Chronic Bacterial Infection Research Articles

Risk Factors of Smoldering Multiple Myeloma: Results from the Screened Istopmm Study

Introduction Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM) that carries a higher risk of progression to MM than monoclonal gammopathy of undetermined significance (MGUS). This study aimed to identify potential risk factors of SMM by analyzing the association of baseline characteristics, body mass index, smoking, alcohol consumption, prior diagnoses of autoimmune diseases and prior chronic infections and SMM in the screened Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study cohort. Methods The iStopMM study is a screening study for MM precursors where 75,422 individuals over 40 years old in Iceland were screened with serum protein electrophoresis (SPEP) and free light chain (FLC) analysis. Those with a positive screening result were randomized to one of the three study arms, with clinical evaluation at the study center, including bone marrow sampling, performed in two of them. MGUS was defined by the presence of a serum M-protein concentration less than 30 g/L and less than 10% clonal plasma cells in the bone marrow, and SMM was defined as 10-60% bone marrow plasma cells and/or M-protein concentration over 30 g/L, both in the absence of MM defining events. IgM MGUS was excluded in this analysis. Height and weight were measured at the first visit to the study center, alcohol and smoking habits were evaluated with questionnaires. Information on previous diagnoses (ICD codes) was obtained from central health registries with almost 100% completeness. Logistic regression models were used to calculate odds ratio (OR) with 95% confidence interval (CI) to compare risk factors in SMM vs. MGUS and SMM vs. controls. All analyses were adjusted for age and sex. Results At the first study center evaluation, 210 individuals were diagnosed with SMM and 1,456 with MGUS. Data from 70,627 controls with negative SPEP and normal FLC analysis were included. Individuals with SMM were older and more frequently male than controls, however there was no statistically significant difference between the sex and age distribution of individuals with SMM and MGUS (Figure). Immunoparesis (OR 3.98; 95% CI: 2.74-5.76), abnormal FLC ratio (OR 3.61; 95% CI: 2.59-5.02), IgA isotype (OR 2.64; 95% CI: 1.83-3.83) and increasing M-protein levels (OR per g/L 1.33; 95% CI: 1.27-1.39) were all associated with increased odds of SMM compared to MGUS. BMI measured at the first study visit was not significantly different between individuals with MGUS and SMM (overweight vs. normal weight OR 1.08; 95% CI: 0.74-1.56). Neither current or previous smoking nor alcohol consumption more than once per week (vs. less) was associated with increased risk of SMM compared to MGUS (OR 0.88; 95% CI: 0.60-1.31, and OR 0.97; 95% CI: 0.62-1.53, respectively) or controls (OR 0.92; 95% CI: 0.64-1.33, and OR 0.85; 95% CI: 0.57-1.27, respectively). Prior diagnosis of autoimmune disease was not associated with SMM as compared to MGUS (OR 1.19; 95% CI: 0.81-1.74) or controls (OR 1.21; 95% CI: 0.85-1.73). A previous diagnosis of a chronic infection was not statistically significantly associated with increased risk of being diagnosed with SMM as compared to MGUS (OR 1.53; 95% CI: 1.00-2.34) but an association was seen when compared to controls (OR 1.54; 95% CI: 1.05-2.28). In individuals with SMM, the most common chronic infections were varicella zoster virus and herpes simplex virus, no diagnoses of hepatitis virus or chronic bacterial infections were observed. Conclusion In this large population-based screening study we did not find an association of smoking, alcohol consumption, BMI, or a prior diagnosis of autoimmune disease and SMM compared to MGUS. We found an association between a previous diagnosis of a chronic infection and SMM which could be explained by reverse causality, i.e., that SMM leads to immune impairment which increases the risk of viral infections. We found no significant age or sex difference between individuals with MGUS and SMM, but results from blood tests, including immunoparesis, abnormal FLC ratio, IgA-isotype, and higher levels of M-protein were all associated with SMM compared to MGUS. Our results indicate that neither lifestyle factors nor chronic inflammatory conditions increase the risk of SMM, and that the differences between individuals with MGUS and SMM can be detected in blood assessments associated with the plasma cell clone, but not in demographic or behavior related factors.

Synergistic Antimicrobial Effects of Ibuprofen Combined with Standard-of-Care Antibiotics against Cystic Fibrosis Pathogens.

Cystic fibrosis (CF) is a common life-shortening genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Lungs of CF patients are often colonized or infected with microorganisms requiring frequent courses of antibiotics. Antibiotic-resistant bacterial infections have been a growing concern in CF patients. Chronic bacterial infections and concomitant airway inflammation damage the lungs, ultimately leading to respiratory failure. Several clinical trials have demonstrated that high-dose ibuprofen reduces the rate of pulmonary function decline in CF patients. This beneficial effect has been attributed to the anti-inflammatory properties of ibuprofen. Previously, we have confirmed that high-dose ibuprofen demonstrates antimicrobial activity against P. aeruginosa both in vitro and in vivo. However, no study has examined the antimicrobial effect of combining ibuprofen with standard-of-care antimicrobials. Here, we evaluated the possible synergistic activity of combinations of common nonsteroidal anti-inflammatory drugs (NSAIDs), namely, ibuprofen, naproxen, and aspirin, with commonly used antibiotics for CF patients. The drug combinations were screened against different CF clinical isolates. Antibiotics that demonstrated increased efficacy in the presence of ibuprofen were further tested for potential synergistic effects between these NSAIDS and antimicrobials. Finally, a survival analysis of a P. aeruginosa murine infection model was used to demonstrate the efficacy of the most potent combination identified in in vitro screening. Our results suggest that combinations of ibuprofen with commonly used antibiotics demonstrate synergistic antimicrobial activity against drug-resistant, clinical bacterial strains in vitro. The efficacy of the combination of ceftazidime and ibuprofen against resistant P. aeruginosa was demonstrated in an in vivo pneumonia model.

Anti-inflammatory effects of cold atmospheric plasma irradiation on the THP-1 human acute monocytic leukemia cell line.

Cold atmospheric plasma (CAP) has been studied and clinically applied to treat chronic wounds, cancer, periodontitis, and other diseases. CAP exerts cytotoxic, bactericidal, cell-proliferative, and anti-inflammatory effects on living tissues by generating reactive species. Therefore, CAP holds promise as a treatment for diseases involving chronic inflammation and bacterial infections. However, the cellular mechanisms underlying these anti-inflammatory effects of CAP are still unclear. Thus, this study aimed to elucidate the anti-inflammatory mechanisms of CAP in vitro. The human acute monocytic leukemia cell line, THP-1, was stimulated with lipopolysaccharide and irradiated with CAP, and the cytotoxic effects of CAP were evaluated. Time-course differentiation of gene expression was analyzed, and key transcription factors were identified via transcriptome analysis. Additionally, the nuclear localization of the CAP-induced transcription factor was examined using western blotting. The results indicated that CAP showed no cytotoxic effects after less than 70 s of irradiation and significantly inhibited interleukin 6 (IL6) expression after more than 40 s of irradiation. Transcriptome analysis revealed many differentially expressed genes (DEGs) following CAP irradiation at all time points. Cluster analysis classified the DEGs into four distinct groups, each with time-dependent characteristics. Gene ontology and gene set enrichment analyses revealed CAP-induced suppression of IL6 production, other inflammatory responses, and the expression of genes related to major histocompatibility complex (MHC) class II. Transcription factor analysis suggested that nuclear factor erythroid 2-related factor 2 (NRF2), which suppresses intracellular oxidative stress, is the most activated transcription factor. Contrarily, regulatory factor X5, which regulates MHC class II expression, is the most suppressed transcription factor. Western blotting revealed the nuclear localization of NRF2 following CAP irradiation. These data suggest that CAP suppresses the inflammatory response, possibly by promoting NRF2 nuclear translocation.

Disruption ofBiofilm by Bacteriophages inClinically Relevant Settings.

Antibiotic-resistant bacteria are a growing threat to civilian and military health today. Although infections were once easily treatable by antibiotics and wound cleaning, the frequent mutation of bacteria has created strains impermeable to antibiotics and physical attack. Bacteria further their pathogenicity because of their ability to form biofilms on wounds, medical devices, and implant surfaces. Methods for treating biofilms in clinical settings are limited, and when formed by antibiotic-resistant bacteria, can generate chronic infections that are recalcitrant to available therapies. Bacteriophages are natural viral predators of bacteria, and their ability to rapidly destroy their host has led to increased attention in potential phage therapy applications. The present article sought to address a knowledge gap in the available literature pertaining to the usage of bacteriophage in clinically relevant settings and the resolution of infections particular to military concerns. PRISMA guidelines were followed for a systematic review of available literature that met the criteria for analysis and inclusion. The research completed for this review article originated from the U.S. Military Academy's library "Scout" search engine, which complies results from 254 available databases (including PubMed, Google Scholar, and SciFinder). The search criteria included original studies that employed bacteriophage use against biofilms, as well as successful phage therapy strategies for combating chronic bacterial infections. We specifically explored the use of bacteriophage against antibiotic- and treatment-resistant bacteria. A total of 80 studies were identified that met the inclusion criteria following PRISMA guidelines. The application of bacteriophage has been demonstrated to robustly disrupt biofilm growth in wounds and on implant surfaces. When traditional therapies have failed to disrupt biofilms and chronic infections, a combination of these treatments with phage has proven to be effective, often leading to complete wound healing without reinfection. This review article examines the available literature where bacteriophages have been utilized to treat biofilms in clinically relevant settings. Specific attention is paid to biofilms on implant medical devices, biofilms formed on wounds, and clinical outcomes, where phage treatment has been efficacious. In addition to the clinical benefit of phage therapies, the military relevance and treatment of combat-related infections is also examined. Phages offer the ability to expand available treatment options in austere environments with relatively low cost and effort, allowing the impacted warfighter to return to duty quicker and healthier.

A rare case of actinomycosis in routine fnac of the face in a tertiary care center in Central India

Actinomycosis is a chronic suppurative bacterial infection. It is caused by gram-positive, non-acid fast, filamentous, anaerobic to microaerophilic bacilli. Actinomycosis on the root of the nose is a rare entity. We report a case of 38 years old male who presented with swelling over the root of the nose since birth. Mucoid material was aspirated. Microscopic examination reveals a filamentous structured colony and crystal against the granular proteinaceous background. Features suggest benign cystic lesion and secondary actinomycosis infection, negative with an acid-fast bacilli stain consistent with Actinomyces species. As stated in most of the literature, mainly males are affected by this condition. Very little information is available on the use of fine-needle aspiration cytology (FNAC) to diagnose these lesions. We are reporting a case of an actinomycotic lesion that was reliably diagnosed with FNAC. So, we emphasized here that FNAC is aninexpensive, rapid, and simple outpatient procedure that helps in the rapid diagnosis of Actinomycosis.

A bioactive tannic acid/vanadium ions co-deposited coating on various surfaces for antifouling, photothermal anti-bacterial, and antioxidant effects

Pathogenic bacteria attached to medical device surfaces result in the persistence of chronic bacterial infections and pose severe threats to human health. In this study, a one-step co-deposition method was developed to fabricate tannic acid (TA)-based vanadium ions (Vn+)-phenolic network coating. The successful co-deposition of PEG-TA/Vn+ on the Ti surfaces was confirmed by Scanning electronic microscopy (SEM), Energy dispersive spectroscopy (EDS), Fourier transform infrared spectroscopy (FITR), and X-ray photoelectron spectroscopy (XPS) analyses. The PEG-TA/Vn+ co-deposited coating showed excellent flexibility and good adhesion on various substrates. The as-prepared coating exhibited remarkable antifouling and photothermal antibacterial properties, preventing biofilm formation and scavenging the reactive oxygen species (ROS) during incubation with cells. The present work provides an efficient strategy for the design of antifouling, antibacterial, and antioxidant surface coating formulations to prevent medical device-associated infections.

Primary Cutaneous Actinomycosis Mimicking Cutaneous Leishmaniasis

Abstract Actinomycosis is a chronic suppurative bacterial infection commonly seen in the tropics, caused by gram-positive, anaerobic bacilli of the genus Actinomyces. There are very few reported cases of primary cutaneous actinomycosis. It can mimic mycetoma, tuberculosis, nocardiosis, and botryomycosis. A high index of clinical suspicion is required for diagnosis in the absence of sinuses. Even with repeated attempts, cultures are mostly negative; and hence, histology reveals the diagnosis in most cases. Here, we report an unusual case of primary cutaneous actinomycosis in a 21-year-old female patient, following a road traffic accident (RTA). A positive Splendore–Hoeppli phenomenon and special stains demonstrated the ray fungus and helped us reach the diagnosis. The patient was started on oral penicillin G and showed good response.

A 13-Year-Old Boy with Chest Wall Actinomycosis Mimicking Ewing Sarcoma on Imaging.

BACKGROUND Actinomyces, a filamentous, branching, anaerobic gram-positive bacillus, typically found as a commensal organism in the oral cavity, can lead to rare chronic bacterial infections in various anatomical regions. Chest wall involvement represents an uncommon presentation, posing significant diagnostic challenges. This report focuses on the case of a 13-year-old boy presenting with chest wall actinomycetoma that closely resembled Ewing sarcoma on imaging. CASE REPORT We present the case of a 13-year-old male with no previous medical history who presented to the Emergency Department with progressive left-sided chest pain following a sports-related fall. Physical examination revealed mild swelling and tenderness on the left anterior chest wall. A chest computed tomography (CT) scan revealed a large tumor involving the lower left chest wall, suggesting Ewing sarcoma. However, a histopathological examination unexpectedly confirmed actinomycosis of the chest wall. Intravenous penicillin G was promptly initiated for 4 weeks. A follow-up CT scan after 4 weeks of therapy demonstrated a significant response with notable reduction in the size of the chest wall mass. The patient then continued with maintenance therapy using oral amoxicillin for 12 months. Throughout this period, complete resolution of the chest wall mass occurred, with no significant adverse events or complications observed. CONCLUSIONS This case highlights the importance of considering uncommon differential diagnoses like chest wall actinomycosis in patients presenting with chest wall masses. The diagnostic complexities associated with this rare condition emphasize the need for a comprehensive evaluation strategy, incorporating histopathological examination and imaging.

Spectrum of activity of Salmonella anti-biofilm compounds: Evaluation of activity against biofilm-forming ESKAPE pathogens

The ESKAPE pathogens are a group of bacteria that are a leading cause of health-care associated infections and are known to be agents of chronic, biofilm-mediated infections. These chronic bacterial infections often respond poorly to antibiotics and in some cases may require surgical intervention in order to cure the infection. As biofilms are often the critical mediator of a chronic infection, it is essential to develop therapies that target bacteria within the biofilm state. Herein, we report the development of a rapid, 96-well plate-based assay that employs conditions specific for each species to optimize biofilm production and allow for easy identification of differences in biofilm mass after treatment with anti-biofilm candidates. We used these ESKAPE-specific biofilm assays to test our previously identified Salmonella anti-biofilm small molecule compounds, JG-1 and M4, for anti-biofilm activity. The results demonstrated that JG-1 and M4 have anti-biofilm activity against Enterobacter spp., S. aureus, E. faecium, P. aeruginosa, and A. baumannii. In addition, we identified that M4 has significant antimicrobial activity against S. aureus and E. faecium at concentrations >10 μM (X μg/mL). These findings support the claim that JG-1 and M4 have broad-spectrum anti-biofilm activity, while M4 has antimicrobial activity against the Gram-positive members of the ESKAPE pathogens. Thus, these compounds have the potential to have a significant impact on treating multiple types of commonly encountered biofilm-mediated infections.

Current paradigms in the management of refractory Helicobacter pylori infection.

Helicobacter pylori is the most prevalent chronic bacterial infection, with approximately half of the world's population estimated to be colonized. The World Health Organization (WHO) has classified Helicobacter pylori as a class-I carcinogen. All main society guidelines recommend its eradication in infected individuals. The global trend indicates that eradication rates are decreasing annually and the likelihood of eradication decreases with each unsuccessful therapeutic attempt. Resistance to antibiotics in H.pyloristrains is the leading cause for eradication failure. Still, drug resistance and treatment failure may be complex, multi-dimensional and associated with several other factors. Knowledge of these factors can aid in optimizing eradication rates. This review will focus on the factors associated with refractory H.pylori, with a particular emphasis on antibiotic resistance mechanisms and their clinical implications. Also, the most recent literature and recommendations available for determining an appropriate regimen after the failure of the first attempt at eradication will be discussed.

Drug-Resistant Helicobacter pylori: Diagnosis and Evidence-Based Approach.

Helicobacter pylori (H. pylori) is the most common chronic bacterial infection, affecting approximately half of the world's population. H. pylori is a Class I carcinogen according to the World Health Organization, and the International Agency for Research on Cancer (IARC) has linked it to 90% of stomach cancer cases worldwide. The overall pattern points to a yearly reduction in eradication rates of H. pylori with the likelihood of success further decreasing after each unsuccessful therapeutic effort. Antimicrobial resistance in Helicobacter pylori is a major public health concern and is a predominant cause attributed to eradication failure. As a result, determining H. pylori's antibiotic susceptibility prior to the administration of eradication regimens becomes increasingly critical. Detecting H. pylori and its antimicrobial resistance has traditionally been accomplished by time-consuming culture and phenotypic drug susceptibility testing. The resistance of H. pylori to different antibiotics is caused by various molecular mechanisms, and advances in sequencing technology have greatly facilitated the testing of antibiotic susceptibility to H. pylori. This review will summarize H. pylori antibiotic resistance patterns, mechanisms, and clinical implications. We will also review the pros and cons of current antibiotic susceptibility testing methods. Along with a comparison of tailored susceptibility-guided regimens and empirical therapy based on the latest evidence, an evidence-based approach to such situations will be explored.

Cat’s Claw Nutrients for Medical Treatments

Uncaria tomentosa (Willd. ex Schult.) DC is commonly known as cat’s claw that is derived from the Spanish word Uña de Gato that identifies the small, curved-back thorns on the stem at the leaf junction. It is a tropical medicinal vine of the Rubiaceae family that is widely distributed in the Amazon rainforest and other areas of South and Central America. Cat's claw, which is scientifically known as Uncaria tomentosa, has been historically used to treat and prevent inflammatory disorders, particularly osteoarthritis. Traditionally, it has been used to treat chronic viral infections, bacterial infections, numerous inflammatory and immunological disorders, asthma, dysentery, cancers, arthritis, and as a birth control agent. Nutraceuticals, including food or products containing cat’s claw, can be used to prevent and modify symptoms in osteoarthritis patients. So, cat’s claw is possibly effective in reducing the pain in patient’s joints. U. tomentosa is a potent complimentary herb for treating most parasites. Various chemical constituents are reported from the extracts of U. tomentosa along with their biological activities. It is worth noting that more than 50 phytochemical molecules have been identified and isolated from U. tomentosa, some of them are considered new to that species. It also was used for the treatment of various ailments including abscesses, urinary tract infections, contraception, rheumatism, and weakness. Additionally, it was used as a treatment option for mental disorders (anxiety). The preclinical assessment revealed that the cat’s claw defends towards various oxidative stresses, involving peroxynitrite that has been included in arthritis and other chronic inflammatory diseases along with inhibiting acute or chronic gastritis caused by high doses of nonsteroidal anti-inflammatory drugs (NSAIDs). U. tomentosa aqueous extract was used to protect against oxidative stress in human erythrocytes and relieve chronic intestinal inflammation. Cat’s claw has antitumor and immunostimulatory effects because of its oxindole alkaloids content. Anti proliferative effect of U. tomentosa against several cancer cell lines, namely cervical carcinoma, osteosarcoma, and breast cancer were documented. U. tomentosa hot water extract prevents inflammatory responses as well as tumor cell proliferation by inhibiting the transcriptional regulator nuclear factor kappa beta (NF-B) activation without interfering with interleukin-2 (IL-2) production or IL-2 receptor signaling. Medical technologists documented the ant proliferative effect of cat’s claw extracts against several cell lines, including glioma, premyelocytic leukemia, MCF7 breast cancer, acute lymphoblastic leukaemia, and neuroblastoma.

Programming lipopeptide nanotherapeutics for tandem treatment of postsurgical infection and melanoma recurrence

Tumor recurrence and chronic bacterial infection constitute two major criteria in postsurgical intervention for malignant melanoma. One plausible strategy is the equipment of consolidation therapy after surgery, which relies on adjuvants to eliminate the residual tumor cells and inhibit bacterial growth. Until now, a number of proof-of-concept hybrid nanoadjuvants have been proposed to combat tumor recurrence and postsurgical bacterial infection, which may suffer from the potential bio-unsafety or involve complex design and synthesis. The batch-to-batch inconsistencies in drug composition further delay the clinical trials. To circumvent these issues, herein we develop a programmable strategy to generate lipopeptide nanotherapeutics with identical constitution for tandem intervention of postsurgical bacterial infection and cancer recurrence of melanoma. Increasing the number of hydrophobic linoleic acid within lipopeptides has been found to be a simple and practical strategy to improve the therapeutic outcomes for both tumor cells and bacteria. Self-assembled lipopeptide nanotherapeutics with two linoleic acid molecules possesses excellent antitumor activity and antimicrobial function toward both susceptible strains and drug-resistant bacteria. Arising from the incorporation of unsaturated linoleic acid, the unavoidable hemolysis of cationic peptide drugs was effectively alleviated. In vivo therapeutic abilities of postsurgical infection and tumor recurrence were investigated in BALB/c nude mice bearing a B16-F10 tumor model, with an incomplete surgical resection and in situ infection by methicillin-resistant Staphylococcus aureus (MRSA). Self-assembled lipopeptide nanotherapeutics could effectively inhibit cancer cell growth and bacterial infection, as well as promote wound healing. The easily scalable large-scale production, broad-spectrum antitumor and antibacterial bioactivities as well as fixed component endows lipopeptide nanotherapeutics as promising adjuvants for clinically postsurgical therapy of melanoma.

A multifunctional cascade nanoreactor based on Fe-driven carbon nanozymes for synergistic photothermal/chemodynamic antibacterial therapy.

Healing bacterial chronic wounds caused by hyperglycemia is of great significance to protect the physical and mental health of diabetic patients. In this context, emerging chemodynamic therapy (CDT) and photothermal therapy (PTT) with broad antibacterial spectra and high spatiotemporal controllability have flourished. However, CDT was challenged by the near-neutral pH and inadequate H2O2 surrounding the chronic wound site, while PTT showed overheating-triggered side effects (e.g., damaging the normal tissue) and poor effects on thermotolerant bacterial biofilms. Therefore, we engineered an all-in-one glucose-responsive photothermal nanozyme, GOX/MPDA/Fe@CDs, consisting of glucose oxidase (GOX), Fe-doped carbon dots (Fe@CDs), and mesoporous polydopamine (MPDA), to efficiently treat chronic diabetic wound bacterial infections and eradicate biofilms without impacting the surrounding normal tissues. Specifically, GOX/MPDA/Fe@CDs produced a local temperature (∼ 45.0°C) to enhance the permeability of the pathogenic bacterium and its biofilm upon near-infrared (NIR) 808 nm laser irradiation, which was seized to initiate endogenous high blood glucose to activate the catalytic activity of GOX on the GOX/MPDA/Fe@CD surface to achieve the simultaneous self-supplying of H2O2 and H+, cascade catalyzing •OH production via a subsequent peroxidase-mimetic activity-induced Fenton/Fenton-like reaction. As such, the in vivo diabetic wound infected with methicillin-resistant Staphylococcus aureus was effectively healed after 12.0 days of treatment. This work was expected to provide an innovative approach to the clinical treatment of bacterially infected diabetic chronic wounds. STATEMENT OF SIGNIFICANCE: An all-in-one glucose-responsive photothermal nanozyme GOX/MPDA/Fe@CDs was constructed. Cascade nanozyme GOX/MPDA/Fe@CDs self-supply H2O2 and H+ to break H2O2 and pH limits to fight bacterial infections. Synergistic chemotherapy and photothermal therapy with nanozyme GOX/MPDA/Fe@CDs accelerates healing of biofilm-infected diabetic wounds.

Masking of typical TLR4 and TLR5 ligands modulates inflammation and resolution by Helicobacter pylori.

Helicobacter pylori is a paradigm of chronic bacterial infection and is associated with peptic ulceration and malignancies. H. pylori uses specific masking mechanisms to avoid canonical ligands from activating Toll-like receptors (TLRs), such as lipopolysaccharide (LPS) modification and specific flagellin sequences that are not detected by TLR4 and TLR5, respectively. Thus, it was believed for a long time that H. pylori evades TLR recognition as a crucial strategy for immune escape and bacterial persistence. However, recent data indicate that multiple TLRs are activated by H. pylori and play a role in the pathology. Remarkably, H. pylori LPS, modified through changes in acylation and phosphorylation, is mainly sensed by other TLRs (TLR2 and TLR10) and induces both pro- and anti-inflammatory responses. In addition, two structural components of the cag pathogenicity island-encoded type IV secretion system (T4SS), CagL and CagY, were shown to contain TLR5-activating domains. These domains stimulate TLR5 and enhance immunity, while LPS-driven TLR10 signaling predominantly activates anti-inflammatory reactions. Here, we discuss the specific roles of these TLRs and masking mechanisms during infection. Masking of typical TLR ligands combined with evolutionary shifting to other TLRs is unique for H. pylori and has not yet been described for any other species in the bacterial kingdom. Finally, we highlight the unmasked T4SS-driven activation of TLR9 by H. pylori, which mainly triggers anti-inflammatory responses.

Maintenance and generation of proton motive force are both essential for expression of phenotypic antibiotic tolerance in bacteria.

Bacterial antibiotic tolerance, a phenomenon first observed in 1944, is known to be responsible for both onset and exacerbation of recurrent and chronic bacterial infections. The development of antibiotic tolerance was previously thought to be due to a switch to physiological dormancy when bacteria encounter adverse growth conditions. Our recent laboratory findings, however, showed that a set of genes related to the maintenance of proton motive force (PMF) are up-regulated under starvation, indicating that the tolerant sub-population, which are commonly known as persisters, can actively maintain their tolerance phenotypes. In this study, we investigated the relative functional roles of proteins involved in the maintenance and active generation of PMF in mediating tolerance formation in bacteria and found that the PspA and RcsB proteins play a key role in PMF maintenance in persisters, as deletion of genes encoding these two proteins resulted in significantly lower tolerance levels. Consistently, expression of the OsmC and Bdm proteins, which is under regulation by RcsB, is required to maintain PMF and the antibiotic tolerance phenotypes. On the other hand, the NuoL, Ndh, AppC, CyoB, and NuoF proteins, which are electron transport chain (ETC) components, were also found to be actively expressed in persisters in order to generate PMF to support functioning of various tolerance mechanisms such as efflux activities. Our data show that active generation of PMF is even more important than the PMF maintenance functions of PspA and RcsB in the expression of antibiotic tolerance phenotypes in persisters. Assessment of double- and triple-gene knockout strains, in which the PMF maintenance genes and those encoding ETC components were simultaneously deleted, confirms that these two groups of genes are both required for the expression of antibiotic tolerance phenotypes and that a lack of these functions would result in complete PMF dissipation and accumulation of antibiotics in the intracellular compartment of persisters and eventually cell death. Products of these genes are, therefore, ideal targets for future development of anti-tolerance agents. IMPORTANCE In this work, bacteria were found to undergo active generation and maintenance of proton motive force (PMF) under adverse conditions, such as starvation so as to support a range of physiological functions in order to survive under such conditions for a prolonged period. The ability to maintain a substantial level of PMF was found to be directly linked to that exhibiting phenotypic antibiotic tolerance under nutrient starvation or other adverse conditions. These findings infer that bacteria do not simply become physiologically dormant when they become antibiotic tolerant, instead they need to produce a wide range of proteins including those which help prevent PMF dissipation, such as PspA and RcsB, and the electron transport chain components, such as NuoL and Ndh, that actively generate PMF even during long-term starvation. As antibiotic tolerant sub-population is known to play a role in eliciting recurrent and chronic infections, especially among patients with a weakened immune system, the PMF maintenance mechanisms identified in this work are potential targets for the development of new strategies to control recurrent and chronic infections.

Urolithin B alleviates Helicobacter pylori-induced inflammation and oxidative stress in mice.

Helicobacter pylori is one of the most common chronic bacterial infections. Active eradication of H. pylori infection is rare due to the fact that most infected patients are asymptomatic and the use of large amounts of antibiotics in eradication therapy leads to severe side effects. Urolithin B (UB) is an additional major intestinal metabolite of ellagic acid (EA), which has been shown to possess anti-inflammatory, antioxidant, and antiapoptotic biological activities. Preventing the incidence of H. pylori-related gastric disease and reducing the damage to the host by H. pylori is a current approach to control H. pylori infection. In this study, we explored the effect of UB on H. pylori infection. The effects of UB on inflammation and oxidative stress induced by H. pylori in vivo and in vitro were investigated by qPCR, ELISA, HE staining, IHC staining, etc. RESULTS: UB reduced the adhesion and colonization of H. pylori and improved H. pylori-induced inflammation and oxidative stress in vivo and in vitro. Moreover, UB had better anti-inflammatory and antioxidant effects than clarithromycin (CLR) and metronidazole (MET). In addition to inhibiting the secretion of CagA, UB reduced tissue damage by H. pylori infection. UB was effective in improving damage caused by H. pylori.

Nitazoxanide Based New Regimens versus Metronidazole Standard Quardable Regimen as Rescue Therapy in Treatment of Resistant H. Pylori gastritis

Abstract Background Helicobacter pylori (H. pylori) is a small, Gram-negative spirochete inhabiting the mucous layer overlying the gastric epithelial cells in humans. It is the most common prevalent chronic human bacterial infection estimated in 50% of the global population Aim of the Work This study aimed to evaluate the efficacy of nitazoxanide and doxycycline as a new regimen in treatment of H.pylori Patients and Methods A Prospective observational cohort study for each patient the time for antibiotic therapy for two weeks and continue PPI therapy for three months. Results In this study we found that there is insignificant difference between both studied groups as regards demographic data. This table shows that there is insignificant difference between both studied groups as regards smoking, chronic illness, main complaint and pelvic-abd US. In this study we demonstrated that there is significant difference between both studied groups as regards PLT and INR. In study in our hands, the eradication rates were found to be higher in LOAD therapy group compared to Concomitant therapy group (83.3% vs. 71.4%), Also there is insignificant difference between both studied groups as regards outcome (P = 0.03) In this thesis we found that increased age is independently associated with higher probability of cure (negative Ag in stool). Conclusion We concluded that LOAD therapy is preferable to clarithromycin-contained triple therapy in H. pylori infection eradication particularly in countries like Egypt with great clarithromycin resistance. This is at least until we can get the bismuth in our country. Recently, the increasing concepts about levofloxacin resistance and decreasing efficacy as a second line treatment directed us towards thinking in levofloxacin contained quadruple therapy including doxycycline and NTZ as alternative line of regimen therapy for better H. pylori eradication in our country. Further studies are needed on larger scale of patients, and culture and sensitivity tests are frequently required to evaluate the resistant emergent bacteria. Although culture and sensitivity might not be carried out, the detection of mutations by molecular methods provides an alternative way in which we can relay in the future.

Chronic pulmonary bacterial infection facilitates breast cancer lung metastasis by recruiting tumor-promoting MHCIIhi neutrophils

Breast cancer can metastasize to various organs, including the lungs. The immune microenvironment of the organs to be metastasized plays a crucial role in the metastasis of breast cancer. Infection with pathogens such as viruses and bacteria can alter the immune status of the lung. However, the effect of chronic inflammation caused by bacteria on the formation of a premetastatic niche within the lung is unclear, and the contribution of specific immune mediators to tumor metastasis also remains largely undetermined. Here, we used a mouse model revealing that chronic pulmonary bacterial infection augmented breast cancer lung metastasis by recruiting a distinct subtype of tumor-infiltrating MHCIIhi neutrophils into the lung, which exhibit cancer-promoting properties. Functionally, MHCIIhi neutrophils enhanced the lung metastasis of breast cancer in a cell-intrinsic manner. Furthermore, we identified CCL2 from lung tissues as an important environmental signal to recruit and maintain MHCIIhi neutrophils. Our findings clearly link bacterial-immune crosstalk to breast cancer lung metastasis and define MHCIIhi neutrophils as the principal mediator between chronic infection and tumor metastasis.

Cystic fibrosis

Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by variants in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR dysfunction results in abnormal chloride and bicarbonate transport in epithelial cells, leading to a multiorgan disease dominated by respiratory and digestive manifestations. The respiratory disease, which is characterized by airway mucus plugging, chronic bacterial infection and progressive development of bronchiectasis, may lead to chronic respiratory failure, which is the main cause of premature death in people with CF. Over the past 50 years, major progress has been obtained by implementing multidisciplinary care, including nutritional support, airway clearance techniques and antibiotics in specialized CF centers. The past 10 years have further seen the progressive development of oral medications, called CFTR modulators, that partially restore ion transport and lead to a major improvement in clinical manifestations and lung function, presumably resulting in longer survival. Although an increasing proportion of people with CF are being treated with CFTR modulators, challenges remain regarding access to CFTR modulators due to their high cost, and their lack of marketing approval and/or effectiveness in people with rare CFTR variants. The anticipated increase in the number of adults with CF and their aging also challenge the current organization of CF care. The purpose of this review article is to describe current status and future perspective of CF disease and care.