Contact-dependent growth inhibition

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Contact-dependent growth inhibition (CDI) is a phenomenon where a bacterial cell may deliver a polymorphic toxin molecule into neighbouring bacterial cells upon direct cell-cell contact, causing growth arrest or cell death.

Contents

Discovery

CDI is now a blanket term to describe interbacterial competition that relies on direct cell-cell contact in bacteria. However, the phenomenon was first discovered in 2005 in the isolate EC93 of Escherichia coli found in rat intestine, and, in this case, was mediated by a Type V secretion system. This isolate dominated the rat's gut flora and appeared to be particularly good at outcompeting lab strains of E. coli when grown in co-culture. The novel part of this discovery was the fact that the inhibitory effects of the isolated E. coli appeared to require direct cell-cell contact. [1] [2] Before CDI was discovered in this isolate, the only systems known to mediate direct interbacterial competition by intoxication were toxins secreted into the extracellular space. Thus, these did not require cell-cell contact. A second system that could mediate CDI was discovered in 2006 in the pathogenic bacterium Vibrio cholerae , the cause of the gastro-intestinal disease cholera, and the opportunistic pathogen Pseudomonas aerugenosa. This system was much different that the Type V secretion system identified in E. coli, and thus formed a new class of CDI: the Type VI Secretion System. [3]

Types of CDI

Type IV

The Type IV Secretion System T4SS is found in many species of Gram-negative and Gram-positive bacteria as well as in archea and are typically associated with conjugation or delivery of virulence proteins to eukaryotic cells. [4] Some species of plant pathogen Xanthomonas , however, possess a particular T4SS capable of mediating CDI by delivering a peptidoglycan hydrolase. This effector kills targets that do not have the cognate immunity protein similar to other CDI systems. [5]

Type V

The first CDI system to be discovered was a Type V secretion system, encoded by the cdiBAI gene cluster found widespread throughout pathogenic Gram-negative bacteria. The first protein encoded in the operon, CdiB, is an outer membrane beta-barrel protein that exports CdiA, presenting it on the cell surface of a CDI-expressing (CDI+) bacterium. CdiA is predicted to form a filament several nanometers long that extends outward from the CDI+ cell in order to interact with neighbouring bacteria via outer membrane protein receptors to which it will bind. [2] The C-terminal 200-300 amino acids of CdiA harbours a highly variable toxic domain (CdiA-CT), which is delivered into a neighbouring bacterium upon receptor recognition, enabling the CDI+ cell to arrest the growth of the cell into which it delivers this CdiA-CT toxin. This toxic domain is linked to the rest of CdiA via a VENN peptide motif and vary significantly more between species than does the rest of CdiA. [6] CdiI is an immunity protein to prevent auto-inhibition by the C-terminal toxin. This also prevents the bacteria from killing or inhibiting the growth of their siblings as long as these possess the immunity gene. [7] Many CDI systems contain additional cdiA-CT/cdiI pairs called "orphans" following the first copy [8] and these orphans can be connected to different main CdiA:s in a modular fashion. [6]

Type VI

The Type VI Secretion System T6SS is widely spread amongst Gram-negative bacteria and consists of a protein complex with 13 core components (TssA to TssM), forming a needle-like structure capable of injecting effector molecules into neighbouring target cells similar to the contractile tail of the T4 bacteriophage [9] [10] . The T6SS is capable of delivering effectors to both prokaryote and eukaryotes target cells [3] [11] . Upon contraction of the T6SS, effectors are transported across the cytosol of the bacteria cell into the target cells. Effectors are loaded onto this dynamic secretion system through interactions with Hcp, VgrG and PAAR-domains. The full list of T6SS effectors is not known.

Rhs toxins

The Rearrangement hotspot system (Rhs) exists in both Gram-negative and Gram-positive bacteria. Similar to CdiA, these systems consists of big proteins with a conserved N-terminal domain and a variable C-terminal toxin domain requiring a cognate immunity protein. Many Rhs systems contain PAAR-domains (Proline-Alanine-Alanine-Arginine) which can interact with the VgrG of the T6SS apparatus making it required for Rhs secretion. [3] [12] The name Rearrangement hotspots comes from the discovery when the system was first identified as elements on the E. coli chromosome that were continuously rearranging. [13] [14] The Gram-positive soil bacterium Bacillus subtilis possesses an Rhs homolog called Wall-associated protein A (WapA) capable of mediating CDI whilst requiring a cognate immunity protein, WapI, to prevent auto-inhibition. [12]

Other functions

Cell aggregation and biofilm formation

In E. coli, CdiA molecules may interact with those found on neighboring cells, independent of the receptor to which CdiA binds. In addition with receptor binding, these homotypic interactions cause cell-cell aggregation and promote biofilm formation for CDI+ bacteria. In a similar fashion, the CdiA homolog BcpA in Burkholderia thailandensis causes up-regulation of genes encoding pili and polysaccharides when delivered to sibling cells which are in possession of the immunity protein BcpI. This change in gene expression leads to increased biofilm formation in the bacterial population through a phenomenon now known as Contact-Dependent Signalling. Furthermore, the T6SS in V. cholerae is active in biofilms, enabling a cell expressing T6SS to kill nearby cells which do not have the specific immunity. [5] . The release of DNA from target cell death can be benificial for gene transfer as well as the release of extra cellular DNA into the matrix.

Antibiotic persistence

In E. coli, CdiA-CT toxins have been found to induce persister cell formation in a clonal population when delivered to cells that lack sufficient levels of CdiI immunity to neutralise the incoming toxins. The intoxication of the cells leads to an increase of cellular (p)ppGpp levels, which in turn leads to degradation of the immunity protein and eventually to a higher extend of intoxication, resulting in persister formation. [15]

Related Research Articles

Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to the N-acetylmuramic acid is an oligopeptide chain made of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. This repetitive linking results in a dense peptidoglycan layer which is critical for maintaining cell form and withstanding high osmotic pressures, and it is regularly replaced by peptidoglycan production. Peptidoglycan hydrolysis and synthesis are two processes that must occur in order for cells to grow and multiply, a technique carried out in three stages: clipping of current material, insertion of new material, and re-crosslinking of existing material to new material.

<span class="mw-page-title-main">Exotoxin</span> Toxin from bacteria that destroys or disrupts cells

An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell. Gram negative pathogens may secrete outer membrane vesicles containing lipopolysaccharide endotoxin and some virulence proteins in the bounding membrane along with some other toxins as intra-vesicular contents, thus adding a previously unforeseen dimension to the well-known eukaryote process of membrane vesicle trafficking, which is quite active at the host–pathogen interface.

<span class="mw-page-title-main">Secretion</span> Controlled release of substances by cells or tissues

Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mechanism of cell secretion is via secretory portals at the plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structures embedded in the cell membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

<i>Burkholderia</i> Genus of bacteria

Burkholderia is a genus of Pseudomonadota whose pathogenic members include the Burkholderia cepacia complex, which attacks humans and Burkholderia mallei, responsible for glanders, a disease that occurs mostly in horses and related animals; Burkholderia pseudomallei, causative agent of melioidosis; and Burkholderia cepacia, an important pathogen of pulmonary infections in people with cystic fibrosis (CF). Burkholderia species is also found in marine environments. S.I. Paul et al. (2021) isolated and characterized Burkholderia cepacia from marine sponges of the Saint Martin's Island of the Bay of Bengal, Bangladesh.

Adhesins are cell-surface components or appendages of bacteria that facilitate adhesion or adherence to other cells or to surfaces, usually in the host they are infecting or living in. Adhesins are a type of virulence factor.

Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:

Cytolysin refers to the substance secreted by microorganisms, plants or animals that is specifically toxic to individual cells, in many cases causing their dissolution through lysis. Cytolysins that have a specific action for certain cells are named accordingly. For instance, the cytolysins responsible for the destruction of red blood cells, thereby liberating hemoglobins, are named hemolysins, and so on. Cytolysins may be involved in immunity as well as in venoms.

The AB5 toxins are six-component protein complexes secreted by certain pathogenic bacteria known to cause human diseases such as cholera, dysentery, and hemolytic–uremic syndrome. One component is known as the A subunit, and the remaining five components are B subunits. All of these toxins share a similar structure and mechanism for entering targeted host cells. The B subunit is responsible for binding to receptors to open up a pathway for the A subunit to enter the cell. The A subunit is then able to use its catalytic machinery to take over the host cell's regular functions.

<span class="mw-page-title-main">Type III secretion system</span> Bacterial virulence factor

The type III secretion system is one of the bacterial secretion systems used by bacteria to secrete their effector proteins into the host's cells to promote virulence and colonisation. While the type III secretion system has been widely regarded as equivalent to the injectisome, many argue that the injectisome is only part of the type III secretion system, which also include structures like the flagellar export apparatus. The T3SS is a needle-like protein complex found in several species of pathogenic gram-negative bacteria.

The RTX toxin superfamily is a group of cytolysins and cytotoxins produced by bacteria. There are over 1000 known members with a variety of functions. The RTX family is defined by two common features: characteristic repeats in the toxin protein sequences, and extracellular secretion by the type I secretion systems (T1SS). The name RTX refers to the glycine and aspartate-rich repeats located at the C-terminus of the toxin proteins, which facilitate export by a dedicated T1SS encoded within the rtx operon.

<span class="mw-page-title-main">Cell–cell recognition</span>

Cell–cell recognition is a cell's ability to distinguish one type of neighboring cell from another. This phenomenon occurs when complementary molecules on opposing cell surfaces meet. A receptor on one cell surface binds to its specific ligand on a nearby cell, initiating a cascade of events which regulate cell behaviors ranging from simple adhesion to complex cellular differentiation. Like other cellular functions, cell-cell recognition is impacted by detrimental mutations in the genes and proteins involved and is subject to error. The biological events that unfold due to cell-cell recognition are important for animal development, microbiomes, and human medicine.

<span class="mw-page-title-main">Toxin-antitoxin system</span> Biological process

A toxin-antitoxin system consists of a "toxin" and a corresponding "antitoxin", usually encoded by closely linked genes. The toxin is usually a protein while the antitoxin can be a protein or an RNA. Toxin-antitoxin systems are widely distributed in prokaryotes, and organisms often have them in multiple copies. When these systems are contained on plasmids – transferable genetic elements – they ensure that only the daughter cells that inherit the plasmid survive after cell division. If the plasmid is absent in a daughter cell, the unstable antitoxin is degraded and the stable toxic protein kills the new cell; this is known as 'post-segregational killing' (PSK).

Bacterial morphological plasticity refers to changes in the shape and size that bacterial cells undergo when they encounter stressful environments. Although bacteria have evolved complex molecular strategies to maintain their shape, many are able to alter their shape as a survival strategy in response to protist predators, antibiotics, the immune response, and other threats.

Bacterial effectors are proteins secreted by pathogenic bacteria into the cells of their host, usually using a type 3 secretion system (TTSS/T3SS), a type 4 secretion system (TFSS/T4SS) or a Type VI secretion system (T6SS). Some bacteria inject only a few effectors into their host’s cells while others may inject dozens or even hundreds. Effector proteins may have many different activities, but usually help the pathogen to invade host tissue, suppress its immune system, or otherwise help the pathogen to survive. Effector proteins are usually critical for virulence. For instance, in the causative agent of plague, the loss of the T3SS is sufficient to render the bacteria completely avirulent, even when they are directly introduced into the bloodstream. Gram negative microbes are also suspected to deploy bacterial outer membrane vesicles to translocate effector proteins and virulence factors via a membrane vesicle trafficking secretory pathway, in order to modify their environment or attack/invade target cells, for example, at the host-pathogen interface.

Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory cell. It takes place in the form of Golgi membrane-bound micro-sized vesicles, termed membrane vesicles (MVs).

The type VI secretion system (T6SS) is molecular machine used by a wide range of Gram-negative bacterial species to transport effectors from the interior of a bacterial cell across the cellular envelope into an adjacent target cell. While often reported that the T6SS was discovered in 2006 by researchers studying the causative agent of cholera, Vibrio cholerae, the first study demonstrating that T6SS genes encode a protein export apparatus was actually published in 2004, in a study of protein secretion by the fish pathogen Edwardsiella tarda.

Polymorphic toxins (PTs) are multi-domain proteins primarily involved in competition between bacteria but also involved in pathogenesis when injected in eukaryotic cells. They are found in all major bacterial clades.

Rhs toxins belong to the polymorphic toxin category of bacterial exotoxins. Rhs proteins are widespread and can be produced by both Gram-negative and Gram-positive bacteria. Rhs toxins are very large proteins of usually more than 1,500 aminoacids with variable C-terminal toxic domains. Their toxic activity can either target eukaryotes or other bacteria.

<span class="mw-page-title-main">Curli</span> A proteinaceous extracellular fiber produced by enteric bacteria

The Curli protein is a type of amyloid fiber produced by certain strains of enterobacteria. They are extracellular fibers located on bacteria such as E. coli and Salmonella spp. These fibers serve to promote cell community behavior through biofilm formation in the extracellular matrix. Amyloids are associated with several human neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, and prion diseases. The study of curli may help to understand human diseases thought to arise from improper amyloid fiber formation. The curli pili are generally assembled through the extracellular nucleation precipitation pathway.

<span class="mw-page-title-main">Bacterial secretion system</span> Protein complexes present on the cell membranes of bacteria for secretion of substances

Bacterial secretion systems are protein complexes present on the cell membranes of bacteria for secretion of substances. Specifically, they are the cellular devices used by pathogenic bacteria to secrete their virulence factors to invade the host cells. They can be classified into different types based on their specific structure, composition and activity. Generally, proteins can be secreted through two different processes. One process is a one-step mechanism in which proteins from the cytoplasm of bacteria are transported and delivered directly through the cell membrane into the host cell. Another involves a two-step activity in which the proteins are first transported out of the inner cell membrane, then deposited in the periplasm, and finally through the outer cell membrane into the host cell.

References

  1. ↑ Aoki SK, Pamma R, Hernday AD, Bickham JE, Braaten BA, Low DA (August 2005). "Contact-dependent inhibition of growth in Escherichia coli". Science. 309 (5738): 1245–1248. Bibcode:2005Sci...309.1245A. doi:10.1126/science.1115109. PMID   16109881. S2CID   23138285.
  2. 1 2 Willett JL, Ruhe ZC, Goulding CW, Low DA, Hayes CS (November 2015). "Contact-Dependent Growth Inhibition (CDI) and CdiB/CdiA Two-Partner Secretion Proteins". Journal of Molecular Biology. 427 (23): 3754–3765. doi:10.1016/j.jmb.2015.09.010. PMC   4658273 . PMID   26388411.
  3. 1 2 3 Cianfanelli FR, Monlezun L, Coulthurst SJ (January 2016). "Aim, Load, Fire: The Type VI Secretion System, a Bacterial Nanoweapon". Trends in Microbiology. 24 (1): 51–62. doi:10.1016/j.tim.2015.10.005. PMID   26549582.
  4. ↑ Christie PJ, Whitaker N, González-Rivera C (August 2014). "Mechanism and structure of the bacterial type IV secretion systems". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1843 (8): 1578–1591. doi:10.1016/j.bbamcr.2013.12.019. PMC   4061277 . PMID   24389247.
  5. 1 2 Garcia EC (April 2018). "Contact-dependent interbacterial toxins deliver a message". Current Opinion in Microbiology. 42: 40–46. doi:10.1016/j.mib.2017.09.011. PMC   5899628 . PMID   29078204.
  6. 1 2 Aoki SK, Diner EJ, de Roodenbeke CT, Burgess BR, Poole SJ, Braaten BA, et al. (November 2010). "A widespread family of polymorphic contact-dependent toxin delivery systems in bacteria". Nature. 468 (7322): 439–442. Bibcode:2010Natur.468..439A. doi:10.1038/nature09490. PMC   3058911 . PMID   21085179.
  7. ↑ Ruhe ZC, Low DA, Hayes CS (May 2013). "Bacterial contact-dependent growth inhibition". Trends in Microbiology. 21 (5): 230–237. doi:10.1016/j.tim.2013.02.003. PMC   3648609 . PMID   23473845.
  8. ↑ Hayes CS, Koskiniemi S, Ruhe ZC, Poole SJ, Low DA (February 2014). "Mechanisms and biological roles of contact-dependent growth inhibition systems". Cold Spring Harbor Perspectives in Medicine. 4 (2): a010025. doi:10.1101/cshperspect.a010025. PMC   3904093 . PMID   24492845.
  9. ↑ Reference 1
  10. ↑ Bingle, Lewis EH, Bailey Christopher M, Pallen Mark J (February 2008). "Type VI secretion a beginner's guide". Current Opinion in Microbiology. 11 (1): 3–8. doi:10.1016/j.mib.2008.01.006. PMID   18289922.{{cite journal}}: Cite has empty unknown parameter: |1= (help); Invalid |display-authors=4 (help)
  11. ↑ Silverman JM, Agnello DM, Zheng H, Andrews BT, Li M, Catalano CE, et al. (September 2013). "Haemolysin coregulated protein is an exported receptor and chaperone of type VI secretion substrates". Molecular Cell. 51 (5): 584–593. doi:10.1016/j.molcel.2013.07.025. PMC   3844553 . PMID   23954347.
  12. 1 2 Jamet A, Nassif X (May 2015). "New players in the toxin field: polymorphic toxin systems in bacteria". mBio. 6 (3): e00285–e00215. doi:10.1128/mBio.00285-15. PMC   4436062 . PMID   25944858.
  13. ↑ Capage M, Hill CW (January 1979). "Preferential unequal recombination in the glyS region of the Escherichia coli chromosome". Journal of Molecular Biology. 127 (1): 73–87. doi:10.1016/0022-2836(79)90460-1. PMID   370413.
  14. ↑ Lin RJ, Capage M, Hill CW (July 1984). "A repetitive DNA sequence, rhs, responsible for duplications within the Escherichia coli K-12 chromosome". Journal of Molecular Biology. 177 (1): 1–18. doi:10.1016/0022-2836(84)90054-8. PMID   6086936.
  15. ↑ Ghosh A, Baltekin Ö, Wäneskog M, Elkhalifa D, Hammarlöf DL, Elf J, Koskiniemi S (May 2018). "Contact-dependent growth inhibition induces high levels of antibiotic-tolerant persister cells in clonal bacterial populations". The EMBO Journal. 37 (9). doi:10.15252/embj.201798026. PMC   5920241 . PMID   29572241.
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