moreover, epithelial cells overloaded with these hyper-replicating cytosolic Salmonella were forced out of the apical side of the epithelial-cell layer—just as when dying cells are extruded out of the epithelium during the normal rapid turnover of epithelial cells that occurs to maintain the gut epithelium. Subsequently, invasive bacteria are released into the lumen and are primed and ready to infect new cells. The extruded host cells then die in a caspase-1-dependent manner and trigger the production of the proinflammatory cytokine interleukin 18—a process which could, in part, explain the high levels of mucosal inflammation observed in Salmonella infections of the gut and gallbladder.


ResearchBlogging.orgKnodler, L., Vallance, B., Celli, J., Winfree, S., Hansen, B., Montero, M., & Steele-Mortimer, O. (2010). Dissemination of invasive Salmonella via bacterial-induced extrusion of mucosal epithelia Proceedings of the National Academy of Sciences, 107 (41), 17733-17738 DOI: 10.1073/pnas.1006098107

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IL-33—a new treatment against sepsis?

New research shows that the novel cytokine interleukin (IL)-33 reduces sepsis and has “therapeutic potential” to treat this often fatal inflammatory condition. According to the study published this week in Nature Medicine, IL-33 promotes neutrophil recruitment to the site of infection, which is a critical host defence response, and the levels of the decoy IL-33 receptor soluble ST2 in serum could affect whether people recover from sepsis.

Sepsis is a serious illness in which the body has a massive inflammatory response to an infection. Severe sepsis and septic shock can affect multiple organs in the body including the heart, lungs, liver and brain, and is life-threatening (30–50% of people with severe sepsis or septic shock die) and requires treatment in intensive care.

Jose Alves-Filho and colleagues used experimental models of sepsis (using cecal ligation and puncture or CLP) to investigate the role of IL-33 during sepsis. The scientists induced sepsis in mice and then treated them with recombinant IL-33; IL-33-treated mice had a marked reduction in mortality compared to untreated controls and IL-33 protected mice from sepsis for 3h after CLP. The researchers found that IL-33 treatment increased the number of neutrophils migrating to the site of infection (by increasing the expression of the chemokine receptor that is crucial for neutrophil recruitment, CXCR2). This neutrophil recruitment promoted clearance of the bacterial infection and IL-33 also reduced the systemic proinflammatory cytokines (e.g. IL-6, tumour necrosis factor α and CXCL2) that occurred in response to the infective bacteria. Furthermore, the scientists analysed blood serum from healthy individuals and people who had sepsis. They found that people with sepsis had higher levels of IL-33 than healthy people, and that serum levels of soluble ST2 (the decoy receptor of IL-33) were substantially higher in people who did not survive sepsis compared to those who recovered from the disease (soluble ST2 serum levels were negligible in healthy individuals).

The research reveals a “previously unknown mechanism of action of IL-33” and further studies will show whether IL-33 could be used as a potentially novel therapy for sepsis.

ResearchBlogging.orgAlves-Filho, J., Sônego, F., Souto, F., Freitas, A., Verri, W., Auxiliadora-Martins, M., Basile-Filho, A., McKenzie, A., Xu, D., Cunha, F., & Liew, F. (2010). Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection Nature Medicine DOI: 10.1038/nm.2156

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Silencing human RSV infection

A new therapy based on RNA interference (RNAi) successfully reduces respiratory syncytial virus (RSV) infection in humans. The study, published free online in PNAS, demonstrates that therapeutic RNAi-based drugs are clinically effective, and suggests that similar ‘silencing’ therapies could be useful against other respiratory pathogens.

RSV is an RNA virus that infects the lungs to cause respiratory tract infections—especially in the lower respiratory tract. RSV infection can be severe in immunocompromised patients, the elderly and young children; in the US alone, the virus has a ten times higher mortality rate in young children than the influenza virus and is the most common cause of infant hospitalisation. No vaccine for RSV exists, and the only approved drug treatment, ribavirin, has limited use and effectiveness. Current treatment strategies for RSV infection are only supportive—namely oxygen and fluids until the infection naturally resolves. Previous work has shown that a small interfering RNA (siRNA) drug—called ALN-RSV01—effectively silences a RSV protein that is critical for virus replication, and has a considerable antiviral effect in a mouse model of RSV infection. Evidence for the clinical effectiveness of siRNA drugs to treat disease in humans is, however, lacking.

DeVincenzo and colleagues tested whether ALN-RSV01 was an effective antiviral drug in adult, human volunteers who were infected with wild-type RSV. The investigators enrolled 88 healthy participants into a double-blind, placebo-controlled trial. They randomly assigned the volunteers to receive a nasal spray containing either ALN-RSV01 or saline as a placebo control. This nasal spray was administered 2 days prior to, and 3 days after, inoculation with RSV. They found that treatment with the siRNA nasal spray decreased the number of people infected with RSV by 38%, with the greatest reduction in people’s symptoms between 4–7 days after RSV inoculation. This antiviral effect was not related to the concentration of proinflammatory cytokines (such as tumor necrosis factor and interferon α) in the nose or whether the participants had pre-existing antibodies against RSV. Furthermore, the scientists showed that intranasal ALN-RSV01 was well tolerated and safe to use in humans.

DeVincenzo et al. argue that their findings represent a “significant advance in the development of human therapies…[and] a definitive demonstration in humans of an RNAi effect using a synthetic siRNA.” More clinical trials are needed to determine whether intranasal ALN-RSV01 can reduce RSV infection in children and adults that are naturally infected by the virus, and to determine the optimal dose and frequency for ALN-RSV01 administration that produces the best antiviral effect and clinical outcome. The results from this study also demonstrate a “broader potential” for “locally delivered siRNAs as unique anti-infective drugs against other respiratory pathogens.”

ResearchBlogging.orgDeVincenzo, J., Lambkin-Williams, R., Wilkinson, T., Cehelsky, J., Nochur, S., Walsh, E., Meyers, R., Gollob, J., & Vaishnaw, A. (2010). A randomized, double-blind, placebo-controlled study of an RNAi-based therapy directed against respiratory syncytial virus Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0912186107

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Hitting the headlines this week

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Hitting the headlines this week

  • skunk users at greater risk of psychosis
  • Obama to attend end of Copenhagen climate summit
  • debate over drug companies and clinical trials still rages
  • Cave spiders return home
  • Would you eat lab grown meat?
  • Measles deaths worldwide reduced by 78%, but more vaccinations needed to prevent the disease resurging.

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Research scientist revealed to be Belle du Jour

Belle du Jour, the once anonymous blogger behind the popular Diary of a London Call Girl blog, which spawned a TV show starring Billie Paper and several books, has today been revealed as Dr. Brooke Magnanti, a research scientist working for the Bristol Initiative for Research of Child Health.

 

Speaking to India Knight in the Sunday times, Magnanti reveals she chose prostitution to fund her life in London whilst writing up her PhD thesis in informatics, epidemiology and forensic science. With little spare time on her hands because she was “still making corrections and preparing for the viva” and money running out fast Magnanti pondered on the perfect profession that “doesn’t require a great deal of training or investment to get started, that’s cash in hand and that leaves me spare time to do my work in”. Her solution was working as a £300/hour escort.

 

Belle’s blog has been accused of glamourising sex work and the revelations that “Belle” is in fact an intelligent and well-educated woman demonstrates that sex workers come from all walks of the life. However, this tale also highlights the perils of undertaking an academic career in scientific research. Doctoral work in any field is an all-consuming affair where the final months of writing up require an other-worldy and single-minded devotion to one thing and one thing only. Finishing. Add to that, the horrors of endless corrections to your thesis, counting your pennies because your funding has run out and finding a job in the highly competitive field of science (a job which can be poorly funded with little stability) and it’s pretty easy to imagine the state of mind when struggling for money that leaps from science to sex work.

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There’s gold in them there bacteria

Scientists have found that the bacterium, Cupriavidus metallidurans, can transform toxic gold compounds to metallic gold, according to research by Reith and colleagues published online on the 7th October in the journal PNAS.

Bacteria are naturally found on gold particles from the earth’s surface; but it is unclear, and controversial, as to whether bacteria have an active role in the formation of these gold particles (biomineralisation). An international team of scientists (from Australia, USA, Canada, Germany, Belgium and France) investigated a metallophilic (metal resistant and able to grow on heavy metals) bacterium called Cupriavidus metallidurans, which forms biofilms (a slimy layer of bacteria stuck together) on grains of gold. They found that C. metallidurans accumulates toxic gold complexes (containing Au III ions) from solution inside the bacterial cell, this accumulation is increased in metabolically active (i.e. living) bacteria. The toxic gold complexes activate bacterial genes involved in the combat against oxidative stress (damage in cells caused by reactive oxygen species, which includes unpaired electrons aka free radicals), and for metal resistance. Also, an uncharacterised cluster of genes which are specifically linked with resistance to gold were activated. Bacteria were then able to detoxify these gold complexes, ultimately turning them into harmless nanoparticles of gold. Similar gold nanoparticles were also seen in bacterial biofilms on grains of gold.

C. metallidurans containing a gold nanoparticle. Reith et al (PNAS 2009).

C. metallidurans containing a gold nanoparticle. Reith et al (PNAS 2009).

The scientists used some very fancy and expensive equipment for their work; including synchotrons at the European Synchotron Radiation Facility (ESRF) and the Advanced Photon Source (APS). Synchotrons are a type of particle accelerator that produces very intense beams of X-rays (1000 billion times brighter than X-rays in hospitals). They were used by the scientists as a super-microscope to see gold particles inside C. metallidurans in great detail.

These findings provide evidence that bacteria in the environment may contribute to the formation of grains of gold, which in turn could form gold nuggets. Gold is a rare and precious metal and these bacteria could be used as a tool to help mineral explorers find new gold deposits.

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