REDQUEEN: €2.5 Million ERC Project to Decode How Bacteria Detect Phages and Engineer Viral Countermeasures
A new €2.5 million European Research Council project at Delft University of Technology will investigate one of the most fundamental questions in bacteriophage biology: how does a bacterium realize that a virus has entered its cell? REDQUEEN, led by molecular microbiologist Professor Stan Brouns, will examine the molecular signals bacteria use to detect different stages of phage infection, how those signals activate antiviral defence systems and how bacteriophages have evolved proteins capable of preventing that detection.
The project goes one step further by attempting to transform those discoveries into tools for phage engineering. REDQUEEN plans to use artificial intelligence-driven protein design to create new proteins capable of interfering with bacterial phage-defence systems, with the longer-term objective of engineering bacteriophages that can overcome immunity more effectively. The European Commission lists the project under the ERC Advanced Grant programme with an EU contribution of €2.5 million. The grant agreement was signed on August 19, 2026, and the five-year project is scheduled to run at TU Delft from December 1, 2026 until November 30, 2031.
The programme addresses a problem that is increasingly important for therapeutic phage development. Finding a bacteriophage that can recognize and attach to a pathogenic bacterium is only the first step toward successful infection. Once the viral genome enters the bacterial cell, it encounters an extensive intracellular immune system capable of detecting foreign nucleic acids, viral proteins, modifications to cellular structures or disturbances produced during phage replication. A phage can therefore possess the correct host receptor and still fail because bacterial immunity arrests infection before enough progeny viruses are produced.
More than 150 distinct bacterial phage-defence systems have now been catalogued, according to the REDQUEEN project description, although the molecular mechanisms responsible for infection sensing remain poorly understood for many of them. CRISPR-Cas is the best-known example, but genomic studies over the past decade have revealed a much larger defensive repertoire including systems such as BREX, DISARM, Thoeris, retrons, CBASS, Gabija, Zorya, Druantia, RADAR and multiple AVAST families. These systems use remarkably different molecular strategies, yet all face the same initial problem: they need to determine that a phage infection is occurring before deploying a response.
This recognition stage is especially important because many antiviral responses are highly destructive. Some defence systems degrade nucleic acids, interfere with essential metabolism, deplete cellular molecules such as NAD+, disrupt membranes or induce an abortive-infection state in which the infected bacterium sacrifices itself before the phage can spread. Such mechanisms cannot simply remain permanently active without imposing a substantial fitness cost on the bacterial population, so they require sensors capable of distinguishing infection from normal physiology.
REDQUEEN is specifically designed to investigate this sensing layer rather than considering bacterial immunity solely through its downstream effectors. The project will ask how different defence systems recognize phage invasion at different points during infection, how recognition is coupled to activation of an antiviral response and which viral adaptations interfere with those processes. This distinction between sensing and killing is important because blocking the sensor could theoretically neutralize an entire defence pathway before its destructive mechanism is activated.
The project builds directly on previous discoveries from the Brouns laboratory. One research direction involves CRISPR-associated regulatory mechanisms capable of responding to invading DNA, while another concerns multidomain nucleases that can respond to RNA generated during infection. These systems illustrate how bacterial cells can monitor different molecular signatures of phage replication rather than relying on a single universal indicator of viral invasion.
Recent work from the Delft group has provided an especially clear example of infection sensing in jumbo phages. In a 2026 study published in Molecular Cell, Aswin Muralidharan, Ana Rita Costa, Stan Brouns and colleagues characterized the bacterial defence system AVAST type 5 and showed how it recognizes an early stage of jumbo-phage infection. Nucleus-forming jumbo phages are particularly difficult targets for bacterial immunity because they protect their genomes within specialized intracellular structures that can shield viral DNA from several DNA-targeting defence systems.
The researchers found that AVAST type 5 does not need direct access to the protected phage genome. Instead, the defence system localizes around an early infection compartment and detects an essential phage protein named JADA, or Jumbo phage Avs5 Defense Activator. Recognition triggers a Sir2-like effector that rapidly hydrolyses NAD+, interfering with formation of the mature phage nucleus and stopping infection. The study demonstrates how bacteria can evolve sensors against a viral activity that phages cannot easily abandon because the detected protein performs an important function early in their life cycle.
That result illustrates the type of molecular logic REDQUEEN aims to investigate more broadly. From the bacterial perspective, an ideal sensor detects something sufficiently characteristic of infection that false activation remains rare. From the phage perspective, any molecule repeatedly used as an infection signature becomes an evolutionary vulnerability, creating pressure for viral variants that hide, modify or suppress the relevant signal.
The resulting evolutionary cycle explains the project's name. Bacterial populations continuously evolve new ways to recognize phages, while bacteriophages evolve new ways to escape those defences. Neither side reaches a permanent solution because every successful innovation changes the selective environment faced by the other, producing an ongoing molecular arms race.
Phages have consequently accumulated extensive counter-defence repertoires of their own. Anti-CRISPR proteins are among the most famous examples, but they represent only one part of a much broader collection of viral factors capable of interfering with bacterial immunity. Some counter-defence proteins are highly specific, whereas others can inhibit several unrelated defence systems.
A 2025 Cell Host & Microbe study from Ana Rita Costa, Daan van den Berg, Stan Brouns and colleagues demonstrated this diversity using Pseudomonas phages of the Pbunavirus group. The researchers identified five anti-defence proteins, including inhibitors targeting Druantia type III, Thoeris type III and Zorya type I. They also discovered two related proteins, Bdi1 and Bdi2, capable of suppressing multiple unrelated bacterial defence systems.
The finding is particularly relevant to REDQUEEN because it suggests that some phage proteins may act at points shared by otherwise different immune pathways. A phage carrying one broad inhibitor could consequently neutralize several barriers rather than requiring a separate countermeasure for every defence encoded by its host. Understanding how such proteins function could reveal molecular vulnerabilities that are especially useful for therapeutic engineering.
The REDQUEEN description refers to this process as “counter-sensing.” Instead of simply resisting the final antibacterial response, phages may interfere with the molecular steps through which bacteria recognize that infection is occurring. If an immune system cannot detect the appropriate viral signal, its downstream effector may never become activated.
Determining exactly where this interference occurs will require more than genomic comparisons. REDQUEEN plans to combine molecular microbiology with sequence- and structure-based genomics, single-molecule biophysics and AI-driven protein design. This interdisciplinary strategy is intended to connect large-scale discovery of candidate defence and counter-defence proteins with direct measurements of how individual molecules interact during infection.
Single-molecule approaches could be particularly informative because many sensing reactions are transient and difficult to resolve from population-level experiments. A defence protein may interact briefly with a viral RNA, DNA structure or protein before undergoing a conformational change that activates a downstream response. Observing those transitions directly can reveal mechanistic steps that would otherwise remain hidden in bulk biochemical measurements.
Structural information will provide another layer. If researchers determine how a bacterial sensor recognizes a particular viral molecule, they can identify the physical interface responsible for activation and investigate how natural phage variants modify that interface. Conversely, structural characterization of viral inhibitors can reveal how surprisingly small proteins disable much larger bacterial immune complexes.
The most ambitious translational component of REDQUEEN is the planned use of artificial intelligence to design entirely new defence inhibitors. Rather than relying exclusively on counter-defence proteins discovered in natural phage genomes, the project intends to develop de novo proteins capable of interfering with the sensing or action of bacterial antiviral systems.
Recent advances in computational protein design make such an approach increasingly plausible. AI-assisted methods can search structural spaces that would be difficult to explore through conventional mutagenesis and can propose proteins designed to bind particular molecular surfaces. REDQUEEN intends to apply these capabilities to bacterial immune systems, although the project is scheduled to begin only in December 2026 and no successful AI-designed anti-defence proteins from the programme have yet been reported.
If successful, such proteins could become modular components for engineered phages. A therapeutic phage that efficiently recognizes a multidrug-resistant bacterium but is blocked by one of its intracellular defence systems could theoretically be equipped with an inhibitor targeting that barrier. Instead of discarding an otherwise promising phage, researchers might be able to modify its counter-defence repertoire.
This possibility is particularly relevant because bacterial pathogens can encode several defence systems simultaneously. Recent comparative-genomic studies have shown that antiviral systems frequently cluster in defence islands and vary substantially between strains of the same species. Two bacterial isolates that appear closely related according to conventional taxonomy can therefore present very different immunological environments to the same bacteriophage.
That variability helps explain why phage host range can be difficult to predict from receptor interactions alone. A phage may adsorb successfully to several strains but produce plaques on only a subset because intracellular defence determines whether the infection proceeds. Therapeutic matching may consequently require knowledge of both the entry mechanisms used by the phage and the defensive repertoire encoded by the target bacterium.
Engineered counter-defence could eventually complement other strategies for expanding phage activity. Researchers are already investigating receptor-binding protein engineering, directed evolution, synthetic genome modification and phage cocktail design as ways to overcome bacterial resistance. REDQUEEN focuses on a different layer of the problem by targeting the molecular immune systems encountered after infection has already begun.
There are important biological constraints to this strategy. Bacterial defence systems are extraordinarily diverse, and a countermeasure effective against one mechanism may provide no benefit against another. Adding genetic cargo to a phage can also affect genome packaging limits, replication kinetics, stability and fitness, meaning that a theoretically effective inhibitor must still function within the constraints of the viral life cycle.
Bacteria can additionally respond evolutionarily to engineered counter-defence. A phage optimized to suppress one immune pathway creates selection pressure favouring bacteria carrying alternative defences or modified versions of the targeted system. Therapeutic engineering therefore does not eliminate the evolutionary arms race that inspired REDQUEEN; it deliberately enters that arms race with a better mechanistic understanding of both sides.
This is one reason why broad counter-defence factors are scientifically attractive. A protein capable of blocking several distinct defence systems could reduce the number of modifications required to create a robust therapeutic phage. At the same time, broad inhibition must be mechanistically understood because different systems may share cellular components whose manipulation could have unexpected consequences for phage replication or bacterial physiology.
REDQUEEN also has significance beyond phage therapy. Several bacterial immune mechanisms share conceptual or evolutionary relationships with innate immune pathways found in more complex organisms. Research on CRISPR-Cas already demonstrated how studying bacterial defence against viruses can uncover molecular systems with applications far beyond microbiology, while recent discoveries involving cyclic nucleotide signalling, STAND proteins and other antiviral pathways have revealed additional parallels between prokaryotic and eukaryotic immunity.
The ERC project explicitly identifies this connection as part of the scientific motivation. Understanding the fundamental principles by which cells sense infection may reveal common strategies that have been repeatedly used or adapted during evolution, even when the molecular components differ substantially between bacteria and animals.
For the Brouns laboratory, REDQUEEN represents a continuation of a research programme that already combines fundamental defence biology with therapeutic phage development. The group at TU Delft's Department of Bionanoscience and Kavli Institute of Nanoscience studies CRISPR and other phage-defence systems, investigates how viruses evade those systems and isolates or engineers bacteriophages for potential therapeutic applications.
The timing of the project is significant because bacterial immunity has moved from a relatively narrow field centred largely on restriction enzymes and CRISPR to an increasingly complex landscape containing hundreds of candidate systems, sensors, effectors and viral antagonists. Genomic discovery is now progressing faster than detailed mechanistic characterization, creating a growing catalogue of immune genes whose triggers and molecular targets remain incompletely understood.
REDQUEEN is designed to address that gap by focusing on the moment when infection becomes recognizable to the bacterial cell. Identifying the triggering event can explain why a defence system responds to some phages but not others, reveal how viruses evolve escape mechanisms and expose molecular points where immunity could potentially be manipulated.
For phage therapy, this could eventually help transform bacterial defence profiling into a design variable rather than simply an obstacle discovered during laboratory screening. A bacterial isolate could theoretically be characterized for both receptor availability and intracellular antiviral systems, allowing researchers to select or engineer phages with countermeasures appropriate to that specific defensive landscape.
Such a level of rational design remains a future objective rather than an existing clinical capability. REDQUEEN is a fundamental ERC research project beginning at the end of 2026, and the European Commission describes engineered phages overcoming bacterial defence as an intended outcome of the research rather than an already demonstrated therapeutic technology.
The distinction is important because overcoming bacterial immunity in culture does not automatically produce a clinically useful phage. Therapeutic candidates must still demonstrate appropriate host specificity, replication kinetics, genetic stability, manufacturing characteristics, safety, pharmacology and efficacy under conditions encountered during infection. Engineered phages may also face additional regulatory requirements depending on how extensively their genomes have been modified.
Nevertheless, identifying exactly how bacterial cells detect viral invasion could provide a missing mechanistic layer for future phage design. Current phage engineering often begins with measurable outcomes such as host range or plaque formation and then modifies viral components to improve them. REDQUEEN instead seeks to understand the molecular surveillance systems responsible for failure and use that knowledge to design targeted countermeasures.
The €2.5 million ERC investment therefore supports a programme positioned between basic molecular microbiology and synthetic phage engineering. Its first objective is to reveal how infection sensing actually works, but its longer-term ambition is to convert that knowledge into proteins and engineered viruses capable of bypassing bacterial antiviral defences.
If those objectives are achieved, future therapeutic phages could potentially be selected not only because they recognize the correct bacterial receptor, but because they are equipped to survive the intracellular immune systems waiting behind it. REDQUEEN will spend the next five years investigating how bacteria detect their viral predators and whether understanding that detection can provide the information required to design better phages against antibiotic-resistant pathogens.
Sources :
European Commission CORDIS — REDQUEEN: Uncovering infection sensing in the molecular arms race between Bacteria and Bacteriophages. Grant Agreement 101265190. CORDIS confirms the €2.5 million EU contribution, August 19, 2026 signature date, December 1, 2026 start, November 30, 2031 end date, TU Delft host institution and the planned use of molecular microbiology, single-molecule biophysics and AI protein design.
https://cordis.europa.eu/project/id/101265190
European Research Council — ERC Advanced Grants 2025: List of Principal Investigators, Life Sciences. The official ERC results identify Stan Brouns, Delft University of Technology, REDQUEEN and the project title “Uncovering infection sensing in the molecular arms race between Bacteria and Bacteriophages” under panel LS6.
https://erc.europa.eu/system/files/2026-06/erc-2025-adg-results-ls.pdf
European Research Council — ERC Advanced Grants: Nearly €840 million to support Europe’s leading researchers, June 23, 2026.
https://erc.europa.eu/news-events/news/erc-2025-advanced-grants-results
Brouns Laboratory, Delft University of Technology — Research interests and phage infection and immunity programme.
https://www.brounslab.org/
Costa AR, van den Berg DF, Esser JQ et al. — “Bacteriophage genomes encode both broad and specific counter-defense repertoires to overcome bacterial defense systems.” Cell Host & Microbe 33 (2025): 1161–1172.e5.
https://doi.org/10.1016/j.chom.2025.06.010
Muralidharan A, Costa AR, Fierlier D et al. — “Molecular basis for anti-jumbo phage immunity by AVAST type 5.” Molecular Cell 86 (2026): 740–756.e9. The study identifies JADA sensing by AVAST type 5 and subsequent NAD+ depletion as a mechanism for blocking jumbo-phage infection.
https://doi.org/10.1016/j.molcel.2026.01.004
van den Berg DF, Costa AR, Esser JQ et al. — “Discovery of phage defense systems through component modularity networks.” bioRxiv (2025), preprint.
https://doi.org/10.1101/2025.09.30.679545
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