Pathogens and disease最新文献

Infections caused by Cryptococcus gattii mainly affect immunocompetent individuals and the treatment presents important limitations. This study aimed to validate the efficacy of selective serotonin reuptake inhibitors (SSRI), fluoxetine hydrochloride (FLH), and paroxetine hydrochloride (PAH) in vitro against C. gattii. The antifungal activity of SSRI using the microdilution method revealed a minimal inhibitory concentration (MIC) of 31.25 µg/ml. The combination of FLH or PAH with amphotericin B (AmB) was analyzed using the checkerboard assay and the synergistic effect of SSRI in combination with AmB was able to reduce the SSRI or AmB MIC values 4-8-fold. When examining the effect of SSRI on the induced capsules, we observed that FLH and PAH significantly decreased the size of C. gattii capsules. In addition, the effects of FLH and PAH were evaluated in biofilm biomass and viability. The SSRI were able to reduce biofilm biomass and biofilm viability. In conclusion, our results indicate the use of FLH and PAH exhibited in vitro anticryptococcal activity, representing a possible future alternative for the cryptococcosis treatment.

Introduction: There is a proven role for hepcidin and the composition of gut microbiota and its derivatives in the pathophysiology of liver fibrosis.

Area covered: This review focuses on the literature search regarding the effect of hepcidin and gut microbiota on regulating liver physiology. We presented the regulating mechanisms of hepcidin expression and discussed the possible interaction between gut microbiota and hepcidin regulation. Furthermore, we investigated the importance of the hepcidin gene in biological processes and bacterial interactions using bioinformatics analysis.

Expert opinion: One of the main features of liver fibrosis is iron accumulation in hepatic cells, including hepatocytes. This accumulation can induce an oxidative stress response, inflammation, and activation of hepatic stellate cells. Hepcidin is a crucial regulator of iron by targeting ferroportin expressed on hepatocytes, macrophages, and enterocytes. Various stimuli, such as iron load and inflammatory signals, control hepcidin regulation. Furthermore, a bidirectional relationship exists between iron and the composition and metabolic activity of gut microbiota. We explored the potential of gut microbiota to influence hepcidin expression and potentially manage liver fibrosis, as the regulation of iron metabolism plays a crucial role in this context.

Visceral leishmaniasis (VL) is a severe form of leishmaniasis, primarily affecting the poor in developing countries. Although several studies have highlighted the importance of toll-like receptors (TLRs) in the pathophysiology of leishmaniasis, the role of specific TLRs and their binding partners involved in Leishmania donovani uptake are still elusive. To investigate the mechanism of L. donovani entry inside the macrophages, we found that the parasite lipophosphoglycan (LPG) interacted with the macrophage TLR4, leading to parasite uptake without any significant alteration of macrophage cell viability. Increased parasite numbers within macrophages markedly inhibited lipopolysachharide-induced pro-inflammatory cytokines gene expression. Silencing of macrophage-TLR4, or inhibition of parasite-LPG, significantly stemmed parasite infection in macrophages. Interestingly, we observed a significant enhancement of macrophage migration, and generation of reactive oxygen species (ROS) in the parasite-infected TLR4-silenced macrophages, whereas parasite infection in TLR4-overexpressed macrophages exhibited a notable reduction of macrophage migration and ROS generation. Moreover, mutations in the leucine-rich repeats (LRRs), particularly LRR5 and LRR6, significantly prevented TLR4 interaction with LPG, thus inhibiting cellular parasite entry. All these results suggest that parasite LPG recognition by the LRR5 and LRR6 of macrophage-TLR4 facilitated parasite entry, and impaired macrophage functions. Therefore, targeting LRR5/LRR6 interactions with LPG could provide a novel option to prevent VL.

Acinetobacter baumannii is Gram-negative pathogen with extensive role in healthcare-associated infections (HAIs). Plasmids in this species are important carriers of antimicrobial resistance genes. In this work, we investigated the plasmids of 227 Brazilian A. baumannii genomes. A total of 389 plasmid sequences with 424 Rep proteins typed to 22 different homology groups (GRs) were identified. The GR2 plasmid group was the most predominant (40.6%), followed by the GR4 group (16.7%), representing ∼57% of all plasmids. There is a wide distribution of plasmids among the isolates and most strains carry more than one plasmid. Our analyses revealed a significant prevalence of GR4 plasmids in Brazilian A. baumannii genomes carrying several antimicrobial resistance genes, notably to carbapenem (39.43%). These plasmids harbor a MOBQ relaxase that might confer increased spreading potential in the environment. Most plasmids of the predominant groups belong to the same plasmid taxonomic unit (PTU-Pse7) and have a AbkA/AbkB toxin-antitoxin system that has a role in plasmid stability and dissemination of carbapenem resistance genes. The results of this work should contribute to our understanding of the molecular content of plasmids in a large and populous country, highlighting the importance of genomics for enhanced epidemiological surveillance.

Staphylococcus aureus is the leading cause of hospital-acquired infections and can cause a wide range of diseases from mild skin infections to invasive diseases including deep surgical site infections, life-threatening bacteremia, and sepsis. This pathogen remains a challenge to manage due to its ability to rapidly develop resistance to antibiotic treatment and to form biofilms. Despite the current infection control measures which involve mainly antibiotics, the burden of infection remains high. The 'omics' approaches have not led to the discovery of novel antibacterials at a pace sufficient to cope with the emergence of multidrug-resistant and biofilm-forming S. aureus, Hence, new strategies for anti-infective therapies need to be explored urgently. One promising strategy is harnessing the immune response to enhance the protective antimicrobial immunity in the host. This review discusses the potential of monoclonal antibodies and vaccines as alternatives to treat and manage infections caused by planktonic and biofilms of S. aureus.

Enterovirus 71 (EV71) can cause severe hand-foot-and-mouth disease with neurological complications. It has evolved multiple mechanisms to compromise the host type I interferon (IFN-I) response. In neuronal cells, EV71-mediated IFN-I antagonism may be associated with neural precursor cell-expressed developmentally downregulated 4-like (Nedd4L), the E3 ubiquitin ligase that can interact with alphaB-crystallin (CRYAB) in the regulation of Nav1.5 stability. Here, we investigated the effect of CRYAB stability on IFN-β promoter activity in neuronal SH-SY5Y cells infected with EV71, and its relations to Nedd4 L and extracellular signal-regulated kinases (ERK). Results showed that EV71 infection significantly caused CRYAB degradation via the Nedd4L-proteasome pathway, which required ERK-mediated phosphorylation of Serine 45 in CRYAB. Subsequently, it was observed that siRNA- or EV71-mediated CRYAB reduction limited Poly(dAT)-activated IFN-β promoter, and CRYAB stabilisation by U0126-mediated inhibition of ERK activation remarkably enhanced the activity of IFN-β promoter upon EV71 challenge. Collectively, we elucidate a novel mechanism by which ERK activation contributes to EV71 immune escape via CRYAB/IFN-β axis in SH-SY5Y cells, indicating that perturbing ERK activation is desirable for anti-EV71 therapy.

Klebsiella pneumoniae is an opportunistic pathogen associated with biofilm-based infections, which are intrinsically antibiotic resistant. Extracellular DNA plays a crucial role in biofilm formation and self-defence, with nucleases being proposed as promising agents for biofilm disruption. This study evaluated the in vitro and in vivo efficacy of DNase I in improving the activity of cefotaxime, amikacin, and ciprofloxacin against K. pneumoniae biofilms. K. pneumoniae ATCC 700603 and a clinical isolate from catheter-related bloodstream infection were cultured for biofilm formation on microtiter plates, and the antibiofilm activity of the antibiotics (0.03-64 mg/L), with or without bovine pancreatic DNase I (1-32 mg/L) was determined by XTT dye reduction test and viable counting. The effect of ciprofloxacin (2 mg/L) and DNase I (16 mg/L) was further evaluated in vitro on 1-cm-long silicon catheter segments, and in a mouse model of subcutaneous catheter-associated infection. Combination with DNase I did not improve the biofilm-preventive capacity of the three antibiotics or the biofilm-eradicating capacity of cefotaxime and amikacin. The biofilm-eradicating capacity of ciprofloxacin was increased by 8-fold and 4-fold in K. pneumoniae ATCC 700603 and clinical isolate, respectively, with DNase I. The combination therapy caused 99% reduction in biofilm biomass in the mouse model.

Borrelia burgdorferi, the spirochete that causes Lyme disease, is a diderm organism that is similar to Gram-negative organisms in that it contains both an inner and outer membrane. Unlike typical Gram-negative organisms, however, B. burgdorferi lacks lipopolysaccharide (LPS). Using computational genome analyses and structural modeling, we identified a transport system containing six proteins in B. burgdorferi that are all orthologs to proteins found in the lipopolysaccharide transport (LPT) system that links the inner and outer membranes of Gram-negative organisms and is responsible for placing LPS on the surface of these organisms. While B. burgdorferi does not contain LPS, it does encode over 100 different surface-exposed lipoproteins and several major glycolipids, which like LPS are also highly amphiphilic molecules, though no system to transport these molecules to the borrelial surface is known. Accordingly, experiments supplemented by molecular modeling were undertaken to determine whether the orthologous LPT system identified in B. burgdorferi could transport lipoproteins and/or glycolipids to the borrelial outer membrane. Our combined observations strongly suggest that the LPT transport system does not transport lipoproteins to the surface. Molecular dynamic modeling, however, suggests that the borrelial LPT system could transport borrelial glycolipids to the outer membrane.