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New mechanism discovered that protects macrophages from Salmonella Typhimurium infections

The excessive prescribing of antibiotics, their overuse in livestock raising or aquiculture, patients' failure to complete their treatments, lack of research into new drugs or hygiene and infection control problems in hospital settings are the main causes of antimicrobial resistance. The estimates made by the government of the United Kingdom indicate that by 2050, the deaths caused by resistant bacteria could reach 10 million, 1.8 million more than those caused by cancer.

Among the microorganisms of greatest concern to experts are the bacteria of the Salmonella genus, especially the strains resistant to fluoroquinolones, considered of high priority in the search for new drugs, according to the World Health Organization. Core facilities, which are already active in the fight against antibiotic-resistant microorganisms through drug discovery platforms or the use of big data, have again played a key role in discovering a new antibacterial mechanism.

Source: NIAID (Wikimedia)

An international team of scientists, led by the University of Barcelona, has discovered a possible pathway to protect macrophages from infections of Salmonella enterica serotype Typhimurium, according to the journal Cell Reports. Researchers have managed to limit the bacteria's attacks on immune system cells, as these microorganisms commonly use macrophages as biological niches in which to replicate and distribute themselves throughout the body. This process is completed through the activation of transcription factors from the nuclear receptor family known as Liver X receptors or LXR.

The team, led by Annabel Valledor, head of the Macrophage, LXR, Inflammation and Immune Response Research Group of the Nurcamein network has identified the molecular mechanism regulated by the LXR nuclear receptor, which reduces the infection of macrophages through transcriptional activation of the multifunctional enzyme CD38, by means of a Salmonella Typhimurium infection model. “LXR agonists reduced the intracellular levels of NAD+ in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages”, state the authors of the study published in Cell Reports.

During the experimental phase of the study, researchers used confocal fluorescence microscopy to determine the percentage of macrophages infected by Salmonella Typhimurium and the intracellular quantity of bacteria, in studies performed both in vitro as well as in vivo. As the scientists report in their article, the technique, “indicated that LXR agonists reduce the amount of intracellular bacteria and the percentage of infected macrophages after 30 min of infection”. On another note, Valledor's team applied flow cytometry to corroborate the inhibitory effects on macrophage infection by these microorganisms, known to be responsible for food poisoning.

A scientist working at the Experimental Toxicology and Ecotoxicology Platform of the Science Park of Barcelona.
Source: Science Park of Barcelona

Further, the research was supported by the technological services offered by the Experimental Toxicology and Ecotoxicology Platform (UTOX-PCB) of the Science Park of Barcelona.  As UTOX researcher Joan Serret tells Biocores, “Annabel Valledor’s group’s participation in the work was limited to the in vivo portion. We performed administrations of Salmonella as well as the trial product.” The platform “is a research and toxicology service center that works for the public as well as the private sector. Our main line of work is regulatory toxicology for registration of human and veterinarian drugs, medical devices, food and food supplements, cosmetics and chemical products and pharmacokinetic, toxicokinetic, pharmacodynamic and metabolism studies, although we also take part in research projects for adoption of alternative methods to in vivo toxicology,” says Serret.

“Our participation in the registration process ranges from in silico toxicology (expert reports, safety evaluations through literature searches and mathematical models) and preliminary in vitro toxicity trials up to the in vitro  pre-clinical safety studies. Our accreditation in Laboratory Best Practices lets us be prepared to present to regulatory authorities the results of toxicology trials with a view to registering the products we test,” states the scientist in remarks to Biocores. “Along these lines, we offer service to external researchers who require guidance as well as any toxicology-related preliminary work for preclinical development for registration,” he adds. This Unit, which is also part of the GRET (consolidated Toxicology Research Group), the CERETOX (Toxicology Research Centre, TECNIO agent) and the CITA (Centre for Innovation and Advanced Technologies of the University of Barcelona), contributed its technical know-how during in vivo studies performed in animal models to confirm or rule out the clinical signs of infection by Salmonella Typhimurium.

“Remarkably, pharmacological treatment with an LXR agonist ameliorated clinical signs associated with Salmonella infection in vivo, and these effects were dependent on CD38 expression in bone-marrow-derived cells”, say the authors of the article when referring to the results achieved by the PCB's Experimental Toxicology Platform. Their study reveals the unknown role of the CD38 enzyme in the interaction between pathogens and host cells through the pharmacological activation of the LXR route. “In consideration of evolving antimicrobial resistance in certain parts of the world, this work strengthens the relevance of LXR agonists or drugs that potentiate CD38 NADase activity as potential therapeutic strategies in host-directed therapy against infections that use the macrophage as a niche for replication”, conclude the scientists.