Recurrent Bacterial Infections Research Articles

Heterozygous Predicted Loss-of-function Variants of TRAF3 in Patients with Common Variable Immunodeficiency.

TRAF3, a versatile adaptor protein within the TRAF family, participates in various signaling pathways involving the tumor necrosis factor receptor, toll-like receptor, and retinoic acid-inducible gene I-like receptor families. In 2010, autosomal dominant TRAF3 deficiency was reported in a patient with herpes simplex virus-1 encephalitis, consistent with the role of TRAF3 in type I interferon production. Recently, a novel, completely different clinical phenotype was described in patients with TRAF3 haploinsufficiency (TRAF3Hl), characterized by recurrent bacterial infections, autoimmune features, systemic inflammation, and hypergammaglobulinemia. In this study, we conducted a TRAF3-targeted reanalysis of next-generation sequencing data from 800 patients with inborn errors of immunity. Through this reassessment and additional familial investigations, we identified three previously unidentified cases of TRAF3Hl within two different families. These individuals harbored stop-gain variants (p.Arg163* and p.Gln407*) and experienced recurrent bacterial infections with hypogammaglobulinemia. Previously, the patients had been diagnosed with common variable immunodeficiency (CVID) and were receiving immunoglobulin replacement therapy. In addition, a TRAF3 start-loss variant (c.3G > A) was identified in a fourth patient, but after familial and molecular studies, it was not considered disease-causing, excluding TRAF3Hl in this patient. This study illustrates the usefulness of targeted reanalysis of genes with reported novel phenotypes. We rescued three patients with TRAF3Hl, presenting similarities and differences with the previously reported patients. The most significant differences were hypogammaglobulinemia and a CVID-like presentation. These data expand the clinical phenotype of TRAF3Hl and pave the way for further investigation into loss-of-function variants in patients with CVID.

LTβR deficiency causes lymph node aplasia and impaired B cell differentiation.

Secondary lymphoid organs (SLOs) provide the confined microenvironment required for stromal cells to interact with immune cells to initiate adaptive immune responses resulting in B cell differentiation. Here, we studied three patients from two families with functional hyposplenism, absence of tonsils, and complete lymph node aplasia, leading to recurrent bacterial and viral infections. We identified biallelic loss-of-function mutations in LTBR, encoding the lymphotoxin beta receptor (LTβR), primarily expressed on stromal cells. Patients with LTβR deficiency had hypogammaglobulinemia, diminished memory B cells, regulatory and follicular T helper cells, and dysregulated expression of several tumor necrosis factor family members. B cell differentiation in an ex vivo coculture system was intact, implying that the observed B cell defects were not intrinsic in nature and instead resulted from LTβR-dependent stromal cell interaction signaling critical for SLO formation. Collectively, we define a human inborn error of immunity caused primarily by a stromal defect affecting the development and function of SLOs.

Intracellular ATP concentration is a key regulator of bacterial cell fate.

ATP, most widely known as the primary energy source for numerous cellular processes, also exhibits the characteristics of a biological hydrotrope. The viable but nonculturable (VBNC) and persister states are two prevalent dormant phenotypes employed by bacteria to survive challenging environments, both of which are associated with low metabolic activity. Here, we investigate the intracellular ATP concentration of individual VBNC and persister cells using a sensitive ATP biosensor QUEEN-7μ and reveal that both types of cells possess a lower intracellular ATP concentration than culturable and sensitive cells, although there is a certain overlap in the intracellular ATP concentrations between antibiotic-sensitive cells and persisters. Moreover, we successfully separated VBNC cells from culturable cells using fluorescence-activated cell sorting based on the intracellular ATP concentration threshold of 12.5 µM. Using an enriched VBNC cell population, we confirm that the precipitation of proteins involved in key biological processes promotes VBNC cell formation. Notably, using green light-illuminated proteorhodopsin (PR), we demonstrate that VBNC cells can be effectively resuscitated by elevating their intracellular ATP concentration. These findings highlight the crucial role of intracellular ATP concentration in the regulation of bacterial cell fate and provide new insights into the formation of VBNC and persister cells.IMPORTANCEThe viable but nonculturable (VBNC) and persister states are two dormant phenotypes employed by bacteria to counter stressful conditions and play a crucial role in chronic and recurrent bacterial infections. However, the lack of precise detection methods poses significant threats to public health. Our study reveals lower intracellular ATP concentrations in these states and establishes an ATP threshold for distinguishing VBNC from culturable cells. Remarkably, we revive VBNC cells by elevating their intracellular ATP levels. This echoes recent eukaryotic studies where modulating metabolism impacts outcomes like osteoarthritis treatment and lifespan extension in Caenorhabditis elegans. Our findings underscore the crucial role of intracellular ATP levels in governing bacterial fate, emphasizing ATP manipulation as a potential strategy to steer bacterial behavior.

Structural determinants of protein kinase A essential for CFTR channel activation

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the anion channel mutated in cystic fibrosis (CF) patients, is activated by the catalytic subunit of protein kinase A (PKA-C). PKA-C activates CFTR both noncatalytically, through binding, and catalytically, through phosphorylation of multiple serines in CFTR's regulatory (R) domain. Here, we identify key molecular determinants of the CFTR/PKA-C interaction essential for these processes. By comparing CFTR current activation in the presence of ATP or an ATP analog unsuitable for phosphotransfer, as well as pseudosubstrate peptides of various lengths, we identify two distinct specific regions of the PKA-C surface which interact with CFTR to cause noncatalytic and catalytic CFTR stimulation, respectively. Whereas the "substrate site" mediates CFTR phosphorylation, a distinct hydrophobic patch (the "docking site") is responsible for noncatalytic CFTR activation, achieved by stabilizing the R domain in a "released" conformation permissive to channel gating. Furthermore, by comparing PKA-C variants with different posttranslational modification patterns, we find that direct membrane tethering of the kinase through its N-terminal myristoyl group is an unappreciated fundamental requirement for CFTR activation: PKA-C demyristoylation abolishes noncatalytic, and profoundly slows catalytic, CFTR stimulation. For the F508del CFTR mutant, present in ~90% of CF patients, maximal activation by demyristoylated PKA-C is reduced by ~10-fold compared to that by myristoylated PKA-C. Finally, in bacterial genera that contain common CF pathogens, we identify virulence factors that demyristoylate PKA-C in vitro, raising the possibility that during recurrent bacterial infections in CF patients, PKA-C demyristoylation may contribute to the exacerbation of lung disease.

Biomimetic Nanozyme-Decorated Smart Hydrogel for Promoting Chronic Refractory Wound Healing.

Chronic refractory wounds have become a serious threat to human health and are characterized by prolonged inflammation, recurrent bacterial infections, and elevated ROS levels. However, current therapeutic strategies usually target a unilateral healing function and are unable to tackle the complexity and sensitivity of chronic refractory wound healing. This study fabricated a biomimetic nanozyme based on rhein (Cu-rhein NSs), which effectively mimics the activity of superoxide dismutase (SOD) for scavenging various free radicals. Additionally, zinc oxide microspheres (ZnO MSs) were prepared to enhance the antibacterial activity and mechanical properties of the modified hydrogel. Cu-rhein NSs and ZnO MSs were comodified onto an extracellular matrix-mimetic dual-network smart hydrogel constructed from oxidized sodium alginate, gelatin, and borax via dynamic borate and Schiff base bonds. The smart hydrogel presented the good biocompatibility and targeted the unique acidic microenvironment with high oxidative stress of chronic refractory wounds, intelligently releasing bionic nanozymes to effectively eliminate bacteria, reduce inflammatory responses, and scavenge multiple free radicals for reducing ROS. In vivo experiments on the rat model based on diabetic infection showed that the smart hydrogel could effectively eliminate bacteria, promote vascular regeneration and collagen deposition, reduce inflammatory response, and accelerate the healing of diabetic-infected wounds (almost complete healing within 14 days). The advantages of an intelligent, biomimetic tissue regeneration cascade management strategy against diabetic infected wound healing are highlighted.

Glucose-activated self-cascade antibacterial and pro-angiogenesis nanozyme-functionalized chitosan-arginine thermosensitive hydrogel for chronic diabetic wounds healing

Affected by persistent hyperglycemia, diabetic neuropathy, and vasculopathy hinder the progression of wound healing by exacerbating susceptibility to recurrent bacterial infection and impairing vascularization. In order to cater to the requirements of diabetic chronic wound healing at various stages, we designed an antibacterial and pro-angiogenic wound dressing with localized glucose-lowering capacity. In this study, we constructed a copper-based metal-organic framework (MOF) nanozyme and loaded with glucose oxidase (GOX) to prepare Cu-MOF/GOX, which was subsequently integrated with CS-Arg (chitosan modified by L-Arginine) and Pluronic (F127) to fabricate multifunctional Cu-MOF/GOX-Gel thermosensitive hydrogel. The GOX generated H2O2 (hydrogen peroxide) and gluconic acid by consuming high blood glucose at the wound site, thus initiating an efficient antibacterial self-cascade catalytic in the initial stages of wound healing. With the further catalysis of in situ generated H2O2, NO (nitric oxide) was gradually released from the hydrogel, facilitating angiogenesis and accumulation of collagen, thereby expediting subsequent phases of wound healing. Overall, the Cu-MOF/GOX-Gel exhibits a comprehensive ability to locally regulate blood glucose levels, while also synergistically promoting antibacterial activity and angiogenesis, that effectively chronic diabetic wounds healing.

PH‐sensitive size/surface charge‐adaptive quaternary ammonium salt copolymer micelles for antibiofilm activity against Staphylococcus aureus

AbstractThe low penetration of antibacterial materials within biofilms results in a 1000‐fold decrease in bactericidal efficiency, complicating the complete removal of biofilms and potentially leading to persistent and recurrent bacterial infections that significantly impact human health. In this study, we present a multifunctional pH‐responsive antibacterial material based on random copolymers poly(dimethylaminoethyl methacrylate decyl ammonium bromide‐co‐polyethylene glycol methacrylate) copolymer (PQACs10‐co‐PEGMA10). The PQACs10‐co‐PEGMA10 copolymers could self‐assemble into micelles in selective solvent water. With the stealth function of polyethylene glycol (PEG), the PQACs10‐co‐PEGMA10 micelles can rapidly penetrate biofilms in a physiological environment and exhibit excellent antibacterial activity by exposing the quaternary ammonium salt (QACs) in an acidic microenvironment to eliminate biofilm. Furthermore, PQACs10‐co‐PEGMA10 micelles were applied as coatings using a dropwise method. The PEG chain formed hydration layer and the QACs chain for sterilization can hinders bacterial adhesion and proliferation, thereby preventing biofilm formation. The results show that the minimal inhibit concentration values and minimum biofilm eradication concentrations of the PQACs10‐co‐PEGMA10 micelles against Gram‐positive Staphylococcus aureus were 64 and 128 μg/mL, respectively. The antifouling and antibacterial rates of micelle coating against S. aureus were more than 99.99%. Taken together, the pH‐responsive PQACs10‐co‐PEGMA10 micelles demonstrate a good ability to clear and prevent biofilms, holding promise for complete biofilm removal and a reduction in biofilm‐related infections.

Antimicrobial and antibiofilm effect of promethazine on bacterial isolates from canine otitis externa: an in vitro study

Otitis externa is an inflammatory disease of the external ear canal of complex and multifactorial etiology associated with recurrent bacterial infection. This study aimed to assess the antimicrobial and antibiofilm activity of promethazine against bacterial isolates from dogs with otitis externa, as well as the effect of this compound on the dynamics of biofilm formation over 120 h. Planktonic bacterial susceptibility to promethazine was evaluated to determine the minimum inhibitory concentrations (MIC). The minimum biofilm eradication concentration (MBEC) was also determined by broth microdilution. To evaluate the effect on biofilm growth, promethazine was tested at three concentrations MIC, MIC/2 and MIC/8, with daily readings at 48, 72, 96 and 120 h. The MICs of promethazine ranged from 48.83 to 781.25 μg mL−1. Promethazine significantly (P < 0.05) reduced mature biofilm biomass, with MBECs ranging from 48.8 to 6250 μg mL−1 and reduced (P < 0.01) biofilm formation for up to the 120-h, at concentrations corresponding to the MIC obtained against each isolate. Promethazine was effective against microorganisms associated with canine otitis externa. The data suggest that promethazine presents antimicrobial and antibiofilm activity and is a potential alternative to treat and prevent recurrent bacterial otitis in dogs. These results emphasize the importance of drug repurposing in veterinary otology as an alternative to reduce antimicrobial resistance.

Macrophages and the microbiome in chronic obstructive pulmonary disease.

COPD is a heterogeneous disease of the lungs characterised by restricted airflow. Chronic inflammation and recurrent bacterial infections are known to be important driving factors in exacerbations of this disease. Despite a marked increase in the number of alveolar macrophages present in the lungs of COPD patients, there is evidence of reduced clearance of pathogenic bacteria, leading to recurrent infection, exacerbation and subsequent lung function decline. This is thought to be attributed to a defect in the phagocytic capability of both alveolar and monocyte-derived macrophages in COPD. In addition to this defect, there is apparent selectivity in bacterial uptake by COPD macrophages because certain pathogenic genera, such as Haemophilus, Moraxella and Streptococcus, are taken up more readily than others. The respiratory microbiome plays a key role in regulating the host immune response both in health and during chronic inflammation. In patients with COPD, there are distinct changes in the composition of the respiratory microbiome, particularly the lower respiratory tract, where dominance of clinically relevant pathogenic species is commonly observed. Whether there are links between these changes in the microbiome and dysfunctional macrophage phagocytosis has not yet been widely studied. This review aims to discuss what is currently known about these phenomena and to explore interactions between macrophages and the respiratory microbiome.

Evaluating the Efficacy of Actinidia deliciosa (Kiwi Fruit) Extract in Inhibiting Pseudomonas aeruginosa Biofilm Formation: An In Vitro Study With Therapeutic Implications.

Background Gram-negative Pseudomonas aeruginosa is a common bacteria that is well-known for its capacity to build biofilms, which are organized cell communities encased in a self-produced polymeric matrix. Treating infections becomes more challenging due to biofilms' capacity to provide immunity and resistance to antibiotics. The search for novel anti-biofilm agents has gained significant momentum, and the diverse range of bioactive compounds found in natural products offers a promising avenue. Rich in vitamins, antioxidants, and various phytochemicals, Actinidia deliciosa (kiwi fruit) has demonstrated potential as an antibacterial agent. Aim of the study This study aims to assess the efficacy of A. deliciosa extract in inhibiting biofilm formation by P. aeruginosa in vitro, providing valuable insights into its potential as a natural therapeutic agent for preventing recurrent bacterial infections. Materials and methodology The antibacterial and antibiofilm properties of A. deliciosa (kiwi fruit) methanolic extract were assessed in this study against P. aeruginosa (PAO1). The fruit was gathered, examined by a botanist for authenticity, and then cold macerated in methanol to create an extract. A two-fold broth dilution procedure was used to calculate the minimum inhibitory concentration (MIC), and agar well-diffusion was used to evaluate the antimicrobial activity. Pyocyanin pigment quantification was carried out after the extract was applied, and the antibiofilm impact was evaluated using a crystal violet assay. GraphPad Prism (GraphPad Software, San Diego, CA) was used for statistical analysis. Results Based on our findings, A. deliciosa was shown to have significant antibacterial and antibiofilm properties against P. aeruginosa (PAO1). At 5 mg/mL, the methanolic extract of A. deliciosa exhibited antibacterial activity with an 8 mm zone of inhibition and suppressed PAO1 growth. At 2.5 mg/mL and 1.25 mg/mL doses, PAO1 significantly decreased the production of biofilms by 60% and 29%, respectively. In addition, pyocyanin pigment synthesis was decreased by 30% and 9.25%, respectively, at sub-MIC doses of 2.5 mg/mL and 1.25 mg/mL. When evaluated at 2.5 mg/mL, the extract did not, however, appreciably affect bacterial growth. Conclusion This study enhances the understanding of antibiotic resistance, alternative treatments, and pathogenic microbes. The in vitro findings suggest that A. deliciosa fruit extract may inhibit pyocyanin production in PAO1. Further research with different formulations is recommended to explore its anti-biofilm properties and potential pharmacological applications.

Sequence variants underlying severe combined immunodeficiency and leukocyte adhesion deficiency type 1 in six consanguineous families.

Inborn errors of immunity (IEI) are defined as genetic disorders affecting the immune system and resulting in diverse clinical signs and symptoms. Despite the lack of diagnosis and unavailability of IEI estimation in the Pakistani population, consanguinity is exacerbating its prevalence. The current study focuses on severe combined immunodeficiency (SCID) and leukocyte adhesion deficiency type 1 (LAD1). SCID is associated with the life-threatening symptoms developing at post-birth. LAD1 is clinically characterized by recurrent bacterial infections related to the skin, mouth, and respiratory tract owing to impaired leukocytes. Herein, in six consanguineous families, flow cytometry was used to evaluate the patient's immune status. Whole-exome sequencing (WES) was then conducted to search for the causative variations in immunodeficiency genes. Sanger sequencing was used to assess the segregation of the variants with the disorder within the families. Sequence analysis revealed five homozygous variants in four different causative genes. This included four novel nonsense variants in CD70 p.(Thr126Profs*33), CD3e p.(Trp151*), IL7R p.(Val138Ilefs*10), and ITGB2 p.(Ser627Valfs*61), and one previously reported in ITGB2 p.(Cys62*). In one of the families, two variants in two different genes, including DNAH6 p.(Tyr2653His) and NIPAL4 p.(Gly121Ser), were detected in an unclassified patient. All the identified variants were found in a homozygous state in the patient but in a heterozygous state in the available parents. The study will facilitate the diagnosis and management of IEI patients.

Battery-Free and Multifunctional Microfluidic Janus Wound Dressing with Biofluid Management, Multi-Indicator Monitoring, and Antibacterial Properties.

The sophisticated environment of chronic wounds, characterized by prolonged exudation and recurrent bacterial infections, poses significant challenges to wound recovery. Recent advancements in multifunctional wound dressings fall short of providing comprehensive, accurate, and comfortable treatment. To address these issues, a battery-free and multifunctional microfluidic Janus wound dressing (MM-JWD) capable of three functions, including exudate management, antibacterial properties, and multiple indications of wound infection detection, has been developed. During the treatment, the fully soft microfluidic Janus membrane not only demonstrated stable unidirectional fluid transport capabilities under various skin deformations for a longer period but also provided antibacterial effects through surface treatment with chitosan quaternary ammonium salts and poly(vinyl alcohol). Furthermore, integrating multiple colorimetric sensors within the Janus membrane's microchannels and a dual-layer structure enabled simultaneous monitoring of the wound's pH, uric acid, and temperature. The monitoring was facilitated by smartphone recognition of color changes in the sensors. In vivo and in vitro tests confirmed the exudate management, antibacterial, and sensing capabilities of the MM-JWD, proving its efficacy in monitoring and promoting the healing of wounds. Overall, this study provides a valuable method for the design of multifunctional wound dressings for chronic wound care.

Novel variant in IGHM gene in a patient with agammaglobulinemia: A case report of a preschool child presenting with recurrent pneumonia

Introduction: Agammaglobulinemia is a primary immunodeficiency characterized by absent B cells and originates from X-linked or autosomal mutations affecting B cell maturation. While the most common agammaglobulinemia is X-linked, one well-documented site of autosomal recessive agammaglobulinemia is within the immunoglobulin μ heavy chain protein, encoded by the IGHM gene. Such variants frequently result in clinical presentations of recurrent bacterial infections early in life. Aim: To describe a case of a five-year-old female with agammaglobulinemia resulting from a novel homozygous IGHM variant, presenting with pneumonia complicated by empyema and H. influenzae bacteremia. Methods: Case data was compiled retrospectively from the patient’s medical chart, including relevant laboratory testing for immunoglobulins, quantitative B cell subsets, and genetic testing using a primary immunodeficiency panel. Results: The proband is a 5-year-old female with a history of recurrent pneumonia, presenting with H. influenzae bacteremia in the context of pneumonia complicated by an empyema. Investigations revealed low immunoglobulin levels, absent vaccine responses, and undetectable B cells on flow cytometry. Genetic testing revealed a novel homozygous variant in the IGHM gene: c.775T&gt;C, p.Trp259Arg. Conclusion: Autosomal recessive agammaglobulinemia is a rare but severe, treatable disorder of the immune system which typically presents in early childhood. Hypomorphic mutations, while less commonly reported in the literature, are an important consideration in atypical presentations of primary immunodeficiencies, such as in the case presented. Statement of Novelty: Herein, we report a case of agammaglobulinemia presenting with a novel homozygous variant in the IGHM gene leading to later onset agammaglobulinemia in a 5-year-old female.

Determinants of active trachoma among rural children aged 1–9 years old in Aw-Bare Wereda, Somali Region of Ethiopia: a cross-sectional study

IntroductionChronic and highly contagious, trachoma is a condition characterized by recurrent bacterial infection with ocular strains of Mycoplasma trachoma. It spreads through fingers, flies, and fomites, especially in situations where there is overcrowding. If untreated, the illness may result in blindness. Trachoma is an ancient disease and has previously been a significant public health problem in many areas of the world, including parts of Europe and North America. There are at least 400 million cases of active trachoma in the world, 8 million of which have resulted in blindness. Trachoma is a serious public health issue that is very common in Ethiopia. Therefore, the objective of this study is to identify the determinants of active trachoma among rural children aged 1–9 years old in Aw-bare woreda, Somali region of Ethiopia.MethodA cross-sectional community-based study involving children aged 1–9 who lived in six selected rural kebeles in the Awbare woreda Somali region and carried out using an ordinal logistic regression model. The study comprised 377 children in total. Our sample youngsters were chosen through a two-stage cluster sampling procedure. Then also chose our sample kebeles by simple random sampling. The main environmental, personal, and demographic factors that influenced the outcomes of active trachoma status were modeled using partial proportional odds modeling and descriptive statistics.ResultThe study showed that the prevalence of active trachoma was found to be 47.7%. The covariate secondary level of education of mother OR = 1.357; 95% CI (1.051, 1.75), P-value = 0.0192, Inside house cooking place of children family OR = 0.789:95% CI (0.687, 0.927), P-value = 0.0031, children stay at home OR = 2.203:95%CI (1.526, 3.473), P-value = 0.0057,rich income family OR = 1.335:95%CI(1.166,1.528),P-value = 0.0001,Amount of water fetched per day OR = 2.129,95%CI(1.780,2.547),P-Vaue = 0.0001 were significant effect on active trachoma. PPOM represents the best fit as it has the smallest AIC and BIC. It is also more parsimonious.ConclusionThe mother’s educational level, the location where the children spent the majority of their time indoors cooking, the fly density during the interview, the family’s income, the child’s age in years, the distance to the water source, the quantity of water fetched daily, and the number of people sharing a room have all been found to be significant predictors of the child’s active trachoma status. Thus, increasing maternal education, access to clean water, and socioeconomic position are all crucial measures in preventing trachoma. Preventing trachoma also involves reducing the number of kids in a room and enhancing activities linked to personal cleanliness, such as giving kids a thorough facial wash to remove debris and discharge from their eyes.

A novel MALT1 variant in an Egyptian patient presenting with exfoliative dermatitis: a case-based review.

Inborn errors of the CARD11-BCL10-MALT1 (CBM) signalosome have recently been shown to underlie severe combined immunodeficiency (SCID) and combined immunodeficiency (CID) with variable immunological and clinical phenotypes, and patients usually present with recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. In the present study, we describe the clinical and immunological characteristics of an Egyptian patient with a mutation in the MALT1 gene. The patient suffered from an itchy exfoliative skin rash and eczematous lesions over his face and flexural surface of the limbs. He also had dental enamel erosion, repeated attacks of diarrhea, and pneumonia. He had elevated serum IgE and normal B- and T-lymphocyte subset counts, but there was an arrest in the B-cell maturation. DOCK8 expression on the lymphocytes by flow cytometry was normal. Next-generation sequencing revealed a novel homozygous variant in the MALT1 gene (c.762dup in exon 5 of 17; p.Ile255TyrfsTer10); this variant is likely pathogenic, thus supporting the genetic diagnosis of immunodeficiency-12 (IMD12). Although the presence of eczema, recurrent sinopulmonary, and staphylococcal infections are suggestive of DOCK8 deficiency, they are also a finding in CARD11 and MALT1 deficiency. Thus, whenever DOCK 8 has been excluded, the molecular diagnosis is mandatory as this could lead to discovering more patients hence better understanding and reporting of the phenotype and natural history of the disease especially since there are very few documented cases. Early diagnosis will also enable the proper patient management by hematopoietic stem cell transplantation (HSCT) prior to the establishment of infections and pulmonary damage leading to a better outcome.

Pseudomonas aeruginosa Bacteriophages and Their Clinical Applications.

Antimicrobial resistance poses a serious risk to contemporary healthcare since it reduces the number of bacterial illnesses that may be treated with antibiotics, particularly for patients with long-term conditions like cystic fibrosis (CF). People with a genetic predisposition to CF often have recurrent bacterial infections in their lungs due to a buildup of sticky mucus, necessitating long-term antibiotic treatment. Pseudomonas aeruginosa infections are a major cause of CF lung illness, and P. aeruginosa airway isolates are frequently resistant to many antibiotics. Bacteriophages (also known as phages), viruses that infect bacteria, are a viable substitute for antimicrobials to treat P. aeruginosa infections in individuals with CF. Here, we reviewed the utilization of P. aeruginosa bacteriophages both in vivo and in vitro, as well as in the treatment of illnesses and diseases, and the outcomes of the latter.

Genotype-phenotype correlations in chronic granulomatous disease: insights from a large national cohort

AbstractNeutrophils are the first line of defense against invading pathogens. Neutrophils execute and modulate immune responses by generating reactive oxygen species (ROS). Chronic granulomatous disease (CGD) is a primary immune deficiency disorder of phagocytes, caused by inherited mutations in the genes of the nicotinamide adenine dinucleotide phosphate reduced oxidase enzyme. These mutations lead to failure of ROS generation followed by recurrent bacterial and fungal infections, frequently associated with hyperinflammatory manifestations. We report a multicenter cumulative experience in diagnosing and treating patients with CGD. From 1986 to 2021, 2918 patients experiencing frequent infections were referred for neutrophil evaluation. Among them, 110 patients were diagnosed with CGD: 56 of Jewish ancestry, 48 of Arabic ancestry, and 6 of non-Jewish/non-Arabic ancestry. As opposed to other Western countries, the autosomal recessive (AR) CGD subtypes were predominant in Israel (71/110 patients). Thirty-nine patients had X-linked CGD, in most patients associated with severe infections (clinical severity score ≥3) and poor outcomes, presenting at a significantly earlier age than AR-CGD subtypes. The full spectrum of infections and hyperinflammatory manifestations is described. Six patients had hypomorphic mutations with significantly milder phenotype, clinical severity score ≤2, and better outcomes. Hematopoietic stem cell transplantation was implemented in 39 of 110 patients (35.5%). Successful engraftment was achieved in 92%, with 82% long-term survival and 71% full clinical recovery. CGD is a complex disorder requiring a multiprofessional team. Early identification of the genetic mutation is essential for prompt diagnosis, suitable management, and prevention.

Ta4C3 Nanosheets as a Novel Therapeutic Platform for Photothermal-Driven ROS Scavenging and Immune Activation against Antibiotic-Resistant Infections in Diabetic Wounds.

The accumulation of excessive reactive oxygen species (ROS) and recurrent infections with drug-resistant bacteria pose significant challenges in diabetic wound infections, often leading to impediments in wound healing. Addressing this, there is a critical demand for novel strategies dedicated to treating and preventing diabetic wounds infected with drug-resistant bacteria. Herein, 2D tantalum carbide nanosheets (Ta4C3 NSs) have been synthesized through an efficient and straightforward approach, leading to the development of a new, effective nanoplatform endowed with notable photothermal properties, biosafety, and diverse ROS scavenging capabilities, alongside immunogenic attributes for diabetic wound treatment and prevention of recurrent drug-resistant bacterial infections. The Ta4C3 NSs exhibit remarkable photothermal performance, effectively eliminating methicillin-resistant Staphylococcus aureus (MRSA) and excessive ROS, thus promoting diabetic wound healing. Furthermore, Ta4C3 NSs enhance dendritic cell activation, further triggering T helper 1 (TH1)/TH2 immune responses, leading to pathogen-specific immune memory against recurrent MRSA infections. This nanoplatform, with its significant photothermal and immunomodulatory effects, holds vast potential in the treatment and prevention of drug-resistant bacterial infections in diabetic wounds.

Biochemical assessment in a cohort of pediatric patients with cystic fibrosis.

Cystic fibrosis (CF) is a recessive inherited disorder caused by genetic mutations in the CF transmembrane conductance regulator (CFTR) gene. It is a multisystem condition that primarily induces abnormal mucus accumulation in the respiratory system and obstructs the intrapancreatic common bile duct, causing a reduction in the delivery of digestive enzymes to the small intestine. Thus, patients with CF are characterized by maldigestion, malabsorption, and recurrent airway bacterial infections. Clinical monitoring of the health status of patients with CF is mandatory for increasing the patients' lifespan. To assess the feasibility of monitoring life quality (LQ) in pediatric patients with cystic fibrosis (CF) and to explore the relationship between biochemical parameters and clinical symptoms, our study analyzed inflammatory responses related to CF, medication, and pulmonary bacterial infections in 52 patients diagnosed with CF. Blood, hypo-pharyngeal exudate, and fecal samples were analyzed using clinical biochemistry, hematology, and microbiology techniques at the Alessandrescu-Rusescu National Institute for Mother and Child Health central laboratory in Bucharest, Romania. All the participants adhered to their prescribed outpatient CF regimens and appeared clinically stable. The overall clinical status of patients with CF was observed and compared with that of a healthy control group, which consisted of individuals similar in number and age. The screened patients with CF presented an impaired lipid status and chronic infections with various bacteria, iron, and vitamin (A, D, and E) deficiencies. Our findings provide insights into the pathophysiological mechanisms of CF and suggest that tailored monitoring and personalized therapeutic strategies could improve patient management.

Rational design of Bacteria-Targeted and Photo-Responsive MOF gel with antibacterial and anti-inflammatory function for infected wound healing

Damaged skin is prone to recurrent bacterial infections, which hinder proper wound healing and exacerbate inflammation. Urgent attention is required to devise versatile dressings possessing antibacterial and anti-inflammatory attributes to facilitate wound recovery. In this study, we engineered a photo-responsive metal–organic frameworks (MOFs) gel, targeting bacteria, and endowed it with antibacterial and anti-inflammatory effects to address infected wound healing. On the one hand, the anionic MOF was choose to support cationic natural drug Berberine (BBR) to achieve slow release of anti-inflammatory drugs. On the other hand, the incorporation of Ag nanoparticles onto MOFs not only facilitates the generation of reactive oxygen species (ROS) via photocatalysis under visible light but also furnishes sites for boric acid group attachment to target bacteria and expedites ROS transfer. The resultant MOFs@Ag-B@BBR exhibited potent photodynamic antibacterial activity against Staphylococcus aureus and MRSA at a low concentration of 37.5 µg mL−1, surpassing the efficacy of most reported MOFs-based nano-antimicrobials. Upon application of the MOFs@Ag-B@BBR composite hydrogel to infected wounds, the released BBR, in conjunction with photodynamic antibacterial action, significantly mitigated inflammatory responses and fostered wound healing. This study provides a widely applicable approach for rational design of MOFs materials with enhance antibacterial and anti-inflammatory functions.