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1.
Viruses ; 16(7)2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-39066209

RESUMO

Infections due to antimicrobial-resistant bacteria have become a major threat to global health. Some patients may carry resistant bacteria in their gut microbiota. Specific risk factors may trigger the conversion of these carriages into infections in hospitalized patients. Preventively eradicating these carriages has been postulated as a promising preventive intervention. However, previous attempts at such eradication using oral antibiotics or probiotics have led to discouraging results. Phage therapy, the therapeutic use of bacteriophage viruses, might represent a worthy alternative in this context. Taking inspiration from this clinical challenge, we built Gut-On-A-Chip (GOAC) models, which are tridimensional cell culture models mimicking a simplified gut section. These were used to better understand bacterial dynamics under phage pressure using two relevant species: Pseudomonas aeruginosa and Escherichia coli. Model mucus secretion was documented by ELISA assays. Bacterial dynamics assays were performed in GOAC triplicates monitored for 72 h under numerous conditions, such as pre-, per-, or post-bacterial timing of phage introduction, punctual versus continuous phage administration, and phage expression of mucus-binding properties. The potential genomic basis of bacterial phage resistance acquired in the model was investigated by variant sequencing. The bacterial "escape growth" rates under phage pressure were compared to static in vitro conditions. Our results suggest that there is specific bacterial prosperity in this model compared to other in vitro conditions. In E. coli assays, the introduction of a phage harboring unique mucus-binding properties could not shift this balance of power, contradicting previous findings in an in vivo mouse model and highlighting the key differences between these models. Genomic modifications were correlated with bacterial phage resistance acquisition in some but not all instances, suggesting that alternate ways are needed to evade phage predation, which warrants further investigation.


Assuntos
Bacteriófagos , Escherichia coli , Microbioma Gastrointestinal , Terapia por Fagos , Pseudomonas aeruginosa , Pseudomonas aeruginosa/virologia , Bacteriófagos/fisiologia , Bacteriófagos/genética , Humanos , Terapia por Fagos/métodos , Escherichia coli/virologia , Dispositivos Lab-On-A-Chip
2.
Nat Microbiol ; 9(6): 1434-1453, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38834776

RESUMO

In contrast to the many reports of successful real-world cases of personalized bacteriophage therapy (BT), randomized controlled trials of non-personalized bacteriophage products have not produced the expected results. Here we present the outcomes of a retrospective observational analysis of the first 100 consecutive cases of personalized BT of difficult-to-treat infections facilitated by a Belgian consortium in 35 hospitals, 29 cities and 12 countries during the period from 1 January 2008 to 30 April 2022. We assessed how often personalized BT produced a positive clinical outcome (general efficacy) and performed a regression analysis to identify functional relationships. The most common indications were lower respiratory tract, skin and soft tissue, and bone infections, and involved combinations of 26 bacteriophages and 6 defined bacteriophage cocktails, individually selected and sometimes pre-adapted to target the causative bacterial pathogens. Clinical improvement and eradication of the targeted bacteria were reported for 77.2% and 61.3% of infections, respectively. In our dataset of 100 cases, eradication was 70% less probable when no concomitant antibiotics were used (odds ratio = 0.3; 95% confidence interval = 0.127-0.749). In vivo selection of bacteriophage resistance and in vitro bacteriophage-antibiotic synergy were documented in 43.8% (7/16 patients) and 90% (9/10) of evaluated patients, respectively. We observed a combination of antibiotic re-sensitization and reduced virulence in bacteriophage-resistant bacterial isolates that emerged during BT. Bacteriophage immune neutralization was observed in 38.5% (5/13) of screened patients. Fifteen adverse events were reported, including seven non-serious adverse drug reactions suspected to be linked to BT. While our analysis is limited by the uncontrolled nature of these data, it indicates that BT can be effective in combination with antibiotics and can inform the design of future controlled clinical trials. BT100 study, ClinicalTrials.gov registration: NCT05498363 .


Assuntos
Antibacterianos , Infecções Bacterianas , Bacteriófagos , Terapia por Fagos , Humanos , Estudos Retrospectivos , Terapia por Fagos/métodos , Bacteriófagos/fisiologia , Bacteriófagos/genética , Feminino , Masculino , Pessoa de Meia-Idade , Antibacterianos/uso terapêutico , Adulto , Infecções Bacterianas/terapia , Resultado do Tratamento , Idoso , Medicina de Precisão/métodos , Adolescente , Adulto Jovem , Bactérias/virologia , Bactérias/genética , Criança , Idoso de 80 Anos ou mais , Pré-Escolar , Bélgica , Lactente
3.
Viruses ; 15(8)2023 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-37632068

RESUMO

The immune system offers several mechanisms of response to harmful microbes that invade the human body. As a first line of defense, neutrophils can remove pathogens by phagocytosis, inactivate them by the release of reactive oxygen species (ROS) or immobilize them by neutrophil extracellular traps (NETs). Although recent studies have shown that bacteriophages (phages) make up a large portion of human microbiomes and are currently being explored as antibacterial therapeutics, neutrophilic responses to phages are still elusive. Here, we show that exposure of isolated human resting neutrophils to a high concentration of the Pseudomonas phage PAK_P1 led to a 2-fold increase in interleukin-8 (IL-8) secretion. Importantly, phage exposure did not induce neutrophil apoptosis or necrosis and did not further affect activation marker expression, oxidative burst, and NETs formation. Similarly, inflammatory stimuli-activated neutrophil effector responses were unaffected by phage exposure. Our work suggests that phages are unlikely to inadvertently cause excessive neutrophil responses that could damage tissues and worsen disease. Because IL-8 functions as a chemoattractant, directing immune cells to sites of infection and inflammation, phage-stimulated IL-8 production may modulate some host immune responses.


Assuntos
Bacteriófagos , Fagos de Pseudomonas , Humanos , Bacteriófago P1 , Neutrófilos , Interleucina-8
4.
Genome Announc ; 3(4)2015 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-26184934

RESUMO

We report the sequence of the Streptococcus pyogenes emm28 strain M28PF1, isolated from a patient with postpartum endometritis. The M28 protein is smaller than that of MGAS6180 (NC_007296.1). Furthermore, the 1,896,976-bp-long chromosome presents, compared to that of MGAS6180, an inversion between the two comX genes.

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