The ‘Nature’ journal has published a groundbreaking article on the HepS protein in Salmonella enterica bacteria, co-authored by dr Grzegorz Grabe from the Department of Structural Biology at the Intercollegiate Faculty of Biotechnology UG and MUG. ‘The knowledge gained in this work can be used to optimise phage therapy, an increasingly important alternative to the growing resistance of bacteria to antibiotics,’ says the scientist.
Dr Grzegorz Grabe, assistant professor and Principal Investigator for several research projects at the Department of Structural Biology of the IFB UG and MUG, is conducting research on the molecular mechanisms responsible for the survival and virulence of the bacterial pathogen Salmonella enterica, which infects both animals and humans.
The prestigious journal ‘Nature’ published an article entitled ‘A prophage-encoded abortive infection protein preserves host and prophage spread’, which was written in collaboration between dr Grzegorz Grabe and the team of prof. Sophie Helaine from Harvard Medical School in the USA. It describes the HepS defence system, which protects the bacterium from infection by bacteriophages (viruses that infect bacteria). ‘What is particularly interesting is that the gene encoding the HepS protein is located within the Gifsy-1 prophage, an integrated, dormant bacteriophage that is an integral part of the Salmonella enterica genome,’ explains dr Grzegorz Grabe.
‘Better to burn one house to save the whole city’
HepS acts as an alarm system: it detects an attack by a foreign virus and destroys key tRNA molecules in the infected cell, preventing the attacking virus from spreading and protecting the bacterial population and the prophage it contains. Thanks to this clever mechanism, both the bacterium and its prophage can survive and spread in the environment.
Simply put, the HepS protein acts as a ‘destruction alarm’ and leads to the elimination of a single cell according to the principle: ‘Better to burn one house to save the whole city.’
‘This is known as abortive infection. The bacteriophage enters the bacterium but is quickly detected. In response, the bacterium ‘commits suicide’, preventing the virus from multiplying inside it and infecting other cells. In this case, the virus is detected by the HepS protein. It forms tetramers (four-molecule complexes) that bind to the viral J protein. After binding, HepS is activated and cuts bacterial tRNA, molecules necessary for protein production. As a result, the cell stops producing proteins and ‘dies’, and the virus is unable to use it,’ says the researcher.
Optimisation of phage therapy and new therapeutic strategies
The article, which appeared in Nature, is a groundbreaking publication in many respects. How can our scientist's discoveries be used in the treatment of salmonella poisoning? ‘The knowledge gained in this work can be used to optimise phage therapy, an increasingly important alternative to the growing resistance of bacteria to antibiotics. In addition, understanding the mechanism of action of the HepS protein opens up the possibility of developing a new therapeutic strategy. Once activated, HepS becomes toxic to the bacterial cell. This makes it possible to design mimetic peptides that would mimic the viral J protein and artificially activate HepS, leading to the inhibition of growth or death of pathogenic bacteria possessing this defence system,’ according to the scientist.
Dr Grzegorz Grabe adds that the HepS protein was discovered during research into the defence mechanisms of bacteria provided by the Gifsy-1 prophage. One defence system encoded by this prophage, the RemAIN system, had already been characterised earlier. However, the removal of RemAIN alone did not cause as large an increase in the susceptibility of bacteria to bacteriophage infection as the removal of the entire Gifsy-1 prophage from the genome. The significantly greater susceptibility of Salmonella bacteria to bacteriophage infection after Gifsy-1 deletion indicated that this prophage must encode an additional, independent defence element. This is how the HepS protein was identified.
Nature is one of the oldest and most prestigious scientific journals, in which numerous Nobel laureates have published their work, including the discoverers of the double helix structure of DNA (1953) and the preliminary three-dimensional structure of myoglobin (1958).
The full text of the article can be found here.