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Bacterial defense mechanisms against bacteriophages



To study the defense mechanisms associated with bacteria against the pathogenicity of bacteriophages and mechanisms which are associated with phages to overcome these bacterial defense mechanisms.
B.G.E.T Jayashantha
B.Sc (ug) Microbiology (Special),
University of Kelaniya, Sri Lanka
Bacterial defense mechanisms
against bacteriophages
To study the defense mechanisms associated with bacteria against the
pathogenicity of bacteriophages and mechanisms which are associated
with phages to overcome these bacterial defense mechanisms.
PIC Source :-
Bacteriophages infect bacteria.
Bacteria have several genetically regulated defense mechanisms to protect
from the phages.
Different bacteria have different defense mechanisms.
Bacteria and Bacteriophages have been co-evolving during the evolutionary
Therefore, phage mechanisms are evolved to overcome these bacterial
This continuous evolutionary relationship between the pathogenicity of
Bacteriophages and the resistance of Bacteria is described by Evolutionary
arms race hypothesis
Anti-phage mechanisms of bacteria
Main mechanisms can be categorized under following topics
1. Preventing phage adsorption
2. Preventing phage DNA entry
3. Restriction modification systems
4. CRISPR-Cas system
5. Abortive infection systems
PIC Source :-
1.) Preventing phage adsorption
Adsorption is the initial step of phage infection to a bacterium.
Phage adsorption to the bacterial cell surface occurs through recognition of a
phage receptor on the surface
Adsorption-blocking mechanisms can be divided into mainly three categories
i) Blocking of phage receptors
ii) Production of extracellular matrix
iii) Production of competitive inhibitors
Blocking of phage receptors
1. Bacteria can become
resistant to phages by
modifying cell surface
receptors which recognize
distinctive pages.
Bacteriophages make resistance
by Adapting to recognize these
new receptors
How phages overcome
this resistance
PIC Source :- Nature reviews | Microbiology
2.) Bacteria can also produce
proteins that mask the phage
Staphylococcus aureus produces
protein A, which reduces phage
When bacteria produce low amount of
Protein A , adsorption is improved
Blocking of phage receptors cond..
Masking Protein
PIC Source :- Nature reviews | Microbiology
E. coli has outer-membrane receptor
protein named as OmpA for many
T-even-like E. coli phages
It is masked and modified its
conformation by protein TraT which is
encoded by the F plasmid,
Escherichia coli produces a
lipoprotein (Llp) that blocks its own
receptor ferrichrome-iron receptor
Llp is expressed at the beginning of
the infection of E.coli by T5
It also prevents superinfection
Blocking of phage receptors cond..
PIC Source :-
1.) Phage adsorption can also be
blocked by the production of
exopolysaccharide (EPS)
but phages overcome the EPS layer by
producing a polysaccharide lyase or a
polysaccharide hydrolase to cleave EPS
Production of extracellular matrix
How phages overcome
this resistance
PIC Source :- Nature reviews | Microbiology
Pseudomonas spp. and Acetobactor spp.
produce Alginates (a type of EPS ) which
increase the resistance against phages
phage F116, targets Pseudomonas,
produces an alginate lyase,
It facilitates the dispersion of the
alginate matrix as well as reducing
the viscosity of this matrix.
Production of extracellular matrix
PIC Source :- PIC Source :-
How phages overcome
this resistance
2.) Phages have also evolved to
specifically recognize polysaccharides
such as LPS O antigens and K
Some bacteria modifies these LPS
antigens . Therefore phage can not
recognize and adsorb to the cell.
Production of extracellular matrix
E.coli O157:H7 has O-antigen and K-
Which are responsible for specific
adsorption of Phage ɸV10
E.coli O157:H7 produces
O-acetyltransferase that modifies the
O157 antigen to block the adsorption
of ɸV10 and similar phages39
PIC Source :- Nature reviews | Microbiology
Molecules that are naturally
present in the bacterial
environment can bind
specifically to the phage
Becoming these receptors are
unavailable for phages
In E. coli ,FhuA is a receptor for adsorption
of coliphages such as T1, T5 and ɸ80
Microcin J25 is an antimicrobial molecule
which is synthesized by phylogenetically
related strains for competition.
It also acts as a competitive inhibitor for
FhuA receptor on E.coli.
Microcin J25 bound FhuA receptors are
resist for adsorption of such coliphages
Production of competitive inhibitors
Superinfection exclusion (Sie) systems responsible for blocking phage DNA
entry in to host cells.
They make immunity against specific phages.
Sie proteins are membrane anchored or associated with membrane
Sie proteins encoding genes can be found in prophages
They are expressed in prophage stage.
They are responsible for phage-phage interactions rather than phage host
2.) Preventing phage DNA entry
Normal phage T4 infection of an
Escherichia coli cell.
The peptidoglycan layer is degraded
Inner-membrane protein is involved
for the translocation of the DNA into
the cytoplasm.
Preventing phage DNA entry contd
How this DNA entry is
PIC Source :- Nature reviews | Microbiology
Phage T4 encodes the protein Imm
It blocks the translocation of phage
DNA into the cytoplasm,
thus preventing infection by other T-
even-like phages.
Preventing phage DNA entry contd
The protein Sp, also encoded by phage T4
It blocks degradation of the peptidoglycan
It causes trapping the DNA between
peptidoglycan layer and the outer
PIC Source :- Nature reviews | Microbiology
The restriction enzyme cleaves specific patterns in the incoming foreign
bacteriophage DNA Restriction
The host cell also protects its own genetic material from enzymatic
degradation by modifying it Modification
These systems are found in 90% of all sequenced prokaryotic genomes
Both activities are mediated by recognition of a short specific DNA sequence
Protection is normally conferred by usually methylation of specific bases in
this recognition sequence in the host genome
All non-methylated DNA are recognized as foreign and they are cleaved
RM systems minimally contains methyltransferase (MTase) gene for
protection of host DNA
Restriction endonuclease (REase) gene performs the foreign restriction
3.) Restriction modification systems
Restriction Modification systems show arms race between bacteria and
In bacteria, defense mechanisms are evolved to protect from pages,
Phages are evolved to overcome these bacterial defense mechanisms
It is a evolutionary continuous process
Evidence for co-evolution of bacteria and phages.
We can describe several RM systems by using E.coli and its infector T4 phage
as models
EM of T4 phages infecting E.coli
PIC Source :-
Phage T4 infecting a susceptible host
(E.coli) cell. It causes the infection
EM of T4 phages infecting E.coli
PIC Source :-
How this infection is
PIC Source :- Nature reviews | Microbiology
Phage T4 infecting a phage-resistant E. coli
cell containing a RM system. The phage
genome is cut at specific sites by the
restriction enzyme
The host cell contains methylase activity to
prevent enzymatic degradation of its own
A classical R-M
The genome of phage T4 contains
hydroxymethylcytosine (HMC) and can also be
Thereby avoiding specific endonucleases.
Resist for host's endonucleases
Bacterial cell is infected
How phage overcome
the host’s resistance
PIC Source :- Nature reviews | Microbiology
Some bacteria have acquired Modification-
Dependent systems (MDS) that can exclusively
cleave HMC-containing DNA
It prevents infection by HMC-containing phages.
Eg:DpnI from Streptococcus pneumoniae
McrA, McrBC and Mrr from E. coli
Phage T4 acquired a resistance to MDSs through
the glucosylation of HMC residues (gluHMC).
Host resistance has been overcame
Bacterial cell is infected
How phage overcome
the host’s resistance
PIC Source :- Nature reviews | Microbiology
Some E. coli strains have acquired a Glucose-modified
restriction (Gmr) system that targets and cleaves
gluHMC-modified phage T4 genomes
Block phage infection.
Two subunits (GmrS and GmrD) specifically cut
gluHMC DNA .
No effect on unglucosylated DNA. Therefore protects
host DNA
Some T4-like phages have a gene encoding
internal protein I (IPI), a protein that hinders the
Phage successfully infect E. coli strains
containing Gmr system.
How phage overcome
the host’s resistance
PIC Source :- Nature reviews | Microbiology
Some E. coli strains achieve a modified Gmr system
It consists translational fusion of GmrS and GmrD is
Presence of such system causes IPI ineffective.
Host cell is not infected
Phage T4 mutants can bypass the GmrSGmrD
fusion by a unknown mechanism,
Leads to a successful infection of the host cell.
How phage overcome
the host’s resistance
PIC Source :- Nature reviews | Microbiology
CRISPR =Clustered Regularly Interspaced Short Palindromic Repeat
Cas = CRISPR associated systems
4.) CRISPR-Cas system
Abi is a collective term describing host mechanisms that interrupt phage
development at different stages such as;
Genomic replication
Packaging of genome
Abi-mediated resistance leads to death (suicide) of the infected bacterial
Prevent further infection
In most Abi systems Phage is trapped inside the cell.
There are few Abi systems are found, mechanisms of some of them are not
understood yet.
Rex system in E.coli is well studied and a typical example for a Abi systems
5.) Abortive infection systems (Abi)
Rex is Two- compornent system
RexA and RexB proteins are involved
RexA is an intracellular sensor that activates the membrane anchored RexB.
RexA is activated during phage infection by production of phage protein DNA
complex as an inter.mediate of replication and recombination.
At least two RexA proteins are needed to activate one RexB protein
Therefore Rex is a protein ratio mediated mechanism.
RexB is an ion channel that reduces membrane potential
Causing reduction of cellular ATP levels
Decrease the synthesis of macromolecules and stopping cell multiplication
Phage infection will also abort, because it needs either ATP or ATP-dependent
cellular components.
Rex Abortive infection system in E .coli
An inactive form of RexA, the sensor protein RexA is activated by the phage proteinDNA
complex that forms as a replication or
recombination intermediate during the phage
Two activated RexA proteins are needed to
trigger the membrane-anchored protein RexB,
which acts as an ion channel .
It allows the passage of monovalent cations
through the bacterial inner membrane,
Cause for destroying the membrane potential
and killing the cell.
1. Lit Abi system in E.coli against phage T4
Translation elongation factor - TU (EF-TU) is cleaved and abort the phage infection.
2. PrrC Abi system in E.coli against phage T4
Cleaves tRNA(lysine) in the anticodon loop and stop the translation. Therefore
protein synthesis is inhibited.
3. PifA Abi system in E.coli against phage T3 & T7
Macromolecule synthesis is severely reduced, only half of the phage genome is
injected into the cell , Limiting the late transcription, bacterial chromosomal DNA
is degraded , membrane permeability is altered causing molecules leaking through
the cell membrane
4. Toxin-Antitoxin (TA) Abi systems in Erwinia
Toxic molecule is formed by different regulatory interactions, including protein
protein, RNARNA or proteinRNA interactions. Expression of these toxic
molecules are causing promoter repression, specific transcriptional termination.
Toxin can be neutralized by antitoxin molecule.
Examples for Some of other Abi systems in bacteria
5. Lactococcal Abi systems ( eg: Lactobacillus lactis )
Abi ( A,F,P,K,T ) Interfere with DNA replication
Abi ( B,G,U ) RNA transcription
Abi C Restricts production of major capsid protein
Abi ( E,I,Q ) Disrupt DNA packaging
Ani 2 Premature lysis of infected cell
Examples for Some of other Abi systems in bacteria contd..
Labrie, S. J., Samson, J. E., & Moineau, S. (2010). Bacteriophage resistance
mechanisms. Nature Reviews Microbiology,8(5), 317-327.
Abedon, S. T. (2012). Bacterial ‘immunity’against
bacteriophages.Bacteriophage,2(1), 50-54.
Stern, A., & Sorek, R. (2011). The phage‐host arms race: shaping the evolution
of microbes. Bioessays,33(1), 43-51.
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Full-text available
Vertebrate animals possess multiple anti-pathogen defenses. Individual mechanisms usually are differentiated into those that are immunologically adaptive vs. more "primitive" anti-pathogen phenomena described as innate responses. Here I frame defenses used by bacteria against bacteriophages as analogous to these animal immune functions. Included are numerous anti-phage defenses in addition to the adaptive immunity associated with CRISPR/cas systems. As these other anti-pathogen mechanisms are non-adaptive they can be described as making up an innate bacterial immunity. This exercise was undertaken in light of the recent excitement over the discovery that CRISPR/cas systems can serve, as noted, as a form of bacterial adaptive immunity. The broader goal, however, is to gain novel insight into bacterial defenses against phages by fitting these mechanisms into considerations of how multicellular organisms also defend themselves against pathogens. This commentary can be viewed in addition as a bid toward integrating these numerous bacterial anti-phage defenses into a more unified immunology.
Bacteria, the most abundant organisms on the planet, are outnumbered by a factor of 10 to 1 by phages that infect them. Faced with the rapid evolution and turnover of phage particles, bacteria have evolved various mechanisms to evade phage infection and killing, leading to an evolutionary arms race. The extensive co-evolution of both phage and host has resulted in considerable diversity on the part of both bacterial and phage defensive and offensive strategies. Here, we discuss the unique and common features of phage resistance mechanisms and their role in global biodiversity. The commonalities between defense mechanisms suggest avenues for the discovery of novel forms of these mechanisms based on their evolutionary traits.
Phages are now acknowledged as the most abundant microorganisms on the planet and are also possibly the most diversified. This diversity is mostly driven by their dynamic adaptation when facing selective pressure such as phage resistance mechanisms, which are widespread in bacterial hosts. When infecting bacterial cells, phages face a range of antiviral mechanisms, and they have evolved multiple tactics to avoid, circumvent or subvert these mechanisms in order to thrive in most environments. In this Review, we highlight the most important antiviral mechanisms of bacteria as well as the counter-attacks used by phages to evade these systems.