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Journal articleLarrouy-Maumus G, Katy J, katheryn H, et al., 2021,
Detection of colistin resistance in Pseudomonas aeruginosa using the MALDIxin test on the routine MALDI Biotyper Sirius mass spectrometer
, Frontiers in Microbiology, Vol: 12, ISSN: 1664-302XColistin is frequently a last resort treatment for Pseudomonas aeruginosa infections caused by multidrug-resistant (MDR) and extensively drug resistant (XDR) strains, and detection of colistin resistance is essential for the management of infected patients. Therefore, we evaluated the recently developed MALDIxin test for the detection of colistin resistance in Pseudomonas aeruginosa clinical strains using the routine matrix-assisted laser desorption ionization (MALDI) Biotyper Sirius system. The test is based on the detection by mass spectrometry of modified lipid A by the addition of 4-amino-L-arabinose (L-ara4N) molecules on one or two phosphate groups, in strains resistant to colistin. Overproduction of L-Ara4N molecules is mainly due to the constitutive activation of the histidine kinase (PmrB) or the response regulator (PmrA) following an amino-acid substitution in clinical strains. The performance of the test was determined on a panel of 14 colistin-susceptible and 14 colistin-resistant Pseudomonas aeruginosa clinical strains, the reference strain PAO1 and positive control mutants PmrB (V28G), PmrB (D172), PhoQ (D240-247) and ParR (M59I). In comparison with the broth microdilution (BMD) method, all the susceptible strains (n=14) and 8/14 colistin-resistant strains were detected in less than 1 hour, directly on whole bacteria. The remaining resistant strains (n=6) were all detected after a short pre-exposure (4h) to colistin before sample preparation. Validation of the method on a larger panel of strains will be the next step before its use in diagnostics laboratories. Our data showed that the MALDIxin test offers rapid and efficient detection of colistin resistant Pseudomonas aeruginosa and is thus a valuable diagnostics tool to control the spread of these emerging resistant strains.
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Journal articleSchrader S, Botella H, Jansen R, et al., 2021,
Multiform antimicrobial resistance from a metabolic mutation
, Science Advances, Vol: 7, Pages: 1-17, ISSN: 2375-2548A critical challenge for microbiology and medicine is how to cure infections by bacteria that survive antibiotic treatment by persistence or tolerance. Seeking mechanisms behind such high survival, we developed a forward-genetic method for efficient isolation of high24 survival mutants in any culturable bacterial species. We found that perturbation of an essential biosynthetic pathway (arginine biosynthesis) in a mycobacterium generated three distinct forms of resistance to diverse antibiotics, each mediated by induction of WhiB7— high persistence and tolerance to kanamycin, high survival upon exposure to rifampicin, and MIC-shifted resistance to clarithromycin. As little as one base change in a gene encoding a metabolic pathway component conferred multiple forms of resistance to multiple antibiotics with different targets. This extraordinary resilience may help explain how sub31 sterilizing exposure to one antibiotic in a regimen can induce resistance to others and invites development of drugs targeting the mediator of multiform resistance, WhiB7.
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Journal articleInnes AJ, Mullish BH, Ghani R, et al., 2021,
Fecal Microbiota Transplant Mitigates Adverse Outcomes Seen in Patients Colonized With Multidrug-Resistant Organisms Undergoing Allogeneic Hematopoietic Cell Transplantation
, Frontiers in Cellular and Infection Microbiology, Vol: 11<jats:p>The gut microbiome can be adversely affected by chemotherapy and antibiotics prior to hematopoietic cell transplantation (HCT). This affects graft success and increases susceptibility to multidrug-resistant organism (MDRO) colonization and infection. We performed an initial retrospective analysis of our use of fecal microbiota transplantation (FMT) from healthy donors as therapy for MDRO-colonized patients with hematological malignancy. FMT was performed on eight MDRO-colonized patients pre-HCT (FMT-MDRO group), and outcomes compared with 11 MDRO colonized HCT patients from the same period. At 12 months, survival was significantly higher in the FMT-MDRO group (70% <jats:italic>versus</jats:italic> 36% <jats:italic>p</jats:italic> = 0.044). Post-HCT, fewer FMT-MDRO patients required intensive care (0% <jats:italic>versus</jats:italic> 46%, <jats:italic>P</jats:italic> = 0.045) or experienced fever (0.29 <jats:italic>versus</jats:italic> 0.11 days, <jats:italic>P</jats:italic> = 0.027). Intestinal MDRO decolonization occurred in 25% of FMT-MDRO patients <jats:italic>versus</jats:italic> 11% non-FMT MDRO patients. Despite the significant differences and statistically comparable patient/transplant characteristics, as the sample size was small, a matched-pair analysis between both groups to non-MDRO colonized control cohorts (2:1 matching) was performed. At 12 months, the MDRO group who did not have an FMT had significantly lower survival (36.4% <jats:italic>versus</jats:italic> 61.9% respectively, <jats:italic>p</jats:italic>=0.012), and higher non relapse mortality (NRM; 60.2% <jats:italic>versus</jats:italic> 16.7% respectively, <jats:italic>p</jats:italic>=0.009) than their paired non-MDRO-colonized cohort. Conversely, there was no difference in survival (70% <jats:italic>versus</jats:italic> 43.4%, <jats:ita
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Journal articleVincent CM, Beckwith EJ, Pearson WH, et al., 2021,
Infection increases activity via <i>Toll</i> dependent and independent mechanisms in <i>Drosophila melanogaster</i>
<jats:title>Abstract</jats:title><jats:p>Host behavioural changes are among the most apparent effects of infection. ‘Sickness behaviour’ can involve a variety of symptoms, including anorexia, depression, and changed activity levels. Here we use a real-time tracking and behavioural profiling platform to show that, in <jats:italic>Drosophila melanogaster</jats:italic>, many systemic bacterial infections cause significant increases in physical activity, and that the extent of this activity increase is a predictor of survival time in several lethal infections. Using various bacteria and <jats:italic>D. melanogaster</jats:italic> immune and activity mutants, we show that increased activity is driven by at least two different mechanisms. Increased activity after infection with <jats:italic>Micrococcus luteus</jats:italic>, a Gram-positive bacterium rapidly cleared by the immune response, strictly requires the <jats:italic>Toll</jats:italic> ligand <jats:italic>spätzle</jats:italic> and Toll-pathway activity in the fat body and the brain. In contrast, increased activity after infection with <jats:italic>Francisella novicida</jats:italic>, a Gram-negative bacterium that cannot be cleared by the immune response, is entirely independent of either <jats:italic>spätzle</jats:italic> or the parallel IMD pathway. The existence of multiple signalling mechanisms by which bacterial infections drive increases in physical activity implies that this effect may be an important aspect of the host response.</jats:p>
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Journal articleFillol-Salom A, Bacigalupe R, Humphrey S, et al., 2021,
The secret life (cycle) of temperate bacteriophages
<jats:title>Abstract</jats:title><jats:p>Lysogenic induction ends the stable association between a bacteriophage and its host, and the transition to the lytic cycle begins with prophage <jats:underline>e</jats:underline>xcision followed by DNA <jats:underline>r</jats:underline>eplication and <jats:underline>p</jats:underline>ackaging (ERP) – a temporal program that is considered universal for most temperate phages. Here we report that the long-standing ERP program is an artefact of the experimentally favoured <jats:italic>Salmonella</jats:italic> phage P22 ts<jats:italic>c<jats:sub>2</jats:sub>29</jats:italic> heat-inducible mutant, and that wildtype P22 actually follows a replication-packaging-excision (RPE) program. We found that unlike P22 ts<jats:italic>c<jats:sub>2</jats:sub>29</jats:italic>, P22 delayed excision to just before it was detrimental to phage production. Thus, at minimal expense to itself, P22 has tuned the timing of excision to balance propagation with lateral transduction, powering the evolution of its host through gene transfer in the interest of self-preservation.</jats:p><jats:sec><jats:title>One Sentence Summary</jats:title><jats:p>Genetic analyses propose a new life cycle for temperate bacteriophages.</jats:p></jats:sec>
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Journal articleNolan LM, Cain AK, Clamens T, et al., 2021,
Identification of tse8 as a type VI secretion system toxin from pseudomonas aeruginosa that targets the bacterial transamidosome to inhibit protein synthesis in prey cells
, Nature Microbiology, Vol: 6, Pages: 1199-+, ISSN: 2058-5276The Type VI secretion system (T6SS) is a bacterial nanomachine that delivers toxic effectors to kill competitors or subvert some of their key functions. Here, we use transposon directed insertion–site sequencing to identify T6SS toxins associated with the H1-T6SS, one of the three T6SS machines found in Pseudomonas aeruginosa. This approach identified several putative toxin–immunity pairs, including Tse8–Tsi8. Full characterization of this protein pair demonstrated that Tse8 is delivered by the VgrG1a spike complex into prey cells where it targets the transamidosome, a multiprotein complex involved in protein synthesis in bacteria that lack either one, or both, of the asparagine and glutamine transfer RNA synthases. Biochemical characterization of the interactions between Tse8 and the transamidosome components GatA, GatB and GatC suggests that the presence of Tse8 alters the fine-tuned stoichiometry of the transamidosome complex, and in vivo assays demonstrate that Tse8 limits the ability of prey cells to synthesize proteins. These data expand the range of cellular components targeted by the T6SS by identifying a T6SS toxin affecting protein synthesis and validate the use of a transposon directed insertion site sequencing–based global genomics approach to expand the repertoire of T6SS toxins in T6SS-encoding bacteria.
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Journal articleAllegretti JR, Kelly CR, Grinspan A, et al., 2021,
Inflammatory Bowel Disease Outcomes Following Fecal Microbiota Transplantation for Recurrent <i>C. difficile</i> Infection
, Inflammatory Bowel Diseases, Vol: 27, Pages: 1371-1378, ISSN: 1078-0998<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Recurrent Clostridioides difficile infection (CDI) in patients with inflammatory bowel disease (IBD) is a clinical challenge. Fecal microbiota transplantation (FMT) has emerged as a recurrent CDI therapy. Anecdotal concerns exist regarding worsening of IBD activity; however, prospective data among IBD patients are limited.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Secondary analysis from an open-label, prospective, multicenter cohort study among IBD patients with 2 or more CDI episodes was performed. Participants underwent a single FMT by colonoscopy (250 mL, healthy universal donor). Secondary IBD-related outcomes included rate of de novo IBD flares, worsening IBD, and IBD improvement—all based on Mayo or Harvey-Bradshaw index (HBI) scores. Stool samples were collected for microbiome and targeted metabolomic profiling.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Fifty patients enrolled in the study, among which 15 had Crohn’s disease (mean HBI, 5.8 ± 3.4) and 35 had ulcerative colitis (mean partial Mayo score, 4.2 ± 2.1). Overall, 49 patients received treatment. Among the Crohn’s disease cohort, 73.3% (11 of 15) had IBD improvement, and 4 (26.6%) had no disease activity change. Among the ulcerative colitis cohort, 62% (22 of 34) had IBD improvement, 29.4% (11 of 34) had no change, and 4% (1 of 34) experienced a de novo flare. Alpha diversity significantly increased post-FMT, and ulcerative colitis patients became more similar to the donor than Crohn’s disease patients (P = 0.04).</jats:p>
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Journal articleVincent CM, Dionne MS, 2021,
Disparate regulation of IMD signaling drives sex differences in infection pathology in Drosophila melanogaster
, Proceedings of the National Academy of Sciences, Vol: 118, Pages: 1-10, ISSN: 0027-8424Male and female animals exhibit differences in infection outcomes. One possible source of sexually dimorphic immunity is the sex-specific costs of immune activity or pathology, but little is known about the independent effects of immune- versus microbe-induced pathology and whether these may differ for the sexes. Here, by measuring metabolic and physiological outputs in Drosophila melanogaster with wild-type and mutant immune responses, we test whether the sexes are differentially impacted by these various sources of pathology and identify a critical regulator of this difference. We find that the sexes exhibit differential immune activity but similar bacteria-derived metabolic pathology. We show that female-specific immune-inducible expression of PGRP-LB, a negative regulator of the immune deficiency (IMD) pathway, enables females to reduce immune activity in response to reductions in bacterial numbers. In the absence of PGRP-LB, females are more resistant to infection, confirming the functional importance of this regulation and suggesting that female-biased immune restriction comes at a cost.
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Journal articlePrendecki M, Clarke C, Edwards H, et al., 2021,
Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression.
, Annals of the Rheumatic Diseases, Vol: 80, Pages: 1322-1329, ISSN: 0003-4967OBJECTIVE: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination. METHODS: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases. RESULTS: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy. CONCLUSION: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.
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Journal articleBrady A, Felipe-Ruiz A, Gallego Del Sol F, et al., 2021,
Molecular basis of lysis-lysogeny decisions in gram-positive phages.
, Annual Review of Microbiology, Vol: 10, Pages: 1-19, ISSN: 0066-4227Temperate bacteriophages (phages) are viruses of bacteria. Upon infection of a susceptible host, a temperate phage can establish either a lytic cycle that kills the host or a lysogenic cycle as a stable prophage. The life cycle pursued by an infecting temperate phage can have a significant impact not only on the individual host bacterium at the cellular level but also on bacterial communities and evolution in the ecosystem. Thus, understanding the decision processes of temperate phages is crucial. This review delves into the molecular mechanisms behind lysis-lysogeny decision-making in Gram-positive phages. We discuss a variety of molecular mechanisms and the genetic organization of these well-understood systems. By elucidating the strategies used by phages to make lysis-lysogeny decisions, we can improve our understanding of phage-host interactions, which is crucial for a variety of studies including bacterial evolution, community and ecosystem diversification, and phage therapeutics. Expected final online publication date for the Annual Review of Microbiology, Volume 75 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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