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Monthly Archives: December 2016

DNA as a weapon of immune defense

To defend themselves, our immune cells have two mechanisms. The first, called phagocytosis, kills bacteria within the phagocytic cell itself. The cell envelops the foreign body and exterminates it specifically by using reactive oxygen species (ozone, hydrogen peroxide, bleach), generated thanks to the enzyme NOX2. However, when the invader is too large to be taken up, cells use a second defense mechanism which consists of expelling their genetic material, that is to say their DNA. This DNA transforms into sticky and poisoned nets called “neutrophil extracellular traps” (NETs). These DNA nets then capture bacteria outside of the cell and kill them.

The ancestor of our innate immune system

In collaboration with researchers from Baylor College of Medicine in Huston (USA), Professor Thierry Soldati’s team from the Department of Biochemistry of the Faculty of Science at UNIGE studies the social amoeba Dictyostelium discoideum. These microorganisms are bacteria predators. But when food is short, they come together and form a “mini animal” of more than 100,000 cells, called a slug. This will then turn into a “fruiting body” made up of a mass of spores on top of a stalk. Dormant spores will survive without food until the wind or other elements disperse them to new areas where they can germinate and find something to eat.

To make up the slug, approximately 20% of cells sacrifice themselves to create the stalk and 80% will become spores. However, there is a small remaining 1% that keeps its phagocytic functions. “This last percentage is made up of cells called “sentinel” cells. They make up the primitive innate immune system of the slug and play the same role as immune cells in animals. Indeed, they also use phagocytosis and DNA nets to exterminate bacteria that would jeopardize the survival of the slug. We have thus discovered that what we believed to be an invention of higher animals is actually a strategy that was already active in unicellular organisms one billion years ago,” explains Thierry Soldati, last author of the study.

From social amoeba to humans

This discovery plays a primordial role in understanding immune system diseases in humans. Patients with chronic granulomatous disease (CGD) are for example incapable of expressing the functional NOX2 enzyme. Therefore, they suffer recurrent infections, since their immune system lacks the reactive oxygene species that kill bacteria inside the phagosome or via DNA nets. By genetically modifying the social amoeba Dictyostelium discoideum, the microbiologists from UNIGE are able to conduct all sorts of experiments on the mechanisms of the innate immune system. This microorganism can therefore serve as a scientific model for the research on defects in these defense processes, opening the way to possible treatments.

Time to put TB on a diet

TB kills over 1.5 million people a year. Although the mortality rate has dropped by 47% since 1990 due to advances in preventive and treatment options, the tuberculosis bacillus is growing increasingly resistant to antibiotics. For this reason, biochemists at the University of Geneva (UNIGE), Switzerland, are attempting to identify the mechanisms that enable the bacterium to reproduce, spread and survive in latent form in our macrophages. The scientists have discovered that the bacterium has the ability to “reprogramm” the cell it infects so that it can feed on its lipids. The UNIGE research results, which will be published in the PLOS Pathogens journal, will pave the way for new treatment opportunities based on starving and weakening the bacterium.

Tuberculosis is a highly contagious disease that spreads through the air via droplets of saliva. Although treatments exist for tuberculosis, new antibiotic-resistant strains are preventing TB from being eradicated. The goal is to find new ways to tackle the disease, which requires a thorough understanding of how the bacterium, known as Mycobacterium tuberculosis, behaves once it takes hold of the macrophages in our lungs. The team headed by Thierry Soldati, Professor at the Biochemistry department in UNIGE’s Science faculty, has been working on a model system that acts like the macrophages in our immune system: the social amoeba Dictyostelium, a unicellular microorganism.

“We infected the amoebae with the Mycobacterium marinumbacterium, which induces tuberculosis in fish,” explains Caroline Barisch, a researcher at UNIGE and the study’s first author. “The pathogen behaves in the same manner as the TB bacillus, which means that we were able to use our simple and ethically responsible system to undertake experiments that could not be carried out directly on humans.” Scientists had previously recognised that for the bacterium to survive, replicate and spread, it needed to consume the lipids that exist in the form of droplets in macrophages. Without this source of food, the bacillus cannot survive latently and wait for a weakness in the immune system in order to develop. It is well worth remembering that 30% of the world’s population is infected by a dormant form of the TB bacillus.

The UNIGE biochemists observed the infection in vitro, analysing each stage of the process whereby the bacterium feeds on the lipids of its host. As Thierry Soldati explains: “We subsequently discovered that the mycobacterium can “reprogramm” the infected cell so that it diverts and attracts all the amoeba’s fat reserves — not just the lipid droplets but also the membranes — so that it can feed on them.” The researchers suppressed the lipid droplets of the host cells, the bacterium’s preferred food source, and found that the bacterium has a back-up plan that allows it to compensate for this shortage by drawing on the lipids within the host’s membranes. This shows that this lipid diet is most likely crucial for the survival of the bacterium.

“We now know that the bacillus is extremely ‘addicted’ to this high-fat food,” continues Caroline Barisch. “Our current aim is to find a way to starve the bacillus by depriving it of access to the fat stores in our macrophages. The goal will be to target the enzymes of the bacillus and render them incapable of absorbing lipids.” It is a discovery that opens the door to the prospect of new forms of treatment for neutralising the strains that are resistant to antibiotics.

Pain often overlooked in premature infants

Premature infants receiving intensive care are exposed to a great deal of pain, and this pain causes damage to the child. Despite this half of the infants admitted to neonatal intensive units will not receive any pain relief, according to a new European study published in The Lancet Respiratory Medicine.

– That is, no one assesses if the infant is experiencing pain or how much pain relief the infant requires, says Mats Eriksson, researcher at Örebro University.

“Premature infants are sensitive to pain because their brain and nervous systems are still in development. But we cannot administer pain relief or sedation simply as a precaution, because pain relief at the wrong time will also lead to damage. Therefore, correct pain assessment is extremely important,” says Mats Eriksson, a specialist nurse in intensive care and researcher in medical science, who has worked on this survey, together with Hugo Lagercrantz at the Karolinska Institute and Ricardo Carbajal from Université Pierre et Marie Curie in Paris, and in cooperation with researchers from 17 other countries.

The international EU project has investigated 6,700 premature infants in 243 neonatal intensive care units in 18 countries, the largest study of its kind. The study shows that just over half of the children received no pain assessment, and a fifth received no pain relief or sedative medication at all.

“It is astonishing that so many children were not assessed. Proper pain assessment is the basis for a good treatment. By checking the baby’s facial expressions, heart rate and breathing, the amount of analgesic needed can be estimated,” says Mats Eriksson.

It is uncertain if the 20 per cent of infants, who never received any pain relief, needed it. However, the study does show that in those cases the infant’s pain was assessed, it was almost double so likely that the child received opioid analgesic such as morphine, or sedative drugs. On the other hand, the earlier a premature child is born, the less likely the child will receive analgesic or sedative drugs.

“20 per cent of the infants never received analgesia, and it is quite likely that many of them may have needed it at least at some point,” says Mats Eriksson.

“In Sweden, we have made considerable progress. We are quite apt at pain assessment and at adapting treatment. We are also good at using alternative methods, such as relieving pain with a sucrose solution or with skin-to-skin contact with a parent. In this way we can relieve pain for the infant without using excessive analgesia or sedatives.”

A good balance between analgesia and sedatives makes it possible to avoid future problems. Experiencing a lot of pain as a newborn may lead to behavioural changes with regards to pain later as an adult. That is, that one is quite simply being more sensitive to pain. In addition, many children develop attention and concentration problems, perhaps developing ADHD.

But there are significant differences between European countries regarding pain assessment and pain management. For example Greece stands out by providing much less analgesia than other countries.

“The goal is that all children should receive similar treatment, not simply based on chance, traditions or what an individual doctor believes or doesn’t believe. There are international guidelines, but they are old and need to be updated. The next step is to develop common European guidelines.”

Great differences in the view of withdrawing futile

The views among physicians and the general public when it comes to deciding whether to withhold or withdraw treatment of terminally ill patients differ greatly. However, in a hypothetical case study at Umeå University in Sweden of a clearly hopeless medical case, great unanimity among physicians’ and the public’s assessments could be seen with regards to cancelling treatment or offering relief at the final stages of life.

Anders Rydvall, physician at the University Hospital of Umeå and doctoral student at the Department of Surgical and Perioperative Sciences, has completed two surveys in Sweden that investigate attitudes and what arguments seem most significant. The development of techniques to prolong life support in intensive care, which is a relatively young speciality, has advanced at high speed and the opportunities are hence greater than ever. At the same time, there are limiting factors set by human physiology that can often be difficult to relate to. In turn, this leads to continuous treatment beyond what is reasonable when the patient is beyond rescue.

“This ethical dilemma is something that many, including family members, are aware of. But the difficulties in these types of situations often arise when caregivers are afraid of receiving criticism for not doing everything in their power. Also, there is a perceived discomfort in being the bearer of bad news and being on the receiving end of the reactions, as well as holding differing views on what rules and regulations actually imply,” explains Anders Rydvall.

The elderly woman with an unpromising prognosis

In a first survey, the attitudes and arguments for and against active treatment (operation) were compared between neurosurgeons (112 of which 70 per cent responded), anaesthesiologist and intensive care physicians (298 of which 70 per cent responded), and the general public (998 of which 50 per cent responded). The hypothetical patient case concerned an older woman with a severe brain haemorrhage and a poor clinical condition. The results showed that caregivers among themselves generally made the same assessments and prioritised the argument “Quality of Life” as the most important one. But anaesthesiologist and intensive care physicians also pointed particularly at the importance of the patient’s previous desires.

A comparison between physicians’ and the general public’s attitudes to this case showed great variations in opinions for or against operation and also in what arguments were considered most important. Out of the physicians, 82 per cent assessed to refrain from operation while only 40 per cent made the same choice out of the general public. But when the case developed to a more hopeless situation, both groups made more unanimous assessments, albeit prioritising different arguments.

The premature baby with severe brain injury

The second survey posed questions regarding a case with a severely brain-injured newborn baby. The survey was submitted to anaesthesiologist and intensive care physicians (299 of which 63 per cent responded), paediatricians and neonatologists (329 of which 67 per cent responded) as well as the general public (585 of which 46 per cent responded). The study compared arguments for the attitude for or against continued respiratory care. A majority of both physicians and the general public supported arguments to withdraw treatment.

The second survey also included questions on whether it could be considered acceptable to give anaesthetics and pain-relief in a dosage to minimize pain or in a higher dosage aimed at shortening the dying process. A large majority of physicians and the general public supported arguments to soothe and minimize pain, also if it in reality and as a consequence could shorten the dying process. Although, when the intention was to actively bring about the inevitable death, the general public seemed much more inclined to accept such an act than caregivers.

“To avoid misunderstandings and communication problems it is important that caregivers take into consideration and has knowledge of the views, expectations and prioritisations of the family. It’s also important that caregivers maintain a setting where information is honest and appropriate and communications open,” says Anders Rydvall.

Anders Rydvall comes from Stockholm and moved to Umeå in the 1970s. He works as a chief physician at the Centre of intensive and postoperative care at the University Hospital of Umeå.

Umeå University — located in the north of Sweden — is characterised by strong research where many of our researchers belong to the global elite in for instance global health, epidemiology, molecular biology, ecology, plant physiology, marine biology and Arctic research. Umeå University is one of Sweden’s largest teaching universities that offers a wide-spanning and attractive selection of courses and programmes, and stimulating environments for working and studying for the over 4,300 employees and 31,000 students. For instance, it was from Umeå University that the work in discovering the gene-editing tool CRISPR-Cas9 was led.