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Journal articleAllegretti JR, Kelly CR, Grinspan A, et al., 2020,
Outcomes of fecal microbiota transplantation in patients with inflammatory bowel diseases and recurrent Clostridioides difficile infection
, Gastroenterology, Vol: 159, Pages: 1982-1984, ISSN: 0016-5085There has been an increase in the burden of Clostridioides difficile infection (CDI),1 especially in high-risk populations such as patients with inflammatory bowel disease (IBD).2 The prevalence of CDI in the IBD population is up to 8-fold higher than comparable controls, with increased rates of recurrence and CDI-associated mortality.3 In addition, CDI may induce an IBD flare, and worsen disease severity and clinical course.4Fecal microbiota transplantation (FMT) is a guideline recommended therapy for recurrent CDI5; however, supportive randomized trials excluded patients with IBD. In retrospective trials of patients with IBD, FMT failure rates had been reported to be approximately 25% to 30%.6 In addition, Khoruts and colleagues reported that patients with IBD and CDI were more likely to fail FMT,7 leading to further uncertainty regarding the safety and efficacy of FMT in IBD patients with concurrent CDI. Accordingly, we conducted the first prospective study examining the efficacy of FMT among patients with IBD and CDI.MethodsWe conducted an open-label, prospective, single-arm, multicenter cohort study at 4 tertiary care FMT referral centers (Brigham and Women’s Hospital, Indiana University, Brown University, and Mount Sinai Hospital; NCT03106844). Patients with a confirmed diagnosis of IBD and 2 or more confirmed CDI episodes within 12 months, including the most recent episode occurring within 3 months, were enrolled. In keeping with CDI clinical guidelines,5 polymerase chain reaction or glutamate dehydrogenase with toxin enzyme immunoassay were permitted for the qualifying CDI episode. Patients with a total or subtotal colectomy, isolated ileal or small bowel Crohn’s disease, those pregnant or breastfeeding, those treated with vancomycin or metronidazole for more than 60 days, or those who had undergone a prior FMT within 12 months were excluded. Baseline IBD and CDI data were collected. All patients underwent a single FMT via colonoscopy. Four robus
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Journal articleHa KP, Clarke RS, Kim G-L, et al., 2020,
Staphylococcal DNA repair Is required for infection
, mBio, Vol: 11, ISSN: 2150-7511To cause infection, Staphylococcus aureus must withstand damage caused by host immune defenses. However, the mechanisms by which staphylococcal DNA is damaged and repaired during infection are poorly understood. Using a panel of transposon mutants, we identified the rexBA operon as being important for the survival of Staphylococcus aureus in whole human blood. Mutants lacking rexB were also attenuated for virulence in murine models of both systemic and skin infections. We then demonstrated that RexAB is a member of the AddAB family of helicase/nuclease complexes responsible for initiating the repair of DNA double-strand breaks. Using a fluorescent reporter system, we were able to show that neutrophils cause staphylococcal DNA double-strand breaks through reactive oxygen species (ROS) generated by the respiratory burst, which are repaired by RexAB, leading to the induction of the mutagenic SOS response. We found that RexAB homologues in Enterococcus faecalis and Streptococcus gordonii also promoted the survival of these pathogens in human blood, suggesting that DNA double-strand break repair is required for Gram-positive bacteria to survive in host tissues. Together, these data demonstrate that DNA is a target of host immune cells, leading to double-strand breaks, and that the repair of this damage by an AddAB-family enzyme enables the survival of Gram-positive pathogens during infection.IMPORTANCE To cause infection, bacteria must survive attack by the host immune system. For many bacteria, including the major human pathogen Staphylococcus aureus, the greatest threat is posed by neutrophils. These immune cells ingest the invading organisms and try to kill them with a cocktail of chemicals that includes reactive oxygen species (ROS). The ability of S. aureus to survive this attack is crucial for the progression of infection. However, it was not clear how the ROS damaged S. aureus and how the bacterium repaired this damage. In this work, we show that ROS cause breaks
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Journal articleNuh A, Ramadan N, Schelenz S, et al., 2020,
Comparative Evaluation of MIRONAUT-AM and CLSI broth microdilution method for antifungal susceptibility testing of <i>Aspergillus species</i> against four commonly used antifungals
, MEDICAL MYCOLOGY, Vol: 58, Pages: 1085-1090, ISSN: 1369-3786- Author Web Link
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- Citations: 7
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Journal articleShenker NS, Perdones-Montero A, Burke A, et al., 2020,
Metabolomic and Metataxonomic Fingerprinting of Human Milk Suggests Compositional Stability over a Natural Term of Breastfeeding to 24 Months
, NUTRIENTS, Vol: 12- Author Web Link
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- Citations: 7
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Journal articlePetropoulou K, Salt LJ, Edwards CH, et al., 2020,
A natural mutation in Pisum sativum L. (pea) alters starch assembly and improves glucose homeostasis in humans
, Nature Food -
Journal articlePrieto JM, Rapún-Araiz B, Gil C, et al., 2020,
Inhibiting the two-component system GraXRS with verteporfin to combat Staphylococcus aureus infections
, Scientific Reports, Vol: 10, ISSN: 2045-2322Infections caused by Staphylococcus aureus pose a serious and sometimes fatal health issue. With the aim of exploring a novel therapeutic approach, we chose GraXRS, a Two-Component System (TCS) that determines bacterial resilience against host innate immune barriers, as an alternative target to disarm S. aureus. Following a drug repurposing methodology, and taking advantage of a singular staphylococcal strain that lacks the whole TCS machinery but the target one, we screened 1.280 off-patent FDA-approved drug for GraXRS inhibition. Reinforcing the connection between this signaling pathway and redox sensing, we found that antioxidant and redox-active molecules were capable of reducing the expression of the GraXRS regulon. Among all the compounds, verteporfin (VER) was really efficient in enhancing PMN-mediated bacterial killing, while topical administration of such drug in a murine model of surgical wound infection significantly reduced the bacterial load. Experiments relying on the chemical mimicry existing between VER and heme group suggest that redox active residue C227 of GraS participates in the inhibition exerted by this FDA-approved drug. Based on these results, we propose VER as a promising candidate for sensitizing S. aureus that could be helpful to combat persistent or antibiotic-resistant infections.
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Journal articleYebra G, Haag AF, Neamah MM, et al., 2020,
Massive genome decay and insertion sequence expansion drive the evolution of a novel host-restricted bacterial pathogen
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The emergence of new pathogens is a major threat to public and veterinary health. Changes in bacterial habitat such as those associated with a switch in host or disease tropism are often accompanied by genetic adaptation.<jats:italic>Staphylococcus aureus</jats:italic>is a multi-host bacterial species comprising strains with distinct tropisms for human and livestock species. A microaerophilic subspecies,<jats:italic>Staphylococcus aureus</jats:italic>subsp.<jats:italic>anaerobius</jats:italic>, is responsible for outbreaks of Morel’s disease, a lymphadenitis in small ruminants. However, the evolutionary history of<jats:italic>S. aureus</jats:italic>subsp.<jats:italic>anaerobius</jats:italic>and its relatedness to<jats:italic>S. aureus</jats:italic>are unknown.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Evolutionary genomic analyses of clinical<jats:italic>S. aureus</jats:italic>subsp.<jats:italic>anaerobius</jats:italic>isolates revealed a highly conserved clone that descended from a<jats:italic>S. aureus</jats:italic>progenitor about 1000 years ago before differentiating into distinct lineages representing African and European isolates.<jats:italic>S. aureus</jats:italic>subsp.<jats:italic>anaerobius</jats:italic>has undergone limited clonal expansion, with a restricted population size, and an evolutionary rate 10-fold slower than<jats:italic>S. aureus</jats:italic>. The transition to its current restricted ecological niche involved acquisition of a pathogenicity island encoding a ruminant host-specific effector of abscess formation, several large chromosomal re-arrangements, and the accumulation of at least 205 pseudogenes resulting in
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Journal articleTaylor H, Serrano-Contreras JI, McDonald JAK, et al., 2020,
Multiomic features associated with mucosal healing and inflammation in paediatric Crohn's disease
, Alimentary Pharmacology and Therapeutics, Vol: 52, Pages: 1491-1502, ISSN: 0269-2813BACKGROUND: The gastrointestinal microbiota has an important role in mucosal immune homoeostasis and may contribute to maintaining mucosal healing in Crohn's disease (CD). AIM: To identify changes in the microbiota, metabolome and protease activity associated with mucosal healing in established paediatric CD. METHODS: Twenty-five participants aged 3-18 years with CD, disease duration of over 6 months, and maintenance treatment with biological therapy were recruited. They were divided into a low calprotectin group (faecal calprotectin <100 μg/g, "mucosal healing," n = 11), and a high calprotectin group (faecal calprotectin >100 μg/g, "mucosal inflammation," n = 11). 16S gene-based metataxonomics, 1 H-NMR spectroscopy-based metabolic profiling and protease activity assays were performed on stool samples. RESULTS: Relative abundance of Dialister species was six times greater in the low calprotectin group (q = 0.00999). Alpha and beta diversity, total protease activity and inferred metagenomic profiles did not differ between groups. Pentanoate (valerate) and lysine were principal discriminators in a machine-learning model which differentiated high and low calprotectin samples using NMR spectra (R2 0.87, Q2 0.41). Mean relative concentration of pentanoate was 1.35-times greater in the low calprotectin group (95% CI 1.03-1.68, P = 0.036) and was positively correlated with Dialister. Mean relative concentration of lysine was 1.54-times greater in the high calprotectin group (95% CI 1.05-2.03, P = 0.028). CONCLUSIONS: This multiomic study identified an increase in Dialister species and pentanoate, and a decrease in lysine, in patients with "mucosal healing." It supports further investigation of these as potential novel therapeutic targets in CD.
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Journal articleFarne H, Kumar K, Ritchie AI, et al., 2020,
Repurposing existing drugs for the treatment of COVID-19
, Annals of the American Thoracic Society, Vol: 17, Pages: 1186-1194, ISSN: 1546-3222The rapid global spread and significant mortality associated with the coronavirus disease (COVID-19) caused by SARS-CoV-2 viral infection has spurred an urgent race to find effective treatments. Repurposing existing drugs is a particularly attractive approach as pharmacokinetic and safety data already exist, thus development can leapfrog straight to clinical trials of efficacy, generating results far more quickly than de novo drug development. This review summarizes the state of play for the principle drugs identified as candidates to be repurposed for treating COVID-19 grouped by broad mechanism of action: antiviral, immune enhancing, and anti-inflammatory or immunomodulatory. Patient selection, particularly with regard to disease stage, is likely to be key. To date only dexamethasone and remedesivir have been shown to be effective, but several other promising candidates are in trials.
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Journal articleArmstrong-James D, Youngs J, Bicanic T, et al., 2020,
Confronting and mitigating the risk of COVID-19 Associated Pulmonary Aspergillosis (CAPA)
, European Respiratory Journal, Vol: 56, Pages: 1-10, ISSN: 0903-1936Cases of COVID-19 associated pulmonary aspergillosis (CAPA) are being increasingly reported and physicians treating patients with COVID-19-related lung disease need to actively consider these fungal co-infections.The SARS-CoV-2 (COVID-19) virus causes a wide spectrum of disease in healthy individuals as well as those with common comorbidities [1]. Severe COVID-19 is characterised acute respiratory distress syndrome (ARDS) secondary to viral pneumonitis, treatment of which may require mechanical ventilation or extracorporeal membrane oxygenation (ECMO) [2]. Clinicians are alert to the possibility of bacterial co-infection as a complication of lower respiratory tract viral infection; for example a recent review found that 72% of patients with COVID-19 received antimicrobial therapy [3]. However, the risk of fungal co-infection, in particular COVID-19 associated pulmonary aspergillosis (CAPA), remains underappreciated.Fungal disease consistent with invasive aspergillosis (IA) has been observed with other severe Coronaviruses such as Severe Acute Respiratory Syndrome (SARS-CoV-2003) [4, 5] and Middle East Respiratory Syndrome (MERS-CoV) [6]. From the outset of the COVID-19 pandemic, there were warning signs of secondary invasive fungal infection; Aspergillus flavus was isolated from the respiratory tract from one of 99 patients in the first COVID-19 cohort from Wuhan to be reported in any detail [2] and Aspergillus spp. were isolated from 2/52 (3.8%) of a subsequent cohort of critically unwell patients from this region [7]. More recently, retrospective case series from Belgium [8], France [9], The Netherlands [10] and Germany [11] have reported evidence of CAPA in an alarming 20–35% of mechanically ventilated patients.
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