An international team led by the Faculty of Biology of the University of Barcelona has identified a new antibacterial mechanism that protects macrophages – defense cells in the immune system- from the infection of the bacteria Salmonella enterica serovar Typhimurium, a pathogen associated with several gastrointestinal diseases. This discovery –published in the journal Cell Reports– could open new exploration channels for pharmacological treatments of some bacterial infections. Joan Serret, researcher at the Experimental Toxicology and Ecotoxicology Technology Platform of the Barcelona Science Park (UTOX-PCB) is one of the co-authors of the study.

Macrophages are specialized cells in the immune system with diverse effector functions against pathogens and invasive agents.  However, although it seems a paradox, they become the preferential biological niche in some bacterial strains to replicate and spread around the body. 

This is the case, for instance, of Salmonella enterica serovar Typhimurium, an enteric bacterium that causes from mild gastroenteritis to severe systemic infections in humans. This strain, in particular, is able to survive and replicate inside the host macrophages as a previous step to spread around the other parts of the body.

S. Typhimurium avoids the bactericidal response so that after adhering to the surface of the macrophage, it secretes factors that modify the F-actin cytoskeleton of the host cell. This mechanism allows the bacteria entering the cell through special phagocytic vacuoles (containing Salmonella). Once they enter the cell, the bacterium transforms the vacuole’s conditions to turn it into a favourable environment to replicate and spread around the infected organism.

Nuclear receptors: how to limit bacterial infection?

Now, in this new study, the scientific team describes a mechanism that limits the capacity of S. Typhimurium to infect cells and spread in other tissues.Joan Serret researcher at researcher at the Experimental Toxicology and Ecotoxicology Technology Platform of the Barcelona Science Park  (UTOX-PCB) is one of the co-authors of the study, led by Prof. Annabel Valledor of the UB Faculty of Biology. 

“Our study reveals that pharmacological activation of transcription factors from the family of nuclear receptors –Liver X receptors or LXR- limits the bacterial infection in macrophages” says Professor Annabel Valledor, who leads the Group Nuclear receptors in Cancer, Metabolism and Inflammation of Nurcamein network. Nuclear receptors are transcription factors that shape physiological processes through the regulation of the gene expression of several targeted genes. LXR, in particular, can be activated by agonists (molecule activators) and play an important role in metabolic functions and the regulation of the immune response.

The UTOX-PCB  has contributed its experience at a technical level to the in vivo methodology of the experimental phase of the study. “As participants in the research, we are pleased and proud to have collaborated with our knowledge in a high impact scientific work. Our Unit combines the activity of a CRO provider of services focused on pre-clinical regulatory toxicology with trials of experimental toxicology for the screening of new drugs, so we keep in touch with pharmaceutical companies, spin-off and start-up of the sector. Collaboration with research groups in the university environment allows us to diversify our activity and to involve ourselves in the preliminary phases of the Discovery and development of new drugs”, said UTOX researcher Joan Serret.

Multiresistant bacteria: a battlefront in global health

According to the World Health Organization (WHO), resistance to antibiotics is one of the big threats for world health, food safety and world development. Despite being a natural phenomenon, bacterial multiresistance is speeding up due the excessive and wrong use of drugs. As a consequence, there are more and more infections that don’t respond to the common treatments due antibiotics losing their efficacy. 

“Facing the dangers that involve the apparition of antibiotic-resistant bacterial strains (more common every day), this new research study established the path of LXRs as a new mechanism in the regulation of the host-pathogen interaction which could be pharmacologically exploited as a potential strategy of “host-directed therapy” in certain bacterial infections” concludes Professor Annabel Valledor. 
 

• More information on the UB website [+]