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Journal articleHughes DA, Archangelidi O, Coates M, et al., 2022,
Journal articleSanchez Garrido J, Alberdi L, Chatterjee S, et al., 2021,
Citrobacter rodentium, a natural mouse pathogen which colonises the colon of immuno-competent mice, provides a robust model for interrogating host-pathogen-microbiota interactions in vivo. This model has been key to providing new insights into local host responses to enteric infection, including changes inintestinal epithelial cell immuno metabolism and mucosal immunity. C. rodent iuminjects 31 bacterial effectors into epithelial cells via a type III secretion system (T3SS). Recently, these effectors were shown to be able to form multiple intracellular subnetworks which can withstand significant contractions whilst maintaining virulence. Here we highlight recent advances in understanding gut mucosal responses to infection and effector biology, as well as potential uses for artificial intelligence (AI) in understanding infectious diseaseand speculate on the role of T3SS effector networks in host adaption.
Journal articleRonneau S, Hill PWS, Helaine S, 2021,
Journal articleHa KP, Edwards AM, 2021,
Journal articleThompson GR, Le T, Chindamporn A, et al., 2021,
Journal articleBrady A, Quiles-Puchalt, Gallego del Sol F, et al., 2021,
The arbitrium system controls prophage induction, Current Biology, Vol: 31, Pages: 5037-5045, ISSN: 0960-9822
Some Bacillus-infecting bacteriophages use a peptide-based communication system, termed arbitrium, to coordinate the lysis-lysogeny decision. In this system the phage produces AimP peptide during the lytic cycle. Once internalised by the host cell, AimP binds to the transcription factor AimR, reducing aimX expression and promoting lysogeny. Although these systems are present in a variety of mobile genetic elements, their role in the phage life cycle has only been characterised in phage phi3T during phage infection. Here, using the B. subtilis SPb prophage, we show that the arbitrium system is also required for normal prophage induction. Deletion of the aimP gene increased phage reproduction, while the aimR deletion significantly reduced the number of phage particles produced after prophage induction. Moreover, our results indicated that AimR is involved in a complex network of regulation and brought forward two new players in the SPb lysis-lysogeny decision system, YopN and the phage repressor YopR. Importantly, these proteins are encoded in an operon, the function of which is conserved across all SPb-like phages encoding the arbitrium system. Finally, we obtained mutant phages in the arbitrium system, which behaved almost identically to the wt phage, indicating that the arbitrium system is not essential in the laboratory but is likely beneficial for phage fitness in nature. In support of this, by possessing a functional arbitrium system the SPb phage can optimise production of infective particles whilst also preserving the number of cells that survive after prophage induction, a strategy that increases phage persistence in nature.
Journal articleFillol-Salom A, Bacigalupe R, Humphrey S, et al., 2021,
Lysogenic induction ends the stable association between a bacteriophage and its host, andthe transition to the lytic cycle begins with early prophage excision followed by DNA replication and packaging (ERP). This temporal program is considered universal for P22-liketemperate phages, though there is no direct evidence to support the timing and sequence ofthese events. Here we report that the long-standing ERP program is an observation of theexperimentally favored Salmonella phage P22 tsc229 heat-inducible mutant, and that wildtype P22 actually follows the replication-packaging-excision (RPE) program. We find that P22tsc229 excises early after induction, but P22 delays excision to just before it is detrimental tophage production. This allows P22 to engage in lateral transduction. Thus, at minimalexpense to itself, P22 has tuned the timing of excision to balance propagation with lateraltransduction, powering the evolution of its host through gene transfer in the interest of selfpreservation.
Journal articleHumphrey S, Fillol-Salom A, Quiles-Puchalt N, et al., 2021,
Bacterial chromosomal mobility via lateral transduction exceeds that of classical mobile genetic elements, Nature Communications, Vol: 12, Pages: 1-12, ISSN: 2041-1723
It is commonly assumed that the horizontal transfer of most bacterial chromosomal genes is limited, in contrast to the frequent transfer observed for typical mobile genetic elements. However, this view has been recently challenged by the discovery of lateral transduction in Staphylococcus aureus, where temperate phages can drive the transfer of large chromosomalregions at extremely high frequencies. Here, we analyse previously published as well as new datasets to compare horizontal gene transfer rates mediated by different mechanisms in S. aureus and Salmonella enterica. We find that the horizontal transfer of core chromosomal genes via lateral transduction can be more efficient than the transfer of classical mobile genetic elements via conjugation or generalized transduction. These results raise questions about our definition of mobile genetic elements, and the potential roles played by lateral transduction in bacterial evolution.
Journal articleMarshall EKP, Dionne MS, 2021,
Journal articlePathania M, Tosi T, Millership C, et al., 2021,
Structural basis for the inhibition of the Bacillus subtilis c-di-AMP cyclase CdaA by the phosphoglucomutase GlmM, Journal of Biological Chemistry, Vol: 297, Pages: 1-15, ISSN: 0021-9258
Cyclic-di-adenosine monophosphate (c-di-AMP) is an important nucleotide signaling molecule that plays a key role in osmotic regulation in bacteria. c-di-AMP is produced from two molecules of ATP by proteins containing a diadenylate cyclase (DAC) domain. In Bacillus subtilis, the main c-di-AMP cyclase, CdaA, is a membrane-linked cyclase with an N-terminal transmembrane domain followed by the cytoplasmic DAC domain. As both high and low levels of c-di-AMP have a negative impact on bacterial growth, the cellular levels of this signaling nucleotide are tightly regulated. Here we investigated how the activity of the B. subtilis CdaA is regulated by the phosphoglucomutase GlmM, which has been shown to interact with the c-di-AMP cyclase. Using the soluble B. subtilis CdaACD catalytic domain and purified full-length GlmM or the GlmMF369 variant lacking the C-terminal flexible domain 4, we show that the cyclase and phosphoglucomutase form a stable complex in vitro and that GlmM is a potent cyclase inhibitor. We determined the crystal structure of the individual B. subtilis CdaACD and GlmM homodimers and of the CdaACD:GlmMF369 complex. In the complex structure, a CdaACD dimer is bound to a GlmMF369 dimer in such a manner that GlmM blocks the oligomerization of CdaACD and formation of active head-to-head cyclase oligomers, thus suggesting a mechanism by which GlmM acts as a cyclase inhibitor. As the amino acids at the CdaACD:GlmM interphase are conserved, we propose that the observed mechanism of inhibition of CdaA by GlmM may also be conserved among Firmicutes.
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