Periodic Reporting for period 2 - DEFEND (Novel mechanisms of adaptive and innate bacteriophage immunity)
Berichtszeitraum: 2022-12-01 bis 2024-05-31
Bacteriophages, or phages for short, are viruses that specifically target and infect bacteria. This interaction is not static; it is dynamic and competitive. Bacteria develop defensive strategies to shield themselves from these viruses, and in response, phages evolve new tactics to bypass these defenses. This continuous struggle between bacteria and phages is similar to an "arms race" in nature, where both the attacker and defender constantly upgrade their strategies to outcompete the other.
To dive deeper into this biological battle, the European Research Council (ERC) has funded a project called DEFEND. The main goal of this project is to thoroughly investigate how phages attack bacterial cells and how these cells defend themselves. By understanding these mechanisms, scientists hope to develop new ways to treat infections caused by bacteria that no longer respond to traditional antibiotics.
At the heart of this research are the defense systems bacteria use. One well-known system is called CRISPR, an adaptive immune mechanism that allows bacteria to "remember" viruses they have encountered before and defend against them more effectively in future encounters. In addition to CRISPR, bacteria have a variety of other innate immune defenses that operate at different levels—molecular, cellular, and within whole communities of bacteria. These defenses help protect bacteria from being overwhelmed by phage attacks.
The DEFEND project plans to explore these defense mechanisms extensively. We will study how these systems work from the smallest scale of individual molecules up to the larger scale of bacterial populations. This comprehensive study will help scientists understand not only how bacteria fight off phages but also identify any potential weaknesses in phage strategies that could be exploited to enhance phage therapy—an emerging treatment method where phages are used to attack antibiotic-resistant bacteria.
By gaining a deeper understanding of the complex interplay between phage attacks and bacterial defenses, the DEFEND project aims to open new avenues for developing effective treatments for stubborn bacterial infections, potentially revolutionizing how we deal with antibiotic resistance.
To dive deeper into this biological battle, the European Research Council (ERC) has funded a project called DEFEND. The main goal of this project is to thoroughly investigate how phages attack bacterial cells and how these cells defend themselves. By understanding these mechanisms, scientists hope to develop new ways to treat infections caused by bacteria that no longer respond to traditional antibiotics.
At the heart of this research are the defense systems bacteria use. One well-known system is called CRISPR, an adaptive immune mechanism that allows bacteria to "remember" viruses they have encountered before and defend against them more effectively in future encounters. In addition to CRISPR, bacteria have a variety of other innate immune defenses that operate at different levels—molecular, cellular, and within whole communities of bacteria. These defenses help protect bacteria from being overwhelmed by phage attacks.
The DEFEND project plans to explore these defense mechanisms extensively. We will study how these systems work from the smallest scale of individual molecules up to the larger scale of bacterial populations. This comprehensive study will help scientists understand not only how bacteria fight off phages but also identify any potential weaknesses in phage strategies that could be exploited to enhance phage therapy—an emerging treatment method where phages are used to attack antibiotic-resistant bacteria.
By gaining a deeper understanding of the complex interplay between phage attacks and bacterial defenses, the DEFEND project aims to open new avenues for developing effective treatments for stubborn bacterial infections, potentially revolutionizing how we deal with antibiotic resistance.
Project DEFEND has yielded a number of discoveries in terms of adaptive and innate immune systems of bacteria. Below I will highlight three of these discoveries:
Throughout the the DEFEND project, our team has conducted extensive research, uncovering significant insights into the immune systems of bacteria. Three notable discoveries have been made, advancing our understanding of bacterial defenses against phage assaults.
Firstly, a novel variant of CRISPR mechanisms, known as CRISPR-controlled proteases, has been identified. Unlike the traditional CRISPR systems that employ nucleases to cleave nucleic acids, these specialized systems utilize a guide RNA to pinpoint phage messenger RNA and subsequently activate proteases. The activation of these proteases represents an alternative pathway, augmenting the bacterial immune response against phage predation through protein degradation cell suicide pathways. This discovery may lead to further molecular biology tools that can edit proteomes in the future.
Secondly, research has uncovered an innovative evasion strategy employed by phages: the encoding of tRNAs that are resistant to cleavage by host defense systems. These phages produce specific tRNAs that function as uncleavable components of the translation machinery, evading bacterial defense systems that typically target and degrade tRNA molecules to deplete the host from the ability to produce proteins, thereby stopping bacteriophage infection. This mechanism of escape signifies a sophisticated level of adaptive evolution among phages, presenting a challenge to the effectiveness of bacterial immune systems. Furthermore, this finding may solve the 50 year old mystery why phages encode their own tRNAs.
Lastly, an a detailed bioinformatic analysis uncovered an accumulation of defense systems in clinical strains of Pseudomonas aeruginosa, resulting in heightened resistance to phage infection. This accumulation signifies a robust defensive stance, enhancing the bacterium's survival against phage attacks. This phenomenon underscores the importance of understanding the dynamics of bacterial immune responses, particularly in clinically relevant contexts where antibiotic resistance is prevalent.
These discoveries, together, contribute to a more comprehensive understanding of the intricate interplay between bacterial defenses and phage offensive strategies. This knowledge is crucial in advancing the development of phage therapies, especially as a potential solution to combat antibiotic-resistant bacterial infections.
Throughout the the DEFEND project, our team has conducted extensive research, uncovering significant insights into the immune systems of bacteria. Three notable discoveries have been made, advancing our understanding of bacterial defenses against phage assaults.
Firstly, a novel variant of CRISPR mechanisms, known as CRISPR-controlled proteases, has been identified. Unlike the traditional CRISPR systems that employ nucleases to cleave nucleic acids, these specialized systems utilize a guide RNA to pinpoint phage messenger RNA and subsequently activate proteases. The activation of these proteases represents an alternative pathway, augmenting the bacterial immune response against phage predation through protein degradation cell suicide pathways. This discovery may lead to further molecular biology tools that can edit proteomes in the future.
Secondly, research has uncovered an innovative evasion strategy employed by phages: the encoding of tRNAs that are resistant to cleavage by host defense systems. These phages produce specific tRNAs that function as uncleavable components of the translation machinery, evading bacterial defense systems that typically target and degrade tRNA molecules to deplete the host from the ability to produce proteins, thereby stopping bacteriophage infection. This mechanism of escape signifies a sophisticated level of adaptive evolution among phages, presenting a challenge to the effectiveness of bacterial immune systems. Furthermore, this finding may solve the 50 year old mystery why phages encode their own tRNAs.
Lastly, an a detailed bioinformatic analysis uncovered an accumulation of defense systems in clinical strains of Pseudomonas aeruginosa, resulting in heightened resistance to phage infection. This accumulation signifies a robust defensive stance, enhancing the bacterium's survival against phage attacks. This phenomenon underscores the importance of understanding the dynamics of bacterial immune responses, particularly in clinically relevant contexts where antibiotic resistance is prevalent.
These discoveries, together, contribute to a more comprehensive understanding of the intricate interplay between bacterial defenses and phage offensive strategies. This knowledge is crucial in advancing the development of phage therapies, especially as a potential solution to combat antibiotic-resistant bacterial infections.
The DEFEND project has made considerable progress in advancing our knowledge of bacterial immune responses, extending beyond the previously established scientific boundaries. These advancements provide a promising trajectory for our understanding of bacteriophage defense and how bacteriophages may be used to treat antibiotic resistant infections more effectively.
The identification of CRISPR-controlled proteases signals a paradigm shift in our understanding of bacterial immune mechanisms. Traditional CRISPR systems, which function through nucleic acid cleavage, have been extensively documented. However, the discovery of CRISPR systems that instead initiate protein degradation via proteases presents a novel line of defense. This understanding opens up new avenues for the manipulation of bacterial or eukaryal proteomes.
The revelation of phage-encoded tRNAs as a means to circumvent bacterial defenses also marks a significant leap forward. It highlights the adaptive capabilities of phages, thereby offering a new layer of complexity to the evolutionary arms race between bacterial hosts and their viral antagonists. This insight is instrumental in the design of next-generation phage therapies that can anticipate and overcome such evasive tactics.
Lastly, the observed accumulation of defense mechanisms in Pseudomonas aeruginosa strains underscores the potential for developing targeted treatments. By understanding the fortifications that make these bacteria particularly robust against phage attacks, we can direct our efforts toward dismantling these defenses, which may prove crucial in combatting stubborn infections. We expect to uncover more breakthroughs towards the conclusion of the DEFEND project.
The identification of CRISPR-controlled proteases signals a paradigm shift in our understanding of bacterial immune mechanisms. Traditional CRISPR systems, which function through nucleic acid cleavage, have been extensively documented. However, the discovery of CRISPR systems that instead initiate protein degradation via proteases presents a novel line of defense. This understanding opens up new avenues for the manipulation of bacterial or eukaryal proteomes.
The revelation of phage-encoded tRNAs as a means to circumvent bacterial defenses also marks a significant leap forward. It highlights the adaptive capabilities of phages, thereby offering a new layer of complexity to the evolutionary arms race between bacterial hosts and their viral antagonists. This insight is instrumental in the design of next-generation phage therapies that can anticipate and overcome such evasive tactics.
Lastly, the observed accumulation of defense mechanisms in Pseudomonas aeruginosa strains underscores the potential for developing targeted treatments. By understanding the fortifications that make these bacteria particularly robust against phage attacks, we can direct our efforts toward dismantling these defenses, which may prove crucial in combatting stubborn infections. We expect to uncover more breakthroughs towards the conclusion of the DEFEND project.