Immunometabolites in viral infections: Action mechanism and function.

The interplay between viral pathogens and host metabolism plays a pivotal role in determining the outcome of viral infections. Upon viral detection, the metabolic landscape of the host cell undergoes significant changes, shifting from oxidative respiration via the tricarboxylic acid (TCA) cycle to increased aerobic glycolysis. This metabolic shift is accompanied by elevated nutrient accessibility, which is vital for cell function, development, and proliferation. Furthermore, depositing metabolites derived from fatty acids, TCA intermediates, and amino acid catabolism accelerates the immunometabolic transition, facilitating pro-inflammatory and antimicrobial responses. Immunometabolites refer to small molecules involved in cellular metabolism regulating the immune response. These molecules include nutrients, such as glucose and amino acids, along with metabolic intermediates and signaling molecules adenosine, lactate, itaconate, succinate, kynurenine, and prostaglandins. Emerging evidence suggests that immunometabolites released by immune cells establish a complex interaction network within local niches, orchestrating and fine-tuning immune responses during viral diseases. However, our current understanding of the immense capacity of metabolites to convey essential cell signals from one cell to another or within cellular compartments remains incomplete. Unraveling these complexities would be crucial for harnessing the potential of immunometabolites in therapeutic interventions. In this review, we discuss specific immunometabolites and their mechanisms of action in viral infections, emphasizing recent findings and future directions in this rapidly evolving field.

Circular RNAs in tuberculosis: From mechanism of action to potential diagnostic biomarker.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tuberculosis), continues to be a major global health concern. Understanding the molecular intricacies of TB pathogenesis is crucial for developing effective diagnostic and therapeutic approaches. Circular RNAs (circRNAs), a class of single-stranded RNA molecules characterized by covalently closed loops, have recently emerged as potential diagnostic biomarkers in various diseases. CircRNAs have been demonstrated to modulate the host's immunological responses against TB, specifically by reducing monocyte apoptosis, augmenting autophagy, and facilitating macrophage polarization. This review comprehensively explores the roles and mechanisms of circRNAs in TB pathogenesis. We also discuss the growing body of evidence supporting their utility as promising diagnostic biomarkers for TB. By bridging the gap between fundamental circRNA biology and TB diagnostics, this review offers insights into the exciting potential of circRNAs in combatting this infectious disease.

Overview of the role and action mechanism of microRNA-128 in viral infections.

Recently in vivo and in vitro studies have provided evidence establishing the significance of microRNAs (miRNAs) in both physiological and pathological conditions. In this regard, the role of miRNA-128 (miR-128) in health and diseases has been found, and its critical regulatory role in the context of some viral diseases has been recently identified. For instance, it has been found that miR-128 can serve as an antiviral mediator and significantly limit the replication and dissemination of human immunodeficiency virus type 1 (HIV-1). Besides, it has been noted that poliovirus receptor-related 4 (PVRL4) is post-transcriptionally regulated by miR-128, representing possible miRNA targets that can modulate measles virus infection. Of note, the downregulation of seminal exosomes eca-miR-128 is associated with the long-term persistence of Equine arteritis virus (EAV) in the reproductive tract, and this particular miRNA is a putative regulator of chemokine ligand 16 (C-X-C motif) as determined by target prediction analysis. In this review, the latest information on the role and action mechanism of miR-128 in viral infections will be summarized and discussed in detail.

Interactions of Neutrophils with the Polymeric Molecular Components of the Biofilm Matrix in the Context of Implant-Associated Bone and Joint Infections.

In the presence of orthopedic implants, opportunistic pathogens can easily colonize the biomaterial surfaces, forming protective biofilms. Life in biofilm is a central pathogenetic mechanism enabling bacteria to elude the host immune response and survive conventional medical treatments. The formation of mature biofilms is universally recognized as the main cause of septic prosthetic failures. Neutrophils are the first leukocytes to be recruited at the site of infection. They are highly efficient in detecting and killing planktonic bacteria. However, the interactions of these fundamental effector cells of the immune system with the biofilm matrix, which is the true interface of a biofilm with the host cells, have only recently started to be unveiled and are still to be fully understood. Biofilm matrix macromolecules consist of exopolysaccharides, proteins, lipids, teichoic acids, and the most recently described extracellular DNA. The latter can also be stolen from neutrophil extracellular traps (NETs) by bacteria, who use it to strengthen their biofilms. This paper aims to review the specific interactions that neutrophils develop when they physically encounter the matrix of a biofilm and come to interact with its polymeric molecular components.

Biofilms in Periprosthetic Orthopedic Infections Seen through the Eyes of Neutrophils: How Can We Help Neutrophils?

Despite advancements in our knowledge of neutrophil responses to planktonic bacteria during acute inflammation, much remains to be elucidated on how neutrophils deal with bacterial biofilms in implant infections. Further complexity transpires from the emerging findings on the role that biomaterials play in conditioning bacterial adhesion, the variety of biofilm matrices, and the insidious measures that biofilm bacteria devise against neutrophils. Thus, grasping the entirety of neutrophil-biofilm interactions occurring in periprosthetic tissues is a difficult goal. The bactericidal weapons of neutrophils consist of the following: ready-to-use antibacterial proteins and enzymes stored in granules; NADPH oxidase-derived reactive oxygen species (ROS); and net-like structures of DNA, histones, and granule proteins, which neutrophils extrude to extracellularly trap pathogens (the so-called NETs: an allusive acronym for "neutrophil extracellular traps"). Neutrophils are bactericidal (and therefore defensive) cells endowed with a rich offensive armamentarium through which, if frustrated in their attempts to engulf and phagocytose biofilms, they can trigger the destruction of periprosthetic bone. This study speculates on how neutrophils interact with biofilms in the dramatic scenario of implant infections, also considering the implications of this interaction in view of the design of new therapeutic strategies and functionalized biomaterials, to help neutrophils in their arduous task of managing biofilms.

Searching for Virulence Factors among Staphylococcus lugdunensis Isolates from Orthopedic Infections: Correlation of ß-hemolysin, hemolysin III, and slush Genes with Hemolytic Activity and Synergistic Hemolytic Activity.

Staphylococcus lugdunensis is an emerging high-virulent pathogen. Here, the presence and expression of virulence genes (icaA, fbl, vwbl, fbpA, slush A, B and C, and genes of the putative ß-hemolysin and hemolysin III) and the ability to induce synergistic hemolytic activity and hemolysis after 24, 48 and 72 h were investigated in a collection of twenty-two S. lugdunensis clinical isolates. The collection of isolates, mainly from implant orthopedic infections, had previously been grouped by ribotyping/dendrogram analysis and studied for biofilm matrices, biomasses and antibiotic resistances. Two isolates, constituting a unique small ribogroup sharing the same cluster, exhibited an amplicon size of the slush operon (S. lugdunensis synergistic hemolysin) which was shorter than the expected 977 bp. This outcome can predict the genetic lineage of the S. lugdunensis strains. One isolate (cra1342) presented two deletions: one of 90 bp in slush A and the other of 91 bp in slush B. Another isolate (N860314) showed a single 193 bp deletion, which encompassed part of the slush B terminal sequence and most of slush C. The isolate N860314 was devoid of hemolytic activity after 24 h, and the first consideration was that the deleted region deals with the coding of the active enzymatic site of the slush hemolysin. On the other hand, cra1342 and N860314 isolates with different slush deletions and with hemolytic activity after 24 and 48 h, respectively, could have replaced the hemolytic phenotype through other processes.

Metabolomic profiling of bacterial biofilm: trends, challenges, and an emerging antibiofilm target.

Biofilm-related infections substantially contribute to bacterial illnesses, with estimates indicating that at least 80% of such diseases are linked to biofilms. Biofilms exhibit unique metabolic patterns that set them apart from their planktonic counterparts, resulting in significant metabolic reprogramming during biofilm formation. Differential glycolytic enzymes suggest that central metabolic processes are markedly different in biofilms and planktonic cells. The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is highly expressed in Staphylococcus aureus biofilm progenitors, indicating that changes in glycolysis activity play a role in biofilm development. Notably, an important consideration is a correlation between elevated cyclic di-guanylate monophosphate (c-di-GMP) activity and biofilm formation in various bacteria. C-di-GMP plays a critical role in maintaining the persistence of Pseudomonas aeruginosa biofilms by regulating alginate production, a significant biofilm matrix component. Furthermore, it has been demonstrated that S. aureus biofilm development is initiated by several tricarboxylic acid (TCA) intermediates in a FnbA-dependent manner. Finally, Glucose 6-phosphatase (G6P) boosts the phosphorylation of histidine-containing protein (HPr) by increasing the activity of HPr kinase, enhancing its interaction with CcpA, and resulting in biofilm development through polysaccharide intercellular adhesion (PIA) accumulation and icaADBC transcription. Therefore, studying the metabolic changes associated with biofilm development is crucial for understanding the complex mechanisms involved in biofilm formation and identifying potential targets for intervention. Accordingly, this review aims to provide a comprehensive overview of recent advances in metabolomic profiling of biofilms, including emerging trends, prevailing challenges, and the identification of potential targets for anti-biofilm strategies.

Immunometabolism in biofilm infection: lessons from cancer.

BACKGROUND: Biofilm is a community of bacteria embedded in an extracellular matrix, which can colonize different human cells and tissues and subvert the host immune reactions by preventing immune detection and polarizing the immune reactions towards an anti-inflammatory state, promoting the persistence of biofilm-embedded bacteria in the host. MAIN BODY OF THE MANUSCRIPT: It is now well established that the function of immune cells is ultimately mediated by cellular metabolism. The immune cells are stimulated to regulate their immune functions upon sensing danger signals. Recent studies have determined that immune cells often display distinct metabolic alterations that impair their immune responses when triggered. Such metabolic reprogramming and its physiological implications are well established in cancer situations. In bacterial infections, immuno-metabolic evaluations have primarily focused on macrophages and neutrophils in the planktonic growth mode. CONCLUSION: Based on differences in inflammatory reactions of macrophages and neutrophils in planktonic- versus biofilm-associated bacterial infections, studies must also consider the metabolic functions of immune cells against biofilm infections. The profound characterization of the metabolic and immune cell reactions could offer exciting novel targets for antibiofilm therapy.

Coronavirus disease 2019 (COVID-19) update: From metabolic reprogramming to immunometabolism.

The field of immunometabolism investigates and describes the effects of metabolic rewiring in immune cells throughout activation and the fates of these cells. Recently, it has been appreciated that immunometabolism plays an essential role in the progression of viral infections, cancer, and autoimmune diseases. Regarding COVID-19, the aberrant immune response underlying the progression of diseases establishes two major respiratory pathologies, including acute respiratory distress syndrome (ARDS) or pneumonia-induced acute lung injury (ALI). Both innate and adaptive immunity (T cell-based) were impaired in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Current findings have deciphered that macrophages (innate immune cells) are involved in the inflammatory response seen in COVID-19. It has been demonstrated that immune system cells can change metabolic reprogramming in some conditions, including autoimmune diseases, cancer, and infectious disease, including COVID-19. The growing findings on metabolic reprogramming in COVID-19 allow an exploration of metabolites with immunomodulatory properties as future therapies to combat this hyperinflammatory response. The elucidation of the exact role and mechanism underlying this metabolic reprograming in immune cells could help apply more precise approaches to initial diagnosis, prognosis, and in-hospital therapy. This report discusses the latest findings from COVID-19 on host metabolic reprogramming and immunometabolic responses.

The deciphering of the immune cells and marker signature in COVID-19 pathogenesis: An update.

The precise interaction between the immune system and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical in deciphering the pathogenesis of coronavirus disease 2019 (COVID-19) and is also vital for developing novel therapeutic tools, including monoclonal antibodies, antivirals drugs, and vaccines. Viral infections need innate and adaptive immune reactions since the various immune components, such as neutrophils, macrophages, CD4+ T, CD8+ T, and B lymphocytes, play different roles in various infections. Consequently, the characterization of innate and adaptive immune reactions toward SARS-CoV-2 is crucial for defining the pathogenicity of COVID-19. In this study, we explain what is currently understood concerning the conventional immune reactions to SARS-CoV-2 infection to shed light on the protective and pathogenic role of immune response in this case. Also, in particular, we investigate the in-depth roles of other immune mediators, including neutrophil elastase, serum amyloid A, and syndecan, in the immunopathogenesis of COVID-19.

The role of miRNA-128 in the development and progression of gastrointestinal and urogenital cancer.

Increasing data have shown the significance of various miRNAs in malignancy. In this regard, parallel to its biological role in normal tissues, miRNA-128 (miR-128) has been found to play an essential immunomodulatory function in the process of cancer initiation and development. The occurrence of the aberrant expression of miR-128 in tumors and the unique properties of miRNAs raise the prospect of their use as biomarkers and the next generation of molecular anticancer therapies. The function of miR-128 in malignancies such as breast, prostate, colorectal, gastric, pancreatic, esophageal, cervical, ovarian and bladder cancers and hepatocellular carcinoma is discussed in this review. Finally, the effect of exosomal miR-128 on cancer resistance to therapeutics and cancer immunotherapy in certain malignancies is highlighted.

Pathogenic role of 25-hydroxycholesterol in cancer development and progression.

Cholesterol is an essential lipid that serves several important functions, including maintaining the homeostasis of cells, acting as a precursor to bile acid and steroid hormones and preserving the stability of membrane lipid rafts. 25-hydroxycholesterol (25-HC) is a cholesterol derivative that may be formed from cholesterol. 25-HC is a crucial component in various biological activities, including cholesterol metabolism. In recent years, growing evidence has shown that 25-HC performs a critical function in the etiology of cancer, infectious diseases and autoimmune disorders. This review will summarize the latest findings regarding 25-HC, including its biogenesis, immunomodulatory properties and role in innate/adaptive immunity, inflammation and the development of various types of cancer.

The emerging role of exosomal miRNAs as a diagnostic and therapeutic biomarker in Mycobacterium tuberculosis infection.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), has been the world's driving fatal bacterial contagious disease globally. It continues a public health emergency, and around one-third of the global community has been affected by latent TB infection (LTBI). This is mostly due to the difficulty in diagnosing and treating patients with TB and LTBI. Exosomes are nanovesicles (40-100 nm) released from different cell types, containing proteins, lipids, mRNA, and miRNA, and they allow the transfer of one's cargo to other cells. The functional and diagnostic potential of exosomal miRNAs has been demonstrated in bacterial infections, including TB. Besides, it has been recognized that cells infected by intracellular pathogens such as Mtb can be secreting an exosome, which is implicated in the infection's fate. Exosomes, therefore, open a unique viewpoint on the investigative process of TB pathogenicity. This study explores the possible function of exosomal miRNAs as a diagnostic biomarker. Moreover, we include the latest data on the pathogenic and therapeutic role of exosomal miRNAs in TB.

Immunometabolism in human brucellosis: An emerging field of investigation.

In recent years, extreme attention has been focused on the role of immunometabolism in the regulation of immune cell responses in healthy individuals during infection, autoimmunity, and cancer. In the infection biology area, it has been shown that there is a close relationship between the immune system and the host metabolic changes. Brucella species is an intracellular coccobacillus that infects humans and mammals, which led to brucellosis. Brucella species with host-specific evolutionary mechanisms allow it to hide from or manipulate cellular immunity and achieve intracellular persistence. Intracellular bacterial pathogens such as Brucella species also employ host cell resources to replicate and persist inside the host. Targeting these host systems is one promising strategy for developing novel antimicrobials to tackle intracellular infections. This study will summarize the role of metabolic reprogramming in immune cells and their relationship to brucellosis.

The emerging role of probiotics as a mitigation strategy against coronavirus disease 2019 (COVID-19).

COVID-19 is an acute respiratory infection accompanied by pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has affected millions of people globally. To date, there are no highly efficient therapies for this infection. Probiotic bacteria can interact with the gut microbiome to strengthen the immune system, enhance immune responses, and induce appropriate immune signaling pathways. Several probiotics have been confirmed to reduce the duration of bacterial or viral infections. Immune fitness may be one of the approaches by which protection against viral infections can be reinforced. In general, prevention is more efficient than therapy in fighting viral infections. Thus, probiotics have emerged as suitable candidates for controlling these infections. During the COVID-19 pandemic, any approach with the capacity to induce mucosal and systemic reactions could potentially be useful. Here, we summarize findings regarding the effectiveness of various probiotics for preventing virus-induced respiratory infectious diseases, especially those that could be employed for COVID-19 patients. However, the benefits of probiotics are strain-specific, and it is necessary to identify the bacterial strains that are scientifically established to be beneficial.

The biofilm-associated bacterial infections unrelated to indwelling devices.

Biofilms are microbial communities established in the self-produced extracellular substances that include up to 80% of associated microbial infections. During biofilm formation, bacterial cells shift from the planktonic forms to aggregated forms surrounded by an extracellular polymeric substance. The bacterial biofilm shows resistance against immune reactions as well as antibiotics and is potentially able to cause disorders by both device-related and nondevice-related infections. The nondevice-related bacterial biofilm infections include dental plaque, urinary tract infections, cystic fibrosis, otitis media, infective endocarditis, tonsillitis, periodontitis, necrotizing fasciitis, osteomyelitis, infectious kidney stones, and chronic inflammatory diseases. In this review, we will summarize and examine the literature about bacterial biofilm infections unrelated to indwelling devices.

Role of microRNAs in Staphylococcus aureus infection: Potential biomarkers and mechanism.

Staphylococcus aureus is known as a common pathogen that colonizes 30% of healthy humans. Additionally, this bacterium can cause a number of serious infections, that is, endocarditis, bacteremia, pneumonia, wound, skin infections, and tissue abscesses. A variety of cellular and molecular pathways and targets are involved in response against S. aureus. Among them, microRNAs (miRNAs) have crucial roles in response against S. aureus. In this regard, it has been shown that these molecules exert their regulatory roles via modulating a wide range of events, such as inflammatory reactions, host innate, and adaptive immunity. Current works have provided insight into the crucial involvement of miRNAs in immune defense toward Staphylococcal infections. Herein, we highlighted the current findings on the deregulation of different miRNAs in S. aureus-infected cells. Moreover, we summarized the mechanisms and targets of miRNAs in S. aureus infections.

Bacterial co-infections with SARS-CoV-2.

The pandemic coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has affected millions of people worldwide. To date, there are no proven effective therapies for this virus. Efforts made to develop antiviral strategies for the treatment of COVID-19 are underway. Respiratory viral infections, such as influenza, predispose patients to co-infections and these lead to increased disease severity and mortality. Numerous types of antibiotics such as azithromycin have been employed for the prevention and treatment of bacterial co-infection and secondary bacterial infections in patients with a viral respiratory infection (e.g., SARS-CoV-2). Although antibiotics do not directly affect SARS-CoV-2, viral respiratory infections often result in bacterial pneumonia. It is possible that some patients die from bacterial co-infection rather than virus itself. To date, a considerable number of bacterial strains have been resistant to various antibiotics such as azithromycin, and the overuse could render those or other antibiotics even less effective. Therefore, bacterial co-infection and secondary bacterial infection are considered critical risk factors for the severity and mortality rates of COVID-19. Also, the antibiotic-resistant as a result of overusing must be considered. In this review, we will summarize the bacterial co-infection and secondary bacterial infection in some featured respiratory viral infections, especially COVID-19.

The importance of intracellular bacterial biofilm in infectious diseases.

Various bacterial species, previously known as extracellular pathogens, can reside inside different host cells by adapting to intracellular modes by forming microbial aggregates with similar characteristics to bacterial biofilms. Additionally, bacterial invasion of human cells leads to failure in antibiotic therapy, as most conventional anti-bacterial agents cannot reach intracellular biofilm in normal concentrations. Various studies have shown that bacteria such as uropathogenic Escherichia coli, Pseudomonas aeruginosa, Borrelia burgdorferi,Moraxella catarrhalis, non-typeable Haemophilus influenzae, Streptococcus pneumonia, and group A Streptococci produce biofilm-like structures within the host cells. For the first time in this review, we will describe and discuss the new information about intracellular bacterial biofilm formation and its importance in bacterial infectious diseases.

Bacterial biofilm in colorectal cancer: What is the real mechanism of action?

Human colorectal cancer is the third most common cancer around the world. Colorectal cancer has various risk factors, but current works have bolded a significant activity for the microbiota of the human colon in the development of this disease. Bacterial biofilm has been mediated to non-malignant pathologies like inflammatory bowel disease but has not been fully documented in the setting of colorectal cancer. The investigation has currently found that bacterial biofilm is mediated to colon cancer in the human and linked to the location of human cancer, with almost all right-sided adenomas of colon cancers possessing bacterial biofilm, whilst left-sided cancer is rarely biofilm positive. The profound comprehension of the changes in colorectal cancer can provide interesting novel concepts for anticancer treatments. In this review, we will summarize and examine the new knowledge about the links between colorectal cancer and bacterial biofilm.