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......@@ -23,13 +23,13 @@ relevantAbstracts:
---
```
2. The following paragraphs
- Description
- Molecular mechanisms
- Example of genomic structure
- Distribution of the system among prokaryotes
- Structure
- Experimental validation
- References with the following syntax : `:ref{doi=my-doi}`.
- Description
- Molecular mechanisms
- Example of genomic structure
- Distribution of the system among prokaryotes
- Structure
- Experimental validation
- References with the following syntax : `:ref{doi=my-doi}`.
- [ ] The header contains all the required information. The information provided in the header is required to display the list of defense systems.
- The mandatory fields are :
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......@@ -25,16 +25,15 @@ In response to this evolutionary pressure, bacteria have developed an arsenal of
## History
The first anti-phage defense system was discovered in the early 1950s by two separate teams of researchers (Luria and Human, 1952 ; Bertani and Wiegle 1952). Luria and Human reported a mysterious phenomenon, where one phage was only capable of infecting a specific bacterial strain once. The progeny phages produced by this first round of infection had lost their ability to infect the same strain again, yet remained able to infect other bacterial strains. For them, this could only mean that "the genotype of the host in which a virus reproduces affects the phenotype of the new virus" (Luria and Human, 1952). A similar phenomenon was shortly after described by Bertani and Wiegle.
The first anti-phage defense system was discovered in the early 1950s by two separate teams of researchers :ref{doi=10.1128/jb.64.4.557-569.1952}, :ref{doi=10.1128/jb.65.2.113-121.1953}. Luria and Human reported a mysterious phenomenon, where one phage was only capable of infecting a specific bacterial strain once. The progeny phages produced by this first round of infection had lost their ability to infect the same strain again, yet remained able to infect other bacterial strains. For them, this could only mean that "the genotype of the host in which a virus reproduces affects the phenotype of the new virus" :ref{doi=10.1128/jb.64.4.557-569.1952}. A similar phenomenon was shortly after described by Bertani and Wiegle.
Their work was in fact the first report of what would later be named Restriction-Modification ([RM](/defense-systems/rm)) system, which is considered to be the first anti-phage defense system discovered.
The sighting of a second defense system occured more than 40 years later, in the late 1980s, when several teams around the world observed arrays containing short, palindromic DNA repeats clustered together on the bacterial genome (Barrangou et al., 2017). Yet, the biological function of these repeats was only elucidated in 2007, when a team of researchers demonstrated that these repeats were part of a new anti-phage defense systems :ref{doi=10.1126/science.1138140}, known as [CRISPR-Cas system](https://en.wikipedia.org/wiki/CRISPR).
The sighting of a second defense system occured more than 40 years later, in the late 1980s, when several teams around the world observed arrays containing short, palindromic DNA repeats clustered together on the bacterial genome :ref{doi=10.1038/nmicrobiol.2017.92}. Yet, the biological function of these repeats was only elucidated in 2007, when a team of researchers demonstrated that these repeats were part of a new anti-phage defense systems :ref{doi=10.1126/science.1138140}, known as [CRISPR-Cas system](https://en.wikipedia.org/wiki/CRISPR).
Following these two major breakthroughs, knowledge of anti-phage systems remained scarce for some years. Yet, in 2011, Makarova and colleagues revealed that anti-phage systems tend to colocalize on the bacterial genome in defense-islands. This led to a guilt-by-association hypothesis : if a gene or a set of genes is frequently found in bacterial genomes in close proximity to known defense systems, such as RM or CRISPR-Cas systems, then it might constitute a new defense system. This concept had a large role in the discovery of an impressive diversity of defense systems in a very short amount of time. To date, more than 60 defense systems have been described.
Following these two major breakthroughs, knowledge of anti-phage systems remained scarce for some years. Yet, in 2011, Makarova and colleagues revealed that anti-phage systems tend to colocalize on the bacterial genome in defense-islands :ref{doi=10.1128/JB.05535-11}. This led to a guilt-by-association hypothesis : if a gene or a set of genes is frequently found in bacterial genomes in close proximity to known defense systems, such as RM or CRISPR-Cas systems, then it might constitute a new defense system. This concept had a large role in the discovery of an impressive diversity of defense systems in a very short amount of time.
## List of known defense systems
To date, more than 60 anti-phage defense systems have been described. An exhaustive list of the systems with experimentally validated anti-phage activity can be found [here](/defense-systems).
To date, more than 150 anti-phage defense systems have been described. An exhaustive list of the systems with experimentally validated anti-phage activity can be found [here](/defense-systems).
## Molecular mechanisms
---
title: Defense system triggers
contributors:
- Avigail Stokar-Avihail
---
# How anti-phage systems sense invading phages
Upon phage infection, the bacterial immune system senses a specific phage component or modification that the phage exerts on the cell to elicit the bacterial immune response. Understanding how bacteria sense phage infection is a fundamental question, which remains unanswered for the majority of recently discovered immune systems. There are dozens of cases in which the mechanism of immunity has been elucidated, but the phage trigger remains elusive. Understanding how antiphage systems are activated is key for a full understanding of bacterial immunity and for repurposing them as molecular tools as has been done for restriction enzymes and CRISPR-Cas.
## Diversity
Various determinants of the phage can elicit bacterial immunity either in a direct or indirect manner. The most common and well known prokaryotic anti-phage systems, restriction enzymes and CRISPR-Cas, recognize and cleave phage DNA or RNA. More recently, a CBASS system has been found to directly bind to a structured phage RNA that triggers immune activation1. In other cases, defense systems are activated by protein coding phage genes. In some cases, the phage protein is directly sensed by the defense systems, as has been beautifully demonstrated for the Avs systems that directly bind either the phage terminase or portal protein2. In other cases, the phage protein can be sensed indirectly by the defense system, for example by detecting its activity in the cell. Such an indirect mechanism has been found for example in the case of some retron defense systems that are triggered by phage tampering with the RecBCD protein complex3,4. For a comprehensive coverage of all recent phage detection mechanisms the recent review by Huiting and Bondy-Denomy5 is highly recommended.
## Method of discovery:
The main method used to pinpoint phage components that trigger a specific defense system of interest has been through a simple classic genetics approach, whereby mutant phages that overcome the defense system are examined. Such mutants often occur spontaneously and can thus be selected for by simply picking phage plaques that are able to form on a lawn of bacteria expressing the defense system4,5. The hypothesis is that the phage mutant escapes bacterial immunity due to a mutation in the component sensed by the system. Thus, sequencing these phage mutants and identification of the mutated locus is the first required step. To validate that the mutated phage component is indeed the actual trigger of the defense system, follow up experiments are required. For example, in some cases expression of this phage component without any other phage genes is sufficient to elicit the activity of bacterial immune system. This approach was used to identify Borvo activation by expression of the phage DNA polymerase4, Dazbog activation by expression of a phage DNA methylase4, retron activation by either phage SSB proteins4 or by proteins that inhibit the host RecBCD3, CapRel triggering by the phage Capsid protein6 and many more5. Additional biochemical pulldown assays can be used to assess binding of the defense system to the suspected phage trigger.
One major caveat in the above approach is that in some cases mutant phages that escape the immune system cannot be isolated. This can occur for example if the defense system senses a general fold of a highly conserved and essential phage protein. In this case a simple mutation in the protein will not suffice for the phage to escape detection. In such cases, an alternative approach can be used that does not rely on isolation of escape mutants. An overexpression library of all phage genes can be co-expressed with the defense system of interest, and then assayed for immune activation. This approach was successfully applied for identification phage components that trigger diverse Avs systems2.
## General concepts:
Although much is still unknown regarding how bacterial immune systems sense phage infection, by combining the data observed so far, several general concepts in immune sensing are beginning to come to light. First, mechanistically diverse immune systems appear to have converged to sense common conserved phage components4. These include the phage core replication machinery, host takeover machinery and structural components. Second, several studies have found cases in which defense occurs in a multi-layered fashion, whereby a second system is activated when the first one fails3,7,8. Research in upcoming years is expected to reveal additional guiding principles in the ways bacteria detect phages.
## References:
1. Banh D V, Roberts C G, Amador A M, Brady S F, & Marraffini L A. (2023) Bacterial cGAS senses a viral RNA to initiate immunity. bioRxiv 2023.03.07.531596 doi:10.1101/2023.03.07.531596.
2. Gao L A, Wilkinson M E, Strecker J, Makarova K S, Macrae R K, Koonin E V, & Zhang F. (2022) Prokaryotic innate immunity through pattern recognition of conserved viral proteins. Science 377: eabm4096.
3. Millman A, Bernheim A, Stokar-Avihail A, Fedorenko T, Voichek M, Leavitt A, Oppenheimer-Shaanan Y, & Sorek R. (2020) Bacterial Retrons Function In Anti-Phage Defense. Cell 183: 1551–1561.
4. Stokar-Avihail A, Fedorenko T, Hör J, Garb J, Leavitt A, Millman A, Shulman G, Wojtania N, Melamed S, Amitai G, & Sorek R. (2023) Discovery of phage determinants that confer sensitivity to bacterial immune systems. Cell 186: 1863-1876.e16.
5. Huiting E & Bondy-Denomy J. (2023) Defining the expanding mechanisms of phage-mediated activation of bacterial immunity. Curr. Opin. Microbiol. 74: 102325.
6. Zhang T, Tamman H, Coppieters ’t Wallant K, Kurata T, LeRoux M, Srikant S, Brodiazhenko T, Cepauskas A, Talavera A, Martens C, Atkinson G C, Hauryliuk V, Garcia-Pino A, & Laub M T. (2022) Direct activation of a bacterial innate immune system by a viral capsid protein. Nature 612: 132–140.
7. Rousset F, Depardieu F, Miele S, Dowding J, Laval A-L, Lieberman E, Garry D, Rocha E P C, Bernheim A, & Bikard D. (2022) Phages and their satellites encode hotspots of antiviral systems. Cell Host Microbe 30: 740–753.
8. Penner M, Morad I, Snyder L, & Kaufmann G. (1995) Phage T4-coded Stp: Double-edged effector of coupled DNA and tRNA-restriction systems. J. Mol. Biol. 249: 857–68.
......@@ -10,6 +10,11 @@ tableColumns:
Activator: Unknown
Effector: Unknown
PFAM: PF14253
relevantAbstracts:
- doi: 10.1023/A:1002027321171
- doi: 10.1016/j.mib.2005.06.006
- doi: 10.1111/j.1574-6968.1996.tb08446.x
---
# AbiH
......@@ -69,15 +74,6 @@ end
style Title3 fill:none,stroke:none,stroke-width:none
style Title4 fill:none,stroke:none,stroke-width:none
</mermaid>
## Relevant abstracts
::relevant-abstracts
---
items:
- doi: 10.1023/A:1002027321171
- doi: 10.1016/j.mib.2005.06.006
- doi: 10.1111/j.1574-6968.1996.tb08446.x
---
::
......@@ -14,16 +14,19 @@ tableColumns:
relevantAbstracts:
- doi: 10.1126/science.aba0372
- doi: 10.1126/science.abm4096
contributors:
- Alex Linyi Gao
---
# Avs
## Description
Avs (antiviral ATPases/NTPases of the STAND superfamily) is a group of anti-phage defense systems, active against some dsDNA phages.
Avs proteins are members of the STAND (signal transduction ATPase with numerous domains) superfamily of P-loop NTPases, which play essential roles in innate immunity and programmed cell death in eukaryotes (E. V. Koonin et al., Cell Death Differ. 9, 394–404 (2002). doi: 10.1038/sj.cdd.4400991; D. D. Leipe et al., J. Mol. Biol. 343, 1–28 (2004). doi: 10.1016/j.jmb.2004.08.023). STAND ATPases include nucleotide-binding oligomerization domain-like receptors (NLRs) in animal inflammasomes and plant resistosomes. They share a common tripartite domain architecture, typically consisting of a central ATPase, a C-terminal sensor with superstructure-forming repeats, and an N-terminal effector involved in inflammation or cell death.
Avs systems are composed of NTPases of the STAND (signal transduction ATPases with numerous associated domains) superfamily (1). STAND-NTPases typically contain a C-terminal helical sensor domain that activates the N-terminal effector domain upon target recognition (1).
## Molecular mechanism
Similar to their eukaryotic counterparts, Avs proteins utilize their C-terminal sensor domains to bind to pathogen-associated molecular patterns (PAMPs). Specifically, Avs1, Avs2, and Avs3 bind to monomers of the large terminase subunit of tailed phages, which account for approximately 96% of all phages, whereas Avs4 binds to monomers of the portal protein. The helical sensor domains of Avs1-4 can recognize diverse variants of terminase or portal proteins, with less than 5% sequence identity in some cases. Binding is mediated by shape complementarity across an extended interface, indicating fold recognition. Additionally, Avs3 directly recognizes active site residues and the ATP ligand of the large terminase.
In eukaryotes, STAND-NTPases are associated with programmed cell death, therefore Gao and colleagues hypothesized that Avs might function through an Abortive infection mechanism.
Upon binding to their cognate phage protein, Avs1-4 assemble into tetramers that activate their N-terminal effector domains, which are often non-specific dsDNA endonucleases. The effector domains are thought to induce abortive infection to disrupt the production of progeny phage.
## Example of genomic structure
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......@@ -75,6 +78,9 @@ watch(facetDistribution, (facetDistri) => {
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