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HEIndividual fellowship2023–2025

BacPro · Decipher the role of late lytic genes activator, a key determinant of active lysogeny in Listeria monocytogenes

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-10-01 → 2025-09-30
EU contribution
€200,538
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

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Results in brief

Decipher the role of late lytic genes activator, a key determinant of active lysogeny in Listeria monocytogenes

Foodborne infections caused by Listeria monocytogenes remain a major public-health concern worldwide. This bacterium can survive in many environments, including food-processing facilities and the human body, making it difficult to control. Surprisingly, Listeria also carries viruses called prophages, which live quietly inside the bacterial genome without killing their host. Although these prophages lead to bacterial killing under stress, they seem to have evolved to support bacterial survival in the mammalian environment. The BacPro project set out to understand how these prophages influence the behaviour and survival of Listeria, especially when the bacterium infects a mammalian host. The focus was on a phage protein called LlgA, which normally activates phage genes involved in viral reproduction. Interestingly, these genes remain off when Listeria is inside a host, and the reasons for this were unknown before the project. The project’s overall objective was to uncover how the bacterium controls these viral genes and how this silent cooperation between bacteria and their resident prophages supports infection. By identifying the molecular signals that switch phage genes on or off, the project contributes to a better understanding of Listeria survival strategies as a pathogen. These insights have broader importance: understanding how prophages shape bacterial virulence can support efforts to design new antimicrobial tools, phage-based therapies, and food-safety strategies. The results of the project help address key public health needs by improving our understanding of how dangerous bacteria remain resilient in the environment and within the human body.

Data: CORDIS, © European Union

Project objective

Listeria monocytogenes (Lm) is an intracellular bacterial pathogen. Lm strain 10403S harbors an active prophage in its genome integrated within the comK gene. It was previously discovered by the Herskovits lab (host lab) that during Lm infection of macrophages, the prophage undergoes excision from comK, yielding an intact and functional comK gene that assists the escape of the bacteria from the macrophages’ phagosomes to the cytosol. Notably, this phage excision does not lead to virion production and bacterial lysis in the mammalian environment, suggesting a cooperative phage behaviour. It was further shown that the phage early genes are transcribed in the intracellular niche, whereas the late lytic genes are not, thereby preventing the progression of the lytic pathway. This type of adaptive phage behaviour was termed “active-lysogeny”, representing cases where prophages cooperate with their hosts. To better understand active-lysogeny in Lm, in this BacPro proposal I aim to decipher the mechanism by which the late lytic genes are repressed in the intracellular niche. It was previously demonstrated that the late genes are positively regulated by LlgA, an ArpU-family transcriptional regulator that is encoded by the phage. Preliminary data in the lab indicate that LlgA is thermo-regulated at the protein level. LlgA regulation at the temperature of the mammalian niche was shown to relay on the bacteria, and to involve a mechanism similar to regulated proteolysis. Based on these findings, in my proposal I aim to identify the bacterial proteases that are involved in its cleavage. Further I aim to determine LlgA active form, as well as its cleavage site/s. These studies will provide a molecular insight into the mechanism by which Lm controls the phage in the mammalian environment, and further increase our understanding of how lysogenic phages interact with bacterial pathogens, an information that might lead to a better design of phages for the use of phage therapy.

Original text from CORDIS.

Participants

  • TEL AVIV UNIVERSITY · Tel AvivCoordinatorIsrael

Links

Data: CORDIS, © European Union