Ancient Immune Systems: Sensing and Signaling in Bacterial-Phage Conflict

<p>Viruses are among the most significant selective pressures shaping the evolution of life on Earth. In the microbial world, bacteriophages (phage) are bacterial viruses and drive a continuous evolutionary arms race that has led to an extraordinary diversity of bacterial defense mechanisms [1]. These systems are thought to have provided the evolutionary foundation for numerous eukaryotic immune strategies [2]. Experimental studies have validated many of these anti-phage defense systems and revealed the mechanisms by which they disrupt phage infection [3]. Nonetheless, major gaps persist in our understanding of how bacterial immune systems recognize bacteriophage infection to trigger immunity. This dissertation examines the molecular basis of this sensing process, offering new perspectives on host–pathogen interactions and illuminating conserved principles of immune defense across domains of life. Our first major discovery revealed that the bacterial Thoeris system, a Toll-interleukin 1 receptor (TIR) domain-based immune system in bacteria, detects specific phage capsid proteins [4]. This recognition event triggers the production of a signaling molecule that activates the depletion of an essential metabolite, limiting viral propagation. The second discovery demonstrated that cyclic oligonucleotide-based antiphage signaling systems (CBASS) recognize infection through the recognition of structured bacteriophage RNAs [5]. These RNAs bind bacterial cyclases, promoting the production of a signaling molecule that activates downstream effectors to mount an immune response. Since CBASS and Thoeris are orthologous to cGAS-STING and Toll-like receptors (TLRs), respectively, in mammalian innate immunity, these findings highlight conserved mechanisms for the activation of antiviral defense pathways across evolutionary domains [1].</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year

2026

Author dc:creator

• Roberts, Cameron Grace

Contributors dc:contributor

• Luciano Marraffini

• phage
• innate immunity
• signaling systems
• cyclic nucleotide
• abortive infection
• sensing
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/839

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1843