ABSTRACT
Inflammatory bowel disease (IBD) is a prototypic complex disease in the gastrointestinal tract that has been increasing in incidence and prevalence in recent decades. Although the precise pathophysiology of IBD remains to be elucidated, a large body of evidence suggests the critical roles of mitochondria and intestinal microbiota in the pathogenesis of IBD. In addition to their contributions to the disease, both mitochondria and gut microbes may interact with each other and modulate disease-causing cell activities. Therefore, we hypothesize that dissecting this unique interaction may help to identify novel pathways involved in IBD, which will further contribute to discovering new therapeutic approaches to the disease. As poorly treated IBD significantly affects the quality of life of patients and is associated with risks and complications, successful treatment is crucial. In this review, we stratify previously reported experimental and clinical observations of the role of mitochondria and intestinal microbiota in IBD. Additionally, we review the intercommunication between mitochondria, and the intestinal microbiome in patients with IBD is reviewed along with the potential mediators for these interactions. We specifically focus on their roles in cellular metabolism in intestinal epithelial cells and immune cells. To this end, we propose a potential therapeutic intervention strategy for IBD.
Subject(s)
Inflammatory Bowel Diseases , Microbiota , Humans , Quality of Life , Inflammatory Bowel Diseases/metabolism , Mitochondria/metabolismABSTRACT
ABSTRACT: Background: Patients with severe coronavirus disease 2019 (COVID-19) are at an increased risk of acute respiratory distress syndrome and mortality. This is due to the increased levels of pro-inflammatory cytokines that amplify downstream pathways that are controlled by immune regulators. Objective: This study aimed to investigate the association between cytokine genetic variants, cytokine serum levels/profiles, and disease severity in critically and noncritically ill COVID-19 patients. Methods: This cross-sectional study recruited 646 participants who tested positive for severe acute respiratory syndrome coronavirus 2 from six collection sites across the United Arab Emirates. Medical files were accessed to retrieve clinical data. Blood samples were collected from all participants. Patients were divided into two clinical groups, noncritical (n = 453) and critical (n = 193), according to World Health Organization classification guidelines for COVID-19 patients. Cytokine analyses were conducted on serum of a subset of the cohort, specifically on 426 participants (noncritical, 264; critical, 162). Candidate gene analyses of 33 cytokine-related genes (2,836 variants) were extracted from a genome-wide association study to identify genetic variants with pleiotropic effects on a specific cytokine and the severity of COVID-19 disease. Results: Age, body mass index (BMI), and pre-existing medical conditions were found to be significant risk factors that contribute to COVID-19 disease severity. After correcting for age, sex, and BMI, IP-10 ( P < 0.001), IFN ( P = 0.001), IL-6 ( P < 0.001), and CXCL-16 ( P < 0.001) serum levels were significantly higher among critical COVID-19 cases, when compared with noncritically ill patients. To investigate if the genetic variants involved in the serum cytokine levels are associated with COVID-19 severity, we studied several genes. Single nucleotide polymorphisms in IL6 (rs1554606; odd ratio (OR) G = 0.67 [0.66, 0.68]; P = 0.017), IFNG (rs2069718; OR G = 0.63 [0.62, 0.64]; P = 0.001), MIP (rs799187; OR A = 1.69 [1.66, 1.72]; P = 0.034), and CXCL16 (rs8071286; OR A = 1.42 [1.41, 1.44]; P = 0.018) were found to be associated with critically ill patients. Polymorphisms in the CXCL10 , CCL2 , IL1 , CCL7 , and TNF genes were not associated with the COVID-19 critical phenotype. The genotypes of IL-6 (gene, IL6 [7p15.3]) and CXCL-16 (gene, CXCL16 [17p13.2]) were significantly associated with the serum levels of the respective cytokine in critical cases of COVID-19. Conclusion: Data obtained from measuring cytokine levels and genetic variant analyses suggest that IL-6 and CXCL-16 could potentially be used as potential biomarkers for monitoring disease progression of COVID-19 patients. The findings in this study suggest that specific cytokine gene variants correlate with serum levels of the specific cytokine. These genetic variants could be of assistance in the early identification of high-risk patients on admission to the clinic to improve the management of COVID-19 patients and other infectious diseases.
Subject(s)
COVID-19 , Cytokines , Humans , Cytokines/genetics , COVID-19/genetics , Interleukin-6/genetics , Genome-Wide Association Study , Cross-Sectional StudiesABSTRACT
BACKGROUND: The epidemiology of extended-spectrum ß-lactamase (ESBL)-producing bacteria is fast evolving with increasing global trend towards community-acquired infections. Limited information available about ESBLs therapy outcomes and control strategies, especially in the Middle Eastern countries. METHODS: We studied 399 ESBL-producing Escherichia coli and Klebsiella pneumoniae isolates from urinary tract infections (UTIs) occurred between 2014 and 2016 in University Hospital Sharjah. We included 124 ESBL-negative E. coli and K. pneumoniae isolates from UTIs as controls. Pearson Chi squares test and independent t-test were used to compare difference between ESBL positives and negatives. Multivariate logistic regression analysis was also performed. RESULTS: Approximately 75% of the E. coli and K. pneumoniae isolates causing UTIs were community-acquired. We found that recurrent UTIs, old age, and catheterization among other risk factors for community-acquired ESBL-positive UTIs. Majority of these ESBL-positive isolates were resistant to antibiotics such as ciprofloxacin (74%) and trimethoprim-sulphamethoxazole (73%) that are commonly used for treatment of community-acquired urinary tract infections. CONCLUSIONS: ESBL-producing E. coli and K. pneumoniae have become major etiological pathogens of community-acquired UTIs in the United Arab Emirates. Healthcare providers should implement better infection control strategies and careful use of antimicrobials especially in out-patient and community settings.
Subject(s)
Community-Acquired Infections/microbiology , Escherichia coli/physiology , Klebsiella pneumoniae/physiology , Urinary Tract Infections/microbiology , beta-Lactam Resistance , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Community-Acquired Infections/drug therapy , Community-Acquired Infections/epidemiology , Community-Acquired Infections/urine , Drug Resistance, Multiple, Bacterial , Escherichia coli/drug effects , Escherichia coli/enzymology , Female , Humans , Klebsiella pneumoniae/drug effects , Klebsiella pneumoniae/enzymology , Male , Microbial Sensitivity Tests , Middle Aged , Prevalence , Retrospective Studies , Risk Factors , United Arab Emirates/epidemiology , Urinary Tract Infections/drug therapy , Urinary Tract Infections/epidemiology , Urinary Tract Infections/urineABSTRACT
Despite the availability of new diagnostic assays and broad-spectrum antifungal agents, invasive fungal infections remain a significant challenge to clinicians and are associated with marked morbidity and mortality. In addition, the number of etiologic agents of invasive mycoses has increased accompanied by an expansion in the immunocompromised patient populations, and the use of molecular tools for fungal identification and characterization has resulted in the discovery of several cryptic species. This article reviews various methods used to identify fungi and perform antifungal susceptibility testing in the clinical laboratory. Recent developments in antifungal resistance are also discussed.
Subject(s)
Drug Resistance, Fungal/physiology , Fungi/isolation & purification , Microbial Sensitivity Tests , Mycoses/drug therapy , Antifungal Agents/therapeutic use , Fungi/physiology , Humans , Laboratories , Mycoses/physiopathologyABSTRACT
Significant interlaboratory variability is observed in testing the caspofungin susceptibility of Candida species by both the CLSI and EUCAST broth microdilution methodologies. We evaluated the influence of treated versus untreated polystyrene microtiter trays on caspofungin MICs using 209 isolates of four Candida species, including 16 C. albicans and 11 C. glabrata isolates with defined FKS mutations. Caspofungin MICs were also determined using the commercially available YeastOne and Etest assays and 102 isolates. All C. glabrata isolates had caspofungin MICs of ≥0.5 µg/ml, the clinical breakpoint for caspofungin resistance in this species, measured using trays made of treated polystyrene, regardless of the FKS status. In contrast, susceptible isolates could readily be distinguished from resistant/non-wild-type isolates when caspofungin MICs were measured using untreated polystyrene trays and both the YeastOne and Etest assays. Similar results were also observed for C. krusei isolates, as all isolates had caspofungin MICs above the threshold for resistance measured using treated polystyrene trays. In contrast, C. albicans isolates could be correctly identified as susceptible or resistant when caspofungin MICs were measured with treated or untreated trays and with the YeastOne and Etest assays. MICs falsely elevated above the resistance breakpoint were also not observed for C. tropicalis isolates. These results demonstrated that the use of treated polystyrene may be one factor that leads to falsely elevated caspofungin in vitro susceptibility results and that this may also be a greater issue for some Candida species than for others.
Subject(s)
Antifungal Agents/pharmacology , Candida/drug effects , Echinocandins/pharmacology , Lipopeptides/pharmacology , Polystyrenes , Candida/isolation & purification , Caspofungin , Humans , Microbial Sensitivity Tests , Reproducibility of ResultsABSTRACT
Azole resistance in Aspergillus fumigatus is an increasing problem. The TR34 L98H and TR46 Y121F T289A mutations that can occur in patients without previous azole exposure have been reported in Europe, Asia, the Middle East, Africa, and Australia. Here, we report the detection of both the TR34 L98H and TR46 Y121F T289A mutations in confirmed A. fumigatus isolates collected in institutions in the United States. These mutations, other mutations known to cause azole resistance, and azole MICs are reported here.
Subject(s)
Antifungal Agents/pharmacology , Aspergillus fumigatus/enzymology , Aspergillus fumigatus/genetics , Azoles/pharmacology , Drug Resistance, Fungal , Mutation, Missense , Sterol 14-Demethylase/genetics , Aspergillosis/microbiology , Aspergillus fumigatus/drug effects , Aspergillus fumigatus/isolation & purification , Humans , Microbial Sensitivity Tests , United StatesABSTRACT
Over the past 20 years, considerable advances have been made toward our understanding of how post-translational modifications affect a wide variety of biological processes, including morphology and virulence, in medically important fungi. Phosphorylation stands out as a key molecular switch and regulatory modification that plays a critical role in controlling these processes. In this article, we first provide a comprehensive and up-to-date overview of the regulatory roles that both Ser/Thr and non-Ser/Thr kinases and phosphatases play in model and pathogenic fungi. Next, we discuss the impact of current global approaches that are being used to define the complete set of phosphorylation targets (phosphoproteome) in medically important fungi. Finally, we provide new insights and perspectives into the potential use of key regulatory kinases and phosphatases as targets for the development of novel and more effective antifungal strategies.
Subject(s)
Fungal Proteins , Fungi , Phosphorylation/physiology , Fungal Proteins/metabolism , Fungal Proteins/physiology , Fungi/enzymology , Fungi/metabolism , Fungi/pathogenicity , Fungi/physiology , Humans , Mycoses , Phosphoproteins , Phosphoric Monoester Hydrolases , Phosphotransferases , ProteomeABSTRACT
Candida albicans, a major human fungal pathogen, is the primary cause of invasive candidiasis in a wide array of immunocompromised patients. C. albicans virulence requires the ability to undergo a reversible morphological transition from yeast to filaments in response to a variety of host environmental cues. These cues are sensed by the pathogen and activate multiple signal transduction pathways to induce filamentation. Reversible phosphorylation events are critical for regulation of many of these pathways. While a variety of protein kinases are known to function as components of C. albicans filamentous growth signal transduction pathways, considerably little is known about the role of phosphatases. Here we demonstrate that PPG1, encoding a putative type 2A-related protein phosphatase, is important for C. albicans filament extension, invasion, and virulence in a mouse model of systemic candidiasis. PPG1 is also important for downregulation of NRG1, a key transcriptional repressor of C. albicans filamentous growth, and is shown to affect the expression of several filament-specific target genes. An epistasis analysis suggests that PPG1 controls C. albicans filamentation via the cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway. We demonstrate that Ppg1 possesses phosphatase activity and that a ppg1 catalytic mutant shows nearly equivalent filamentation, invasion, and virulence defects compared to those of a ppg1Δ/Δ strain. Overall, our results suggest that phosphatases, such as Ppg1, play critical roles in controlling and fine-tuning C. albicans filament extension and virulence as well as signal transduction pathways, transcriptional regulators, and target genes associated with these processes.