Replication of Legionella Pneumophila in Human Cells: Why are We Susceptible?

Legionella pneumophila is the causative agent of Legionnaires’ disease, a serious and often fatal form of pneumonia. The susceptibility to L. pneumophila arises from the ability of this intracellular pathogen to multiply in human alveolar macrophages and monocytes. L. pneumophila also replicates in several professional and non-professional phagocytic human-derived cell lines. With the exception of the A/J mouse strain, most mice strains are restrictive, thus they do not support L. pneumophila replication. Mice lacking the NOD-like receptor Nlrc4 or caspase-1 are also susceptible to L. pneumophila. On the other hand, in the susceptible human hosts, L. pneumophila utilizes several strategies to ensure intracellular replication and protect itself against the host immune system. Most of these strategies converge to prevent the fusion of the L. pneumophila phagosome with the lysosome, inhibiting host cell apoptosis, activating survival pathways, and sequestering essential nutrients for replication and pathogenesis. In this review, we summarize survival mechanisms employed by L. pneumophila to maintain its replication in human cells. In addition, we highlight different human-derived cell lines that support the multiplication of this intracellular bacterium. Therefore, these in vitro models can be applicable and are reproducible when investigating L. pneumophila/phagocyte interactions at the molecular and cellular levels in the human host

Biofilm, a Cozy Structure for <em>Legionella pneumophila</em> Growth and Persistence in the Environment

Legionella pneumophila (L. pneumophila) is the causative agent of Legionnaires’ disease. Transmission to humans is mediated via inhalation of contaminated water droplets. L. pneumophila is widely distributed in man-made water systems, multiple species of protozoa, and nematodes. L. pneumophila persist within multi-species biofilms that cover surfaces within water systems. Virulence, spread, and resistance to biocides are associated with survival of L. pneumophila within multi-organismal biofilm. Outbreaks of Legionellosis are correlated with the existence of L. pneumophila in biofilms, even after the intensive chemical and physical treatments. Several factors negatively or positively modulate the persistence of L. pneumophila within the microbial consortium-containing L. pneumophila. Biofilm-forming L. pneumophila continue to be a public health and economic burden and directly influence the medical and industrial sectors. Diagnosis and hospitalization of patients and prevention protocols cost governments billions of dollars. Dissecting the biological and environmental factors that promote the persistence and physiological adaptation in biofilms can be fundamental to eliminating and preventing the transmission of L. pneumophila. Herein, we review different factors that promote persistence of L. pneumophila within the biofilm consortium, survival strategies used by the bacteria within biofilm community, gene regulation, and finally challenges associated with biofilm resistance to biocides and anti-Legionella treatments

Autophagy in Cystic Fibrosis Pathogenesis and Treatment

Cystic fibrosis (CF) is a fatal, genetic disorder that critically affects the lungs and is directly caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in defective CFTR function. In epithelial cells, the CFTR channel conducts anions and plays a critical role in regulating the volume and composition of airway surface liquid. This thin layer of aqueous fluid and mucus covering the airway surface facilitates mucociliary clearance, bacterial killing, and epithelial cell homeostasis. The importance of the CFTR channel in macrophages was revealed in recent work that demonstrated that defective CFTR function is accompanied by impaired innate immune responses to specific infections. Notably, most CF-associated infections are caused by microbes that are cleared by autophagy in healthy cells. Autophagy is a highly regulated biological process that provides energy during periods of stress and starvation. Autophagy clears pathogens, inflammatory molecules, and dysfunctional protein aggregates within macrophages. However, this process is impaired in CF patients and CF mice, as their cells exhibit limited autophagy activity. The mechanisms linking a malfunctioning ion channel function to the defective autophagy remains unclear. In this chapter, we describe and discuss the recent findings indicating the presence of several mechanisms leading to defective autophagy in CF cells. Thus, these novel data advance our understanding of mechanisms underlying the pathobiology of CF and provide a new therapeutic platform for restoring CFTR function and autophagy in patients with CF

EVOLVING ROLE OF CAR T-CELL IN CANCER IMMUNOTHERAPY

Safety profiles of newly developed anti-cancer therapies is the main goal for efficient treatments to improve survival rates. Therefore, continuous efforts carried out to develop a therapeutic strategy with better outcomes. The concept of immune-oncology, which utilizes and enhances the capacity of human immune system was developed as an eventual opportunity to enhance remissions and limit the relaps of the disease. Later progression of cellular immunetherapies involve the introduction of genetically engineered T cells having chimeric antigen receptors (CARs) that embraced an antibody-derived antigen recognition domain connected to an internal T-cell signaling domain, so can recognize their targets with high degree of tumor selectivity. This approach showed vigorous antitumor outcomes and full recovery in end-stage patients suffering from liquid cancers as leukemia and lymphoma. However, still there is a challenge for bringing genetically modified T-cell immunotherapy to many patients with different tumor types including solid tumor. On other hand, studies indicated the potential to broaden T-cell–based therapies and foster for other possible applications beyond oncology as organ transplantation and autoimmunity. Therefore, this review aimed to illustrate the clinical applications, challenges, and approaches for more efficient clinical employment of CAR T cell therapies

The role of oxidative stress in antipsychotics induced ovarian toxicity

This study tested the hypothesis that oxidative stress could be an underlying mechanism for APs-induced ovarian cytotoxicity and reproductive dysfunction. Rat ovarian theca interstitial cells (TICs) were isolated and treated with four APs [chlorpromazine (CPZ), haloperidol (HAL), risperidone (RIS) and clozapine (CLZ)]. MTT assay was used to test the effects of these antipsychotics on TICs viability and to estimate their 50% inhibitory concentrations (IC50s). The effects of APs (IC50s and 1 μM concentrations) on the activities of caspases-3, -8 and -9, reactive oxygen species (ROS) production, total intracellular glutathione and lipid peroxidation (LPO) in TICs were assessed. The effect of antioxidants (reduced glutathione (GSH) and quercetin) on the APs-induced cytotoxicity on TICs was investigated. MTT assay showed all APs to reduce TICs viability. CPZ, HAL and CLZ significantly increased the activity of caspases-3, -8 and -9 (P < 0.0001, < 0.0001 and < 0.01, respectively). All APs at IC50s significantly (P < 0.0001) increased ROS production, decreased total intracellular glutathione and increased LPO. MTT assay in the presence of antioxidants (reduced GSH (5 mM) or quercetin (50 mM)) showed each antioxidant to significantly inhibit the effects of APs at their IC50s on TICs viability. In conclusion, oxidative stress seems to be a possible mechanism for APs-induced ovarian and reproductive toxicity

Robust Expression of Tumor Suppressor miRNA\u27s Let-7 and miR-195 Detected in Plasma of Saudi Female Breast Cancer Patients.

Background Female breast cancer is frequently diagnosed at a later stage and the leading cause of cancer deaths world-wide. Levels of cell-free circulating microRNAs (miRNAs) can potentially be used as biomarkers to measure disease progression in breast cancer patients in a non-invasive way and are therefore of high clinical value. Methods Using quantitative RT-PCR, circulating miRNAs were measured in blood samples collected from disease-free individuals (n = 34), triple-negative breast tumours (TNBC) (n = 36) and luminal tumours (n = 57). In addition to intergroup comparisons, plasma miRNA expression levels of all groups were analyzed against RNASeq data from cancerous breast tissue via The Cancer Genome Atlas (TCGA). Results A differential set of 18 miRNAs were identified in the plasma of breast cancer patients and 10 miRNAs were uniquely identified based on ROC analysis. The most striking findings revealed elevated tumor suppressor let-7 miRNA in luminal breast cancer patients, irrespective of subtype, and elevated miR-195 in plasma of TNBC breast cancer patients. In contrast, hsa-miR-195 and let-7 miRNAs were absent from cancerous TCGA tissue and strongly expressed in surrounding non-tumor tissue indicating that cancerous cells may selectively export tumor suppressor hsa-miR-195 and let-7 miRNAs in order to maintain oncogenesis. Conclusions While studies have indicated that the restoration of let-7 and miR-195 may be a potential therapy for cancer, these results suggested that tumor cells may selectively export hsa-miR-195 and let-7 miRNAs thereby neutralizing their potential therapeutic effect. However, in order to facilitate earlier detection of breast cancer, blood based screening of hsa-miR-195 and let-7 may be beneficial in a female patient cohort

A Study of the Spatial Heterogeneity of Some Chemical Properties of Terabhor Back Using GIS

تمت دراسة تغاير ترب الهور وتغاير صفات ترب الهور في محافظة ميسان , إذ تم حفر ستة بيدونات ووصفت أفاق البيدونات وصفآ مورفولوجيآ أصوليآ, وكذلك أستحصال عينات بينية عشوائية على أربعة أعماق متساوية 25-0 سم و50-25 سم و75-50 سم و100-75 سم , وقد أشارت نتائج التغاير المكاني لصفات ترب الهور وخرائط التوزيع المكاني تغاير جميع صفات ترب الهور الكيميائية ,فقد اشارت النتائج الى تغاير الافاق في المسافة المؤثرة التي تصف تغاير الصفات الكيميائية , إذ كانت الايصالية الكهربائية EC تتراوح بين 0.48 - 5.46 &nbsp;والجبس تراوح بين 0.15 - 4.61 &nbsp;أكثر الصفات تغايرآ , ثم تلتها المادة العضوية الذي تراوحت بين 0.27 - 4.50 والسعة التبادلية للأيونات الموجبة&nbsp; &nbsp;CECبين 18.66 - 38.42 . أما الصفات الاقل تغايرآ فقد كان تفاعل التربة &nbsp;pHالذي تراوحت بين 7.05 - 7.62 يليه كاربونات الكالسيوم 284.28 -438.71 &nbsp;, إذ كانت المسافة المؤثرة Range عالية في تلك الصفات . بينت النتائج أن النموذج الملائم الذي يصف تغاير الصفات الكيميائية كان النموذج الدائري Circular هو النموذج الملائم لوصف تغايرها بنسبة 54%, يليه النموذج الكروي Spherical نسبة 43% والنموذج الكأسي Gussin نسبة 4%.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; صنفت ترب الدراسة بحسب النظام الأمريكي الحديث 2014 الى رتبتين هما رتبة Entisols ورتبة Mollisols .&nbsp; Done studying the variability of the soils And the heterogeneity of the characteristics of the soils of the Euphrates, where 6 boreons were described and described the horizons of the pidoons as morphological and fundamental, as well as obtaining random samples on four equal depths 25-0 cm, 50-25 cm, 75-50 cm and 100-75 cm. The results of spatial heterogeneity Turbidity and Spatial Distribution Maps The heterogeneity of all the characteristics of chemical faecal soil is indicated by the results. The results indicate the variance of the horizons in the moving distance that describe the heterogeneity of the chemical properties, Electrical conductivity of EC Ranging between 0.48-5.46 and gypsum Ranging between 0.15 - 4.61 qualities more heterogeneous, and then followed by organic matter Ranging between 0.27-4.50 and CEC Ranging between 18.66-38.42 .&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; The least heterogeneous properties were soil pH Ranging between 7.05- 7.62, followed by calcium carbonate Ranging between 284.28 - 438.71, where the range was high &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; The results showed that the appropriate model describing the heterogeneity of the chemical properties was the circular model, the appropriate model for describing its variation by 54%, followed by the spherical model of 43% and the gussin model of 4%. The soil of the study according to the modern American system 2014 is classified into two levels: Entisols and Mollisols .&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp