Vilnius University Scientists Publish Discovery of New Bacterial Immune Signal in Nature

Scientists at Vilnius University’s Life Sciences Centre (VU LSC), together with colleagues from the Weizmann Institute of Science (Israel) and Harvard Medical School (USA), have uncovered a previously unknown type of immune signalling molecule produced by the Thoeris II defence system in bacteria — a major finding published today in Nature. The study, entitled “TIR domains produce histidine-ADPR as an immune signal in bacteria”, was led by Dr Giedrė Tamulaitienė’s research group.

This newly identified molecule is remarkable for its unique structure, linking two biologically essential components: histidine, an amino acid used to build proteins, and an adenine nucleotide, a building block of RNA. Until now, all known signalling molecules were composed solely of nucleotides. This discovery significantly broadens the scientific understanding of the diversity of immune signalling mechanisms in nature.

Like humans, animals, and plants, bacteria are constantly threatened by viruses. Over the course of evolution, they have developed a wide range of defence systems – some of which served as the evolutionary precursors to immune system components in higher organisms. Interest in bacterial antiviral systems surged after their applications were realised in genetic engineering. Landmark examples such as restriction–modification systems and CRISPR-Cas "molecular scissors" have even been recognised with Nobel Prizes.

Scientists have identified over 250 distinct antiviral defence systems in bacteria. Following previous work by Vilnius University researchers showing that small molecules can serve as infection signals within these systems, attention turned to exploring the diversity of such signalling mechanisms.

Discoveries like this not only deepen understanding of bacterial immune strategies but also lay the groundwork for innovations in genetic engineering, biotechnology, and even the development of new antibacterial therapies.

In this latest study, Dr Tamulaitienė’s group closely examined the Thoeris II system, composed of a sensor protein (TIR), which detects viruses, and a transmembrane effector protein (Macro), which receives the signal and triggers a response. Upon detecting viral infection, the TIR sensor synthesises a unique small molecule signal – His-ADPR.

“This ‘message’ – the signalling molecule – is recognised by the system’s effector, the Macro protein, which is embedded in the bacterial cell membrane,” explains Dr Tamulaitienė. “Once it receives the signal, the Macro proteins start to assemble with each other, damaging the cell membrane. In this way the infected bacterium sacrifices itself before the virus can replicate, allowing neighbouring bacteria to survive and preserve the population.”

Using X-ray crystallography, the VU LSC team determined the structure of the effector protein bound to the new signalling molecule. Meanwhile, the team at the Weizmann Institute confirmed that this molecule is indeed synthesised in bacteria upon viral infection. Researchers at Harvard Medical School revealed the structure of a viral anti-Thoeris ‘sponge’ protein – a countermeasure the virus uses to evade the defence system – with His-ADPR bound inside.

The research published in Nature was carried out by Dr Giedrė Tamulaitienė’s team in collaboration with leading global experts in bacterial antiviral systems – Professor Rotem Sorek (Weizmann Institute of Science, Israel) and Professor Philip Kranzusch (Harvard Medical School, USA). The main body of research at VU LSC was conducted by PhD student Džiugas Sabonis, with valuable contributions from PhD student Deividas Vilutis, Audronė Rukšėnaitė, Dr Arūnas Šilanskas, and Dr Mindaugas Zaremba.

The Weizmann Institute team consisted of Carmel Avraham, Ehud Herbst, Azita Leavitt, Erez Yirmiya, Ilya Osterman, and Gil Amitai. The research at Harvard Medical School was carried out by Renee Chang, Allen Lu and Hunter Toyoda.

Nature is among the most highly cited and prestigious scientific journals in the world. It publishes the best peer-reviewed research across all areas of science and technology, selected for its originality, significance, interdisciplinarity, relevance, accessibility, and often surprising conclusions.