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New study sheds light on how Salmonella spreads in the body

last modified May 27, 2016 12:23 PM
Research could have major implications for improving treatment and vaccination.

Findings of Cambridge scientists, published today in the journal PLoS Pathogens, show a new mechanism used by bacteria to spread in the body with the potential to identify targets to prevent the dissemination of the infection process.

Salmonella enterica is a major threat to public health, causing systemic diseases (typhoid and paratyphoid fever), gastroenteritis and non-typhoidal septicaemia (NTS) in humans and in many animal species worldwide. In the natural infection, salmonellae are typically acquired from the environment by oral ingestion of contaminated water or food or by contact with a carrier.  Current vaccines and treatments for S. enterica infections are not sufficiently effective, and there is a need to develop new therapeutic strategies.

Dr Andrew Grant, lead author of the study from the University of Cambridge, said: “A key unanswered question in infectious diseases is how pathogens such as Salmonella grow at the single-cell level and spread in the body.  This gap in our knowledge is hampering our ability to target therapy and vaccines with accuracy.”

During infection, salmonellae are found mainly within cells of the immune system where they are thought to grow and persist.  To do so the bacteria adapt to their surrounding environment and resist the antimicrobial activity of the cell.  Research from the Cambridge group has shown that the situation is more complex in that the bacteria must also escape from infected cells to spread to distant sites in the body, avoiding the local escalation of the immune response and thus playing a ‘catch me if you can’ game with the host immune system.

A body of knowledge has been built using in vitro (test tube) cell culture experiments that indicates that replication of Salmonella enterica within host cells in vitro is somewhat dependent on the bacteria making a syringe-like structure, called a Type 3 Secretory System (T3SS). This then injects bacterial proteins into the host cell, which in turn enhance bacterial replication inside that cell.  This T3SS is encoded by genes in a region of the bacterial chromosome called Salmonella Pathogenicity Island 2 (or SPI-2). Translating this cell culture work into whole animals, it has become accepted dogma that the SPI-2 T3SS is also required for bacterial intracellular replication in cells inside the body.

However, using fluorescence and confocal microscopy (which are imaging techniques), the Cambridge team has dispelled this dogma concerning the requirement for the SPI-2 T3SS for intracellular replication in the body. The researchers have shown that mutants lacking SPI-2 can reach high numbers within individual host cells, a situation that does not happen in in vitro cell culture.

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First randomised controlled trial to show spinal cord regeneration in dogs

last modified May 27, 2016 12:26 PM
Researchers have shown it is possible to restore co-ordinated limb movement in dogs with severe spinal cord injury (SCI).

In a collaboration between the University’s Veterinary School and MRC’s Regenerative Medicine Centre, scientists used a unique type of cell to regenerate the damaged part of the dogs’ spines. The researchers are cautiously optimistic that the work could have a future role in the treatment of human patients with similar injuries if used alongside other treatments.

Scientists have been aware for over a decade that olfactory ensheathing cells (OEC) might be useful in treating the damaged spinal cord because of their unique properties. The cells have the ability to support nerve fibre growth that maintains a pathway between the nose and the brain.

Previous research using laboratory animals has already revealed that OECs can aid regeneration of the parts of nerve cells that transmit signals (axons) so as to form a ‘bridge’ between damaged and undamaged spinal cord tissue. A Phase 1 trial in human patients with SCI established that the procedure is safe.

The study, published in the latest issue of the neurology journal Brain, is the first double-blinded randomised controlled trial to test the effectiveness of these transplants to improve function in ‘real-life’ spinal cord injury. The trial was performed on animals that had spontaneous and accidental injury rather than in the controlled environment of a laboratory, and some time after the injury occurred.  This far more closely resembles the way in which the procedure might be used in human patients.

The 34 pet dogs had all suffered severe spinal cord injury. Twelve months or more after the injury, they were unable to use their back legs to walk and unable to feel pain in their hindquarters. Many of the dogs were dachshunds which are particularly prone to this type of injury. Dogs are also more likely to suffer from SCIs because the spinal cord may be damaged as a result of what in humans is the relatively minor condition of a slipped disc.

In the study, funded by the MRC, one group of dogs had olfactory ensheathing cells from the lining of their own nose injected into the injury site. The other group of dogs was injected with just the liquid in which the cells were transplanted. Neither the researchers nor the owners (nor the dogs!) knew which injection they were receiving.

The dogs were observed for adverse reactions for 24 hours before being returned to their owners. From then on, they were tested at one month intervals for neurological function and to have their gait analysed on a treadmill while being supported in a harness. In particular, the researchers analysed the dogs’ ability to co-ordinate movement of their front and back limbs.

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Scientists build a clearer picture of the spread of bovine tuberculosis

last modified May 27, 2016 12:29 PM

Each year thousands of cattle are slaughtered to control the spread of bovine tuberculosis. New research reveals that testing misses many animals harbouring the disease and shows that large herds are particularly vulnerable to rapid transmission.

A team of scientists has used mathematical tools to develop models for estimating the efficiency of cattle-based controls for bovine tuberculosis (bTB). These models will help policy-makers to understand, and thus to control, a disease which costs the UK taxpayer around £91 million per annum for testing, slaughter of animals and compensation to farmers.

The models built by the team represent an advance over previous models as they are informed directly by extensive data on reported incidence and spread of the disease, rather than expert opinion. Importantly, they provide a first estimate of the quantity of infection missed by cattle testing and the contribution of this hidden burden of infection to the persistence of bTB within herds.

Applied to recent data, the models suggest that around one in five of British herds that have been cleared of restrictions, following testing for bTB, may harbour the infection. It also points to a higher incidence, and faster spread, of the disease in large herds.

The Defra-funded research was undertaken by a cross-disciplinary group of experts at the Department of Veterinary Medicine, University of Cambridge, and the Animal Health and Veterinary Agency. It was led by Dr Andrew Conlan, a researcher in Cambridge’s Disease Dynamics Group, who specialises in mathematical modelling and also works on the spread of childhood diseases.

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