Contact-dependent growth inhibition

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.

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, encoded by several different genes, forming "needle-like" structure capable of injecting effector molecules into neighbouring target cells similar to the contractile tail of the T4 bacteriophage. One T6SS may have several different effectors such as PAAR-domain toxins or Hcp toxins and some species can deliver these toxins into both prokaryotes and eukaryotes.[3][9]

Rhs toxins
Main article: 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][10] 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.[11][12] 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.[10]

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]

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.[13]

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. 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. 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. 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. 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. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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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