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  • Journal article
    Sanchez Garrido J, Alberdi L, Chatterjee S, Frankel G, Mullineaux-Sanders Cet al., 2021,

    Type III secretion system effector subnetworks elicit distinct host immune responses to infection

    , Current Opinion in Microbiology, Vol: 64, Pages: 19-26, ISSN: 1369-5274

    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 article
    Liu B, Li S, Liu Y, Chen H, Hu Z, Wang Z, Zhao Y, Zhang L, Ma B, Wang H, Matthews S, Wang Y, Zhang Ket al., 2021,

    Bacteriophage Twort protein Gp168 is a β-clamp inhibitor by occupying the DNA sliding channel.

    , Nucleic Acids Res, Vol: 49, Pages: 11367-11378

    Bacterial chromosome replication is mainly catalyzed by DNA polymerase III, whose beta subunits enable rapid processive DNA replication. Enabled by the clamp-loading complex, the two beta subunits form a ring-like clamp around DNA and keep the polymerase sliding along. Given the essential role of β-clamp, its inhibitors have been explored for antibacterial purposes. Similarly, β-clamp is an ideal target for bacteriophages to shut off host DNA synthesis during host takeover. The Gp168 protein of phage Twort is such an example, which binds to the β-clamp of Staphylococcus aureus and prevents it from loading onto DNA causing replication arrest. Here, we report a cryo-EM structure of the clamp-Gp168 complex at 3.2-Å resolution. In the structure of the complex, the Gp168 dimer occupies the DNA sliding channel of β-clamp and blocks its loading onto DNA, which represents a new inhibitory mechanism against β-clamp function. Interestingly, the key residues responsible for this interaction on the β-clamp are well conserved among bacteria. We therefore demonstrate that Gp168 is potentially a cross-species β-clamp inhibitor, as it forms complex with the Bacillus subtilis β-clamp. Our findings reveal an alternative mechanism for bacteriophages to inhibit β-clamp and provide a new strategy to combat bacterial drug resistance.

  • Journal article
    Humphrey S, Fillol-Salom A, Quiles-Puchalt N, Ibarra-Chávez R, Haag A, Chen J, Penades Jet 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 article
    Fillol-Salom A, Bacigalupe R, Humphrey S, Chiang YN, Chen J, Penades Jet al., 2021,

    Lateral transduction is inherent to the life cycle of the archetypical Salmonella phage P22

    , Nature Communications, Vol: 12, Pages: 1-11, ISSN: 2041-1723

    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 article
    Marshall EKP, Dionne MS, 2021,

    Drosophila versus Mycobacteria: A model for mycobacterial host-pathogen interactions

    , MOLECULAR MICROBIOLOGY, ISSN: 0950-382X
  • Journal article
    Pathania M, Tosi T, Millership C, Hoshiga F, Morgan RML, Freemont PS, Gründling Aet al., 2021,

    Structural basis for the inhibition of the Bacillus subtilis c-di-AMP cyclase CdaA by the phosphoglucomutase GlmM.

    , J Biol Chem, Vol: 297

    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.

  • Journal article
    Pathania M, Tosi T, Millership C, Hoshiga F, Morgan RML, Freemont PS, Grundling Aet 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.

  • Journal article
    Pruski P, Dos Santos Correia G, Lewis H, Capuccini K, Inglese P, Chan D, Brown R, Kindinger L, Lee Y, Smith A, Marchesi J, McDonald J, Cameron S, Alexander-Hardiman K, David A, Stock S, Norman J, Terzidou V, Teoh TG, Sykes L, Bennett P, Takats Z, MacIntyre Det al., 2021,

    Direct on-swab metabolic profiling of vaginal microbiome host interactions during pregnancy and preterm birth

    , Nature Communications, Vol: 12, ISSN: 2041-1723

    The pregnancy vaginal microbiome contributes to risk of preterm birth, the primary cause of death in children under 5 years of age. Here we describe direct on-swab metabolic profiling by Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) for sample preparation-free characterisation of the cervicovaginal metabolome in two independent pregnancy cohorts (VMET, n = 160; 455 swabs; VMET II, n = 205; 573 swabs). By integrating metataxonomics and immune profiling data from matched samples, we show that specific metabolome signatures can be used to robustly predict simultaneously both the composition of the vaginal microbiome and host inflammatory status. In these patients, vaginal microbiota instability and innate immune activation, as predicted using DESI-MS, associated with preterm birth, including in women receiving cervical cerclage for preterm birth prevention. These findings highlight direct on-swab metabolic profiling by DESI-MS as an innovative approach for preterm birth risk stratification through rapid assessment of vaginal microbiota-host dynamics.

  • Journal article
    Ronneau S, Hill PW, Helaine S, 2021,

    Antibiotic persistence and tolerance: not just one and the same.

    , Curr Opin Microbiol, Vol: 64, Pages: 76-81

    Distinguished by their penetrance within a population, antibiotic tolerance and persistence are superficially similar phenomena by which growth-restricted bacteria survive treatment with bactericidal antibiotics. Owing to their apparent similarity, it is often assumed that the same physiological states and molecular mechanisms underlie the ability of individual antibiotic tolerant and persistent bacteria to survive treatment. Experimentally, antibiotic persistence is an extremely challenging phenomenon to study due to both its transience and the co-existence of persisters with non-persisters in the population of interest. In contrast, antibiotic tolerance operates at the whole population level as a result of bacteria acquiring genetic mutations or encountering environmental conditions that result in growth restriction. Therefore, studying antibiotic tolerance is often used as a convenient way to understand the molecular mechanisms governing antibiotic persistence. In this opinion, we discuss our current understanding of these two phenomena, outlining how tolerance and persistence can be distinguished experimentally. We argue that this approach will help avoid controversies in the field, especially in instances where the two phenomena co-exist. Finally, we evaluate the clinical evidence implicating tolerance and persistence in recalcitrance and relapse of bacterial infections.

  • Journal article
    Humphrey S, San Millan A, Toll-Riera M, Connolly J, Flor-Duro A, Chen J, Ubeda C, MacLean RC, Penades Jet al., 2021,

    Staphylococcal phages and pathogenicity islands drive plasmid evolution

    , Nature Communications, Vol: 12, Pages: 1-15, ISSN: 2041-1723

    Conjugation has classically been considered the main mechanism driving plasmid transfer in nature. Yet bacteria frequently carry so-called non-transmissible plasmids, raising questions about how these plasmids spread. Interestingly, the size of many mobilizable and non transmissible plasmids coincides with the average size of phages (~40kb) or that of a family of pathogenicity islands, the phage-inducible chromosomal islands (PICIs, ~11 kb). Here, we show that phages and PICIs from Staphylococcus aureus can mediate intra- and inter-species plasmid transfer via generalised transduction, potentially contributing to non-transmissible plasmid spread in nature. Further, staphylococcal PICIs enhance plasmid packaging efficiency, and phages and PICIs exert selective pressures on plasmids via the physical capacity of their capsids, explaining the bimodal size distribution observed for non-conjugative plasmids. Our results highlight that transducing agents (phages, PICIs) have important roles in bacterial plasmid evolution and, potentially, in antimicrobial resistance transmission.

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.

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