Search

Background Methods Results Conclusions Humans are subjected to various environmental stressors (bacteria, viruses, pollution) throughout life. As such, an inherent relationship exists between the effect of these exposures with age. The impact of these environmental stressors can manifest through DNA methylation (DNAm). However, whether these epigenetic effects selectively target genes, pathways, and biological regulatory mechanisms remains unclear. Due to the frequency of human rhinovirus (HRV) infections throughout life (particularly in early development), we propose the use of HRV under controlled conditions can model the effect of multiple exposures to environmental stressors.We generated a prediction model by combining transcriptome and DNAm datasets from human epithelial cells after repeated HRV infections. We applied a novel experimental statistical design and method to systematically explore the multifaceted experimental space (number of infections, multiplicity of infections and duration). Our model included 35 samples, each characterized by the three parameters defining their infection status.Trainable genes were defined by a consistent linear directionality in DNAm and gene expression changes with successive infections. We identified 77 trainable genes which could be further explored in future studies. The identified methylation sites were tracked within a pediatric cohort to determine the relative changes in candidate‐trained sites with disease status and age.Repeated viral infections induce an immune training response in bronchial epithelial cells. Training‐sensitive DNAm sites indicate alternate divergent associations in asthma compared to healthy individuals. Our novel model presents a robust tool for identifying trainable genes, providing a foundation for future studies. [ABSTRACT FROM AUTHOR]

Dysregulation and hyperactivation of innate immune responses can lead to the onset of systemic autoinflammatory diseases. Monogenic autoinflammatory diseases are caused by inborn genetic errors and based on molecular mechanisms at play, can be divided into inflammasomopathies, interferonopathies, relopathies, protein misfolding, and endogenous antagonist deficiencies. On the other hand, more common autoinflammatory diseases are multifactorial, with both genetic and non‐genetic factors playing an important role. During the last decade, long‐term memory characteristics of innate immune responses have been described (also called trained immunity) that in physiological conditions provide enhanced host protection from pathogenic re‐infection. However, if dysregulated, induction of trained immunity can become maladaptive, perpetuating chronic inflammatory activation. Here, we describe the mechanisms of genetic and epigenetic dysregulation of the innate immune system and maladaptive trained immunity that leads to the onset and perpetuation of the most common and recently described systemic autoinflammatory diseases. [ABSTRACT FROM AUTHOR]

Innate immune cells have been acknowledged as trainable in recent years. While intestinal tuft cells are recognized for their crucial roles in the host defense against intestinal pathogens, there remains uncertainty regarding their trainability. Enterovirus 71 (EV71), a prevalent enterovirus that primarily infects children but rarely infects adults. At present, there is a significant expansion of intestinal tuft cells in the EV71-infected mouse model, which is associated with EV71-induced interleukin-25 (IL-25) production. Further, we found that IL-25 pre-treatment at 2 weeks old mouse enabled tuft cells to acquire immune memory. This was evidenced by the rapid expansion and stronger response of IL-25-trained tuft cells in response to EV71 infection at 6 weeks old, surpassing the reactivity of naïve tuft cells in mice without IL-25-trained progress. Interestingly, IL-25-trained intestinal tuft cells exhibit anti-enteroviral effect via producing a higher level of IL-25. Mechanically, IL-25 treatment upregulates spermidine/spermine acetyl-transferase enzyme (SAT1) expression, mediates intracellular polyamine deficiency, further inhibits enterovirus replication. In summary, tuft cells can be trained by IL-25, which supports faster and higher level IL-25 production in response to EV71 infection and further exhibits anti-enteroviral effect via SAT1-mediated intracellular polyamine deficiency. Given that IL-25 can be induced by multiple gut microbes during human growth and development, including shifts in gut flora abundance, which may partially explain the different susceptibility to enteroviral infections between adults and children. Synopsis: Our present study implies that intestinal tuft cells can be trained by IL-25 and it may explain the different susceptibility in enteroviral infections between adults and children from an immune training perspective. EV71 mediated tuft cell expansion via promoting IL-25 production in EV71-infected mouse model. IL-25-trained tuft cells were quickly increased and displayed a stronger IL-25-SAT1 axis response and exhibited a more powerful antiviral effect as compared to naïve tuft cells. IL-25 supported the host defense via upregulating SAT1 expression, together with a lower polyamine level, which affected a broad enteroviral replication. Our present study implies that intestinal tuft cells can be trained by IL-25 and it may explain the different susceptibility in enteroviral infections between adults and children from an immune training perspective. [ABSTRACT FROM AUTHOR]

Problem: Preeclampsia (PE) and fetal growth restriction (FGR) are often associated with maternal inflammation and an increased risk of cardiovascular and metabolic disease in the affected mothers. The mechanism responsible for this increased risk of subsequent disease may involve reprogramming of innate immune cells, characterized by epigenetic modifications. Method of Study: Circulating monocytes from women with PE, FGR, or uncomplicated pregnancies (control) were isolated before labor. Cytokine release from monocytes following exposure to lipopolysaccharide (LPS) and the presence of lysine 4‐trimethylated histone 3 (H3K4me3) within TNF promoter sequences were evaluated. Single‐cell transcriptomic profiles of circulating monocytes from women with PE or uncomplicated pregnancies were assessed. Results: Monocytes from women with PE or FGR exhibited increased IL‐10 secretion and decreased IL‐1β and GM‐CSF secretion in response to LPS. While TNFα secretion was not significantly different in cultures of control monocytes versus those from complicated pregnancies with or without LPS exposure, monocytes from complicated pregnancies had significantly decreased levels of H3K4me3 associated with TNF promoter sequences. Cluster quantification and pathway analysis of differentially expressed genes revealed an increased proportion of anti‐inflammatory myeloid cells and a lower proportion of inflammatory non‐classical monocytes among the circulating monocyte population in women with PE. Conclusions: Monocytes from women with PE and FGR exhibit an immune tolerance phenotype before initiation of labor. Further investigation is required to determine whether this tolerogenic phenotype persists after the affected pregnancy and contributes to increased risk of subsequent disease. [ABSTRACT FROM AUTHOR]

Treatment for higher‐risk non‐muscle invasive bladder cancer (NMIBC) involves intravesical immunotherapy with Bacillus Calmette Guérin (BCG); however, disease recurrence and progression occur frequently. Systemic immunity is critical for successful cancer immunotherapy; thus, recurrence of NMIBC may be due to suboptimal systemic activation of anti‐tumor immunity after local immunotherapy. We previously reported that systemically acquired trained immunity (a form of innate immune memory) in circulating monocytes is associated with increased time‐to‐recurrence in patients with NMIBC treated with BCG. Herein, we used a mouse model of NMIBC to compare the effects of intravesical versus intravenous (systemic) BCG immunotherapy on the local and peripheral immune microenvironments. We also assessed whether BCG‐induced trained immunity modulates anti‐tumor immune responses. Compared with intravesical BCG, which led to a tumor‐promoting immune microenvironment, intravenous BCG resulted in an anti‐tumoral bladder microenvironment characterized by increased proportions of cytotoxic T lymphocytes (CTLs), and decreased proportions of myeloid‐derived suppressor cells. Polarization toward anti‐tumoral immunity occurred in draining lymph nodes, spleen, and bone marrow following intravenous versus intravesical BCG treatment. Pre‐treatment with intravesical BCG was associated with increased rate of tumor growth compared with intravenous BCG pre‐treatment. Trained immunity contributed to remodeling of the tumor immune microenvironment, as co‐instillation of BCG‐trained macrophages with ovalbumin‐expressing bladder tumor cells increased the proportion of tumor‐specific CTLs. Furthermore, BCG‐trained dendritic cells exhibited enhanced antigen uptake and presentation and promoted CTL proliferation. Our data support the concept that systemic immune activation promotes anti‐tumor responses, and that BCG‐induced trained immunity is important in driving anti‐tumor adaptive immunity. [ABSTRACT FROM AUTHOR]

Disseminated fungal infections account for ~1.5 million deaths per year worldwide, and mortality may increase further due to a rise in the number of immunocompromised individuals and drug-resistance fungal species. Since an approved antifungal vaccine is yet to be available, this study explored the immunogenicity and vaccine efficacy of a DNA polymerase mutant strain of Candida albicans. CNA25 is a pol32ΔΔ strain that exhibits growth defects and does not cause systemic candidiasis in mice. Immunized mice with live CNA25 were fully protected against C. albicans and C. parapsilosis but partially against C. tropicalis and C. glabrata infections. CNA25 induced steady expression of TLR2 and Dectin-1 receptors leading to a faster recognition and clearance by the immune system associated with the activation of protective immune responses mostly mediated by neutrophils, macrophages, NK cells, B cells, and CD4+ and CD8+ T cells. Molecular blockade of Dectin-1, IL-17, IFNγ, and TNFα abolished resistance to reinfection. Altogether, this study suggested that CNA25 collectively activates innate, adaptive, and trained immunity to be a promising live whole-cell vaccine against systemic candidiasis. Synopsis: CNA25 is a DNA polymerase subunit knockout strain of pathogenic yeast Candida albicans. Immunization with live CNA25 prevents systemic candidiasis in mice. It is recognised by innate immune cells leading to its clearance. Activation of CD4+ and CD8 + T cells in vaccinated mice prevents fungal reinfection. Trained innate cells are also involved in protective immune responses. CNA25 is a DNA polymerase subunit knockout strain of pathogenic yeast Candida albicans. Immunization with live CNA25 prevents systemic candidiasis in mice. [ABSTRACT FROM AUTHOR]

This article explores the concept of "trained immunity" in bone-marrow-derived macrophages and its role in the development of type 1 diabetes. The study focuses on macrophages from nonobese diabetic (NOD) mice and finds that they exhibit characteristics of trained immunity, such as increased histone methylation, glycolysis, and proinflammatory cytokine production. The authors suggest that previous infections or changes in gut microbiota may train myeloid cells in the bone marrow, leading to an amplified proinflammatory response and the initiation of autoimmunity in type 1 diabetes. The article also discusses the potential therapeutic effects of a peptide called FhHDM-1, secreted by the parasitic worm Fasciola hepatica, in preventing type 1 diabetes in mice. Administering FhHDM-1 to mice resulted in a reduction in histone methylation, a shift in macrophage metabolism, and a decrease in proinflammatory responses. These findings suggest that FhHDM-1 may alter the epigenetic imprint of macrophages, regulating immune responses and potentially preventing type 1 diabetes and other autoimmune/inflammatory disorders. [Extracted from the article]

Summary: Innate immune memory endows innate immune cells with antigen independent heightened responsiveness to subsequent challenges. The durability of this response can be mediated by inflammation induced epigenetic and metabolic reprogramming in hematopoietic stem and progenitor cells (HSPCs) that are maintained through differentiation to mature immune progeny. Understanding the mechanisms and extent of trained immunity induction by pathogens and vaccines, such as BCG, in HSPC remains a critical area of exploration with important implications for health and disease. Here we review these concepts and present new analysis to highlight how inflammatory reprogramming of HSPC can potently alter immune tone, including to enhance specific anti‐tumor responses. New findings in the field pave the way for novel HSPC targeting therapeutic strategies in cancer and other contexts of immune modulation. Future studies are expected to unravel diverse and extensive effects of infections, vaccines, microbiota, and sterile inflammation on hematopoietic progenitor cells and begin to illuminate the broad spectrum of immunologic tuning that can be established through altering HSPC phenotypes. The purpose of this review is to draw attention to emerging and speculative topics in this field where we posit that focused study of HSPC in the framework of trained immunity holds significant promise. [ABSTRACT FROM AUTHOR]

Summary: Conventionally, it was thought that innate immunity operated through a simple system of nonspecific responses to an insult. However, this perspective now seems overly simplistic. It has become evident that intricate cooperation and networking among various cells, receptors, signaling pathways, and protein complexes are essential for regulating and defining the overall activation status of the immune response, where the distinction between innate and adaptive immunity becomes ambiguous. Given the evolutionary timeline of vertebrates and the success of plants and invertebrates which depend solely on innate immunity, immune memory cannot be considered an innovation of only the lymphoid lineage. Indeed, the evolutionary innate immune memory program is a conserved mechanism whereby innate immune cells can induce a heightened response to a secondary stimulus due to metabolic and epigenetic reprogramming. Importantly, the longevity of this memory phenotype can be attributed to the reprogramming of self‐renewing hematopoietic stem cells (HSCs) in the bone marrow, which is subsequently transmitted to lineage‐committed innate immune cells. HSCs reside within a complex regulated network of immune and stromal cells that govern their two primary functions: self‐renewal and differentiation. In this review, we delve into the emerging cellular and molecular mechanisms as well as metabolic pathways of innate memory in HSCs, which harbor substantial therapeutic promise. [ABSTRACT FROM AUTHOR]

This study investigates Bacillus Calmette‐Guérin (BCG) as a potential treatment for hepatocellular carcinoma (HCC), a condition often associated with unfavorable treatment outcomes. Exploiting BCG's recognized immune‐boosting properties, preclinical trials are conducted using HCC mice, with a single subcutaneous dose of BCG administered post‐tumor formation. Results indicate that BCG treatment effectively diminishes tumor burden and extends survival in both male and female HCC mice. Positive influences on hepatic fibrosis and metabolism are observed, leading to a reduction in lipid levels. Spatial analysis underscores BCG's tumor‐specific effects, inducing the enrichment of metabolic pathways and inhibiting various cancer‐related pathways. Furthermore, BCG promotes immune cell infiltration, including CD4+, CD8+ T cells, and M1 macrophages, in both v‐akt murine thymoma viral oncogene homolog 1(AKT)/neutoblastoma RAS viral oncogene homolog (RAS) and β‐catenin positive HCC models. Interestingly, blocking T cells, trained immunity, and Interferon‐γ (IFN‐γ) function reverses BCG's anti‐HCC effects. In conclusion, BCG emerges as a promising treatment option for HCC, characterized by a favorable safety profile and efficacy in inhibiting fibrosis, improving metabolism, and engaging both trained immunity and T cells in therapeutic mechanisms. [ABSTRACT FROM AUTHOR]

Innate immune training involves myelopoiesis, dynamic gene modulation, and functional reprogramming of myeloid cells in response to secondary heterologous challenges. The present study evaluates whether systemic innate immune training can protect tissues from local injury. Systemic pretreatment of mice with β‐glucan, a trained immunity agonist, reduces the mortality rate of mice with bleomycin‐induced lung injury and fibrosis, as well as decreasing collagen deposition in the lungs. β‐Glucan pretreatment induces neutrophil accumulation in the lungs and enhances efferocytosis. Training of mice with β‐glucan results in histone modification in both alveolar macrophages (AMs) and neighboring lung epithelial cells. Training also increases the production of RvD1 and soluble mediators by AMs and efferocytes. Efferocytosis increases trained immunity in AMs by stimulating RvD1 release, thus inducing SIRT1 expression in neighboring lung epithelial cells. Elevated epithelial SIRT1 expression is associated with decreased epithelial cell apoptosis after lung injury, attenuating tissue damage. Further, neutrophil depletion dampens the effects of β‐glucan on macrophage accumulation, epigenetic modification in lung macrophages, epithelial SIRT1 expression, and injury‐mediated fibrosis in the lung. These findings provide mechanistic insights into innate immune training and clues to the potential ability of centrally trained immunity to protect peripheral organs against injury‐mediated disorders. [ABSTRACT FROM AUTHOR]

Trained immunity defines the long‐term memory of innate immunity based on innate immune signalling, metabolic changes and epigenetic rewiring of trained innate immune cells, which are characterised by elevated inflammatory responses towards secondary stimuli. The activation of this non‐specific protection‐mediated memory in innate immune cells was identified to benefit host defences as well as play a detrimental role in inflammatory diseases. In this review, we focused on summing up the current progress about the inducers, effector cells, molecular mechanisms and protective effects of trained immunity that have been identified in both mammals and teleost fish, and discussing the future research and application of trained immunity in aquaculture. Revealing the mechanisms of trained immunity will not only provide a novel aspect for understanding the evolution of innate immune memory and their longer‐term protections, but also contribute to the rational design and evaluation of immunopotentiators, adjuvants and potential vaccines in aquaculture. [ABSTRACT FROM AUTHOR]

Cervical cancer is caused mostly by human papillomavirus (HPV), and several HPV vaccines have been developed to prevent its onset. Vaccines include antigens as well as adjuvants, with adjuvants playing an important role in activating the innate immune responses necessary for inducing adaptive immunological responses. Recent research has shown the presence of trained immunity inside the innate immune system. However, trained immunity conferred by HPV vaccinations is not well understood. In this work, we explored the innate immune responses and trained immunity caused by two HPV vaccines, Cervarix and Gardasil. Cervarix includes monophosphoryl lipid A and an aluminum adjuvant, and it significantly increased the expression of IL‐6 and IFN‐β mRNAs in RAW264.7 cells. On the contrary, Gardasil, which only includes an aluminum adjuvant, exhibited little cytokine expression but increased the expression of TLRs. Furthermore, Cervarix significantly increased IL‐1β secretion from mouse macrophages, while Gardasil only mildly induced IL‐1β secretion. Interestingly, initial stimulation with Gardasil enhanced the expression of IL‐6 and TNF‐α mRNAs upon secondary stimulation with TLR ligands, indicating that Gardasil induced trained immunity in macrophages. Moreover, Gardasil injection into mice resulted in enhanced TNF‐α production in sera following secondary TLR stimulation. Our findings suggest that HPV vaccinations have the ability to induce trained immunity that modulate TLR ligand responses. [ABSTRACT FROM AUTHOR]

Cancer vaccines hold great potential for clinical cancer treatment by eliciting T cell‐mediated immunity. However, the limited numbers of antigen‐presenting cells (APCs) at the injection sites, the insufficient tumor antigen phagocytosis by APCs, and the presence of a strong tumor immunosuppressive microenvironment severely compromise the efficacy of cancer vaccines. Trained innate immunity may promote tumor antigen‐specific adaptive immunity. Here, a personalized cancer vaccine is developed by engineering the inactivated probiotic Escherichia coli Nissle 1917 to load tumor antigens and β‐glucan, a trained immunity inducer. After subcutaneous injection, the cancer vaccine delivering model antigen OVA (BG/OVA@EcN) is highly accumulated and phagocytosed by macrophages at the injection sites to induce trained immunity. The trained macrophages may recruit dendritic cells (DCs) to facilitate BG/OVA@EcN phagocytosis and the subsequent DC maturation and T cell activation. In addition, BG/OVA@EcN remarkably enhances the circulating trained monocytes/macrophages, promoting differentiation into M1‐like macrophages in tumor tissues. BG/OVA@EcN generates strong prophylactic and therapeutic efficacy to inhibit tumor growth by inducing potent adaptive antitumor immunity and long‐term immune memory. Importantly, the cancer vaccine delivering autologous tumor antigens efficiently prevents postoperative tumor recurrence. This platform offers a facile translatable strategy to efficiently integrate trained immunity and adaptive immunity for personalized cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Fungal skin infections are distributed worldwide and can be associated with economic and social traits. The immune response related to skin cells is complex and its understanding is essential to the comprehension of each cell's role and the discovery of treatment alternatives. The first studies of trained immunity (TI) described the ability of monocytes, macrophages and natural killer (NK) cells to develop a memory‐like response. However, the duration of TI does not reflect the shorter lifespan of these cells. These conclusions supported later studies showing that TI can be observed in stem and haematopoietic cells and, more recently, also in non‐immune skin cells such as fibroblasts, highlighting the importance of resident cells in response to skin disorders. Besides, the participation of less studied proinflammatory cytokines in the skin immune response, such as IL‐36γ, shed light into a new possibility of inflammatory pathway blockade by drugs. In this review, we will discuss the skin immune response associated with fungal infections, the role of TI in skin and clinical evidence supporting opportunities and challenges of TI and other inflammatory responses in the pathogenesis of fungal skin infections. [ABSTRACT FROM AUTHOR]

On the basis of the mechanisms of action and characteristics of immune effects, immunity is commonly categorized into innate and adaptive immunity. Adaptive immunity is associated with the response to non‐self‐entities and is characterized by high specificity and memory properties. In contrast, innate immunity has traditionally been considered devoid of memory characteristics. However, an increasing number of studies have sought to challenge this conventional immunological dogma and shown that innate immune cells exhibit a more robust and rapid response to secondary stimulation, thus providing evidence of the immunological memory in innate immunity. Macrophages, which are among the most important innate immune cells, can also acquire memory phenotype that facilitates the mediation of recall responses. Macrophage memory is a relatively new concept that is revolutionizing our understanding of macrophage biology and immunological memory and could lead to a new class of vaccines and immunotherapies. In this review, we describe the characteristics and mechanisms of macrophage memory, as well as its essential roles in various diseases. [ABSTRACT FROM AUTHOR]

Epidemic peaks of respiratory viruses that co‐circulate during the winter‐spring seasons can be synchronous or asynchronous. The occurrence of temporal patterns in epidemics caused by some respiratory viruses suggests that they could negatively interact with each other. These negative interactions may result from a programme of innate immune memory, known as trained immunity, which may confer broad protective effects against respiratory viruses. It is suggested that stimulation of innate immune cells by a vaccine or a pathogen could induce their long‐term functional reprogramming through an interplay between metabolic and epigenetic changes, which influence the transcriptional response to a secondary challenge. During the coronavirus disease 2019 pandemic, the circulation of most respiratory viruses was prevented by non‐pharmacological interventions and then resumed at unusual periods once sanitary measures were lifted. With time, respiratory viruses should find again their own ecological niches. This transition period provides an opportunity to study the interactions between respiratory viruses at the population level. [ABSTRACT FROM AUTHOR]

A high‐salt diet (HSD) elicits sustained sterile inflammation and worsens tissue injury. However, how this occurs after stroke, a leading cause of morbidity and mortality, remains unknown. Here, we report that HSD impairs long‐term brain recovery after intracerebral hemorrhage, a severe form of stroke, despite salt withdrawal prior to the injury. Mechanistically, HSD induces innate immune priming and training in hematopoietic stem and progenitor cells (HSPCs) by downregulation of NR4a family and mitochondrial oxidative phosphorylation. This training compromises alternative activation of monocyte‐derived macrophages (MDMs) without altering the initial inflammatory responses of the stroke brain. Healthy mice transplanted with bone marrow from HSD‐fed mice retain signatures of reduced MDM reparative functions, further confirming a persistent form of innate immune memory that originates in the bone marrow. Loss of NR4a1 in macrophages recapitulates HSD‐induced negative impacts on stroke outcomes while gain of NR4a1 enables stroke recovery in HSD animals. Together, we provide the first evidence that links HSD‐induced innate immune memory to the acquisition of persistent dysregulated inflammatory responses and unveils NR4a1 as a potential therapeutic target. Synopsis: High‐salt intake induces trained immunity through metabolic reprogramming and downregulation of NR4a nuclear receptors. Trained monocyte‐derived macrophages reduce reparative activities in the stroke brain, and consequently, hematoma clearance, brain repair, and functional recovery are impaired.Excessive dietary salt intake impedes long‐term stroke recovery even after high‐salt withdrawal prior to injury.High‐salt intake triggers immunological priming and training of bone marrow progenitor cells.The trained property is retained, which leads to diminished reparative macrophage polarization in the stroke brain.Pharmacological activation of NR4a1 by celastrol treatment rescues the adverse effects induced by high‐salt diet. [ABSTRACT FROM AUTHOR]

HIV-associated neurocognitive disorders (HAND) is a term describing a complex set of cognitive impairments accompanying HIV infection. Successful antiretroviral therapy (ART) reduces the most severe forms of HAND, but milder forms affect over 50% of people living with HIV (PLWH). Pathogenesis of HAND in the ART era remains unknown. A variety of pathogenic factors, such as persistent HIV replication in the brain reservoir, HIV proteins released from infected brain cells, HIV-induced neuroinflammation, and some components of ART, have been implicated in driving HAND pathogenesis in ART-treated individuals. Here, we propose another factor--impairment of cholesterol homeostasis and lipid rafts by HIV-1 protein Nef--as a possible contributor to HAND pathogenesis. These effects of Nef on cholesterol may also underlie the effects of other pathogenic factors that constitute the multifactorial nature of HAND pathogenesis. The proposed Nef- and cholesterol-focused mechanism may provide a long-sought unified explanation of HAND pathogenesis that takes into account all contributing factors. Evidence for the impairment by Nef of cellular cholesterol balance, potential effects of this impairment on brain cells, and opportunities to therapeutically target this element of HAND pathogenesis are discussed. [ABSTRACT FROM AUTHOR]

This article discusses recent research that challenges the traditional understanding of the immune system, which categorizes it into two components: innate and adaptive immunity. While the innate immune system is typically described as rapid and non-specific, and the adaptive immune system as delayed but specific and possessing memory, recent studies have shown that certain innate immune cells can exhibit features of adaptive immunity, including immunological memory. The article explores the specific cellular and molecular mechanisms underlying innate immune memory, focusing on natural killer cells, myeloid cells, innate lymphoid cells, and innate T cells. The authors suggest that this new understanding of innate immune memory may have implications for vaccine strategies and the assessment of long-lived immune responses. [Extracted from the article]

Some metabolic diseases, such as diabetes and hyperlipidemia, are associated with a state of inflammation, which adversely affects cardiovascular health. Emerging evidence suggests that long‐term hyperactivation of innate immune cells and their bone marrow progenitors, termed trained immunity, functions to accelerate atherosclerosis and its complications in cardiometabolic diseases. This review will focus on how trained immunity is established, particularly through metabolic and epigenetic reprogramming, to cause persistent and deleterious changes in immune cell function, even after the original stimulus has been corrected or removed. Understanding the mechanisms driving maladaptive trained immunity and its fundamental contribution to cardiovascular disease might enable the development of novel disease‐modifying therapeutics for the reduction in cardiovascular risk in diabetes, hyperlipidemia, and related cardiometabolic states. [ABSTRACT FROM AUTHOR]

Periodontitis is a chronic, inflammatory, and destructive disease caused by the imbalance of host immune response and dental biofilm, and has strong epidemiological and pathogenesis correlations with systemic diseases. The immune response in periodontitis involves both innate and adaptive immunity, with numerous immune cells and inflammatory pathways participating in a complex network of interactions. In the past decade, the concept of "trained immunity" has emerged, which highlights the memory characteristics of innate immunity, thus opening up a new avenue of research. There is growing interest in exploring the role of trained immunity in chronic inflammatory and metabolic diseases such as atherosclerosis and diabetes mellitus. Evidence suggests that trained immunity may also regulate the onset and progression of periodontitis, serving as a bridge between periodontitis‐related comorbidities. In this review, we summarize concepts related to trained immunity and its development. Furthermore, we present current evidence that endorses the notion of trained immunity in periodontitis and analyze possible roles it may assume regarding periodontitis‐associated inflammatory reactions from a cellular perspective. Finally, we discuss various clinical therapeutic strategies for periodontitis and its associated comorbidities that target trained immunity. We hope that more researchers will pay attention to this emerging concept, thereby providing deeper insights into this novel field. [ABSTRACT FROM AUTHOR]

Vitiligo is caused by an autoimmune reaction against melanocytes leading to melanocyte loss. The cause of vitiligo is an interaction between genetic susceptibility and environmental factors. Both the adaptive immune system—through cytotoxic CD8+ T cells and melanocyte specific antibodies—and the innate immune system are involved in these immune processes in vitiligo. While recent data stressed the importance of innate immunity in vitiligo, the question remains why vitiligo patients' immune response becomes overly activated. Could a long‐term increase in innate memory function, described as trained immunity after vaccination and in other inflammatory diseases, play a role as an enhancer and continuous trigger in the pathogenesis of vitiligo? After exposure to certain stimuli, innate immune system is able to show an enhanced immunological response to a secondary trigger, indicating a memory function of the innate immune system, a concept termed trained immunity. Trained immunity is regulated by epigenetic reprogramming, including histone chemical modifications and changes in chromatin accessibility that cause sustained changes in the transcription of specific genes. In responses to an infection, trained immunity is beneficial. However, there are indications of a pathogenic role of trained immunity in inflammatory and autoimmune diseases, with monocytes presenting features of a trained phenotype, resulting in increased cytokine production, altered cell metabolism through mTOR signaling, and epigenetic modifications. This hypothesis paper focusses on vitiligo studies that have shown these indications, suggesting the involvement of trained immunity in vitiligo. Future studies focusing on metabolic and epigenetic changes in innate immune cell populations in vitiligo could help in elucidating the potential role of trained immunity in vitiligo pathogenesis. [ABSTRACT FROM AUTHOR]

This article discusses the roles of innate and adaptive immunity in providing protection against COVID-19 through inactivated viral vaccines. The emergence of the Omicron variant has raised concerns about immune evasion and the effectiveness of existing vaccination strategies. Studies have shown that administering a third dose of an mRNA or inactivated vaccine can reduce the severity of symptoms and mortality. The research highlights the importance of adaptive immunity, particularly CD4+ T-cell memory pools, in responding to SARS-CoV-2 infections. Additionally, the article explores the role of innate immunity, including monocytes, dendritic cells, and natural killer cells, in the initial defense against viral infections. The study also suggests that inactivated vaccines can induce "trained immunity" in myeloid cells, enhancing their functionality and antiviral response. Overall, this research provides valuable insights into the immunomodulatory effects of inactivated virus vaccines and can inform future vaccine development and immunization strategies. [Extracted from the article]

In the past decade, the concept of immunological memory, which has long been considered a phenomenon observed in the adaptive immunity of vertebrates, has been extended to the innate immune system of various organisms. This de novo immunological memory is mainly called "innate immune memory", "immune priming", or "trained immunity" and has received increased attention because of its potential for clinical and agricultural applications. However, research on different species, especially invertebrates and vertebrates, has caused controversy regarding this concept. Here we discuss the current studies focusing on this immunological memory and summarize several mechanisms underlying it. We propose "innate immune memory" as a multidimensional concept as an integration between the seemingly different immunological phenomena. [ABSTRACT FROM AUTHOR]

Exposure of human cells to interferon‐γ (IFNγ) results in a mitotically heritable yet reversible state called long‐term transcriptional memory. We previously identified the clustered GBP genes as strongly primed by IFNγ. Here, we discovered that in primed cells, both interferon‐responsive transcription factors STAT1 and IRF1 target chromatin with accelerated kinetics upon re‐exposure to IFNγ, specifically at promotors of primed genes. Priming does not alter the degree of IFNγ‐induced STAT1 activation or nuclear import, indicating that memory does not alter upstream JAK–STAT signaling. We found STAT1 to be critical to establish transcriptional memory but in a manner that is independent of mere transcription activation. Interestingly, while Serine 727 phosphorylation of STAT1 was maintained during the primed state, STAT1 is not required for the heritability of GBP gene memory. Our results suggest that the memory of interferon exposure constitutes a STAT1‐mediated, heritable state that is established during priming. This renders GBP genes poised for subsequent STAT1 and IRF1 binding and accelerated gene activation upon a secondary interferon exposure. Synopsis: Gene activation by interferon‐γ results in mitotically heritable priming of clustered GBP genes. This study shows target gene transcription is not sufficient to induce memory but relies on STAT1‐dependent gene activation. Once primed, memory is maintained in the absence of STAT1 function. Transcription of memorized GBP genes is not sufficient to induce the primed state.Interferon‐gamma induction results in accelerated STAT1 and IRF1 recruitment in primed cells.STAT1 is essential to establish the primed state but dispensable for the memory of interferon‐γ exposure.Priming does not alter the rate of JAK–STAT signaling upon reencounter of interferon‐γ.STAT1 S727 phosphorylation is maintained during the primed state and has a role in memory. [ABSTRACT FROM AUTHOR]

Teleost fish are indispensable model organisms for comparative immunology research that should lead to an improved understanding of the general principles of vertebrate immune system design. Although numerous studies on fish immunology have been conducted, knowledge about the cell types that orchestrate piscine immune systems remains limited. Here, we generated a comprehensive atlas of immune cell types in zebrafish spleen on the basis of single‐cell transcriptome profiling. We identified 11 major categories from splenic leukocyte preparations, including neutrophils, natural killer cells, macrophages/myeloid cells, T cells, B cells, hematopoietic stem and progenitor cells, mast cells, remnants of endothelial cells, erythroid cells, erythroid progenitors, and a new type of serpin‐secreting cells. Notably, we derived 54 potential subsets from these 11 categories. These subsets showed differential responses to spring viremia of carp virus (SVCV) infection, implying that they have diverse roles in antiviral immunity. Additionally, we landscaped the populations with the induced expression of interferons and other virus‐responsive genes. We found that trained immunity can be effectively induced in the neutrophil and M1‐macrophage subsets by vaccinating zebrafish with inactivated SVCV. Our findings illustrated the complexity and heterogeneity of the fish immune system, which will help establish a new paradigm for the improved understanding of fish immunology. [ABSTRACT FROM AUTHOR]

The immune system of vertebrates includes innate immunity and adaptive immunity, and the network between them enables the host to fight against invasions of various pathogens. Recently, studies discovered that immune memory is one of the features of innate immunity, breaking the previous opinion that immune memory exists only in adaptive immunity. Immune memory supports innate immune cells to respond efficiently upon reinfection or restimulation. During the Plasmodium infection, the innate immune system is the first to be triggered, and innate immune cells are activated by components from Plasmodium or Plasmodium‐infected red blood cells. Innate immune cells could be induced to develop memory after the activation and may play an important role in the subsequent infection of Plasmodium or other pathogens and stimulation. This review will discuss the recent findings relevant to trained immunity and Plasmodium infection, facilitating the understanding of the role of trained immunity in malaria and other diseases and the development of therapeutic strategies based on trained immunity. [ABSTRACT FROM AUTHOR]

DNA methylation comprises a cumulative record of lifetime exposures superimposed on genetically determined markers. Little is known about methylation dynamics in humans following an acute perturbation, such as infection. We characterized the temporal trajectory of blood epigenetic remodeling in 133 participants in a prospective study of young adults before, during, and after asymptomatic and mildly symptomatic SARS‐CoV‐2 infection. The differential methylation caused by asymptomatic or mildly symptomatic infections was indistinguishable. While differential gene expression largely returned to baseline levels after the virus became undetectable, some differentially methylated sites persisted for months of follow‐up, with a pattern resembling autoimmune or inflammatory disease. We leveraged these responses to construct methylation‐based machine learning models that distinguished samples from pre‐, during‐, and postinfection time periods, and quantitatively predicted the time since infection. The clinical trajectory in the young adults and in a diverse cohort with more severe outcomes was predicted by the similarity of methylation before or early after SARS‐CoV‐2 infection to the model‐defined postinfection state. Unlike the phenomenon of trained immunity, the postacute SARS‐CoV‐2 epigenetic landscape we identify is antiprotective. Synopsis: Characterization of the temporal dynamics of blood methylation changes in young adults following asymptomatic and mild SARS‐CoV‐2 infection brings insights into the long‐term memory of environmental exposure and potential disease associations.Both symptomatic and asymptomatic infections induce methylation changes that are not always associated with gene expression changes.Methylation changes persist for longer than gene expression changes.The complex dynamics of methylation alterations can be used to predict the timing of infection.Contrary to the trained immunity phenomenon, the presence of a post‐infection‐like methylation state at baseline is anti‐protective for subsequent SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]

Cryptococcosis is a mycosis caused by Cryptococcus neoformans and C. gattii species complexes. Although this infection is potentially lethal, no prophylactic vaccine is yet commercially available, and the immune memory that enables prevention is still under investigation. These pathogens have a capsule layer for immune evasion and a sophisticated mechanism to advance the infection, and it is expected that these characteristics will make it difficult to develop prophylactic vaccines and to decipher the protective immunity. The current vaccine studies are focused on subunit, mRNA, DNA, and viral vector vaccines, with whole‐cell vaccines also proving successful against cryptococcal infections. Cryptococcal whole‐cell vaccines have been composed of highly immunostimulating strains with low‐pathogenicity that are modified by genetic recombination technology. Examples include the whole‐cell vaccines H99γ, sgl1∆, fbp1∆, znf2oe, cda1/2/3∆, cap59∆, and cap60∆. Some of these whole‐cell vaccines were found to be highly effective in prolonging life and suppressing the fungal burden after an infection challenge in mice, and to be cross‐reactive to C. neoformans, C. gattii, and other fungal pathogens. Furthermore, for some vaccines, the protective effect can be retained even in an immunocompromised host depleted of CD4+ T cells. These findings have provided new insights into protective immunity that should aid in vaccine development. In this review, we highlight the upsides and downsides of whole‐cell vaccines against cryptococcosis. [ABSTRACT FROM AUTHOR]

Summary: The principle of trained immunity represents innate immune memory due to sustained, mainly epigenetic, changes triggered by endogenous or exogenous stimuli in bone marrow (BM) progenitors (central trained immunity) and their innate immune cell progeny, thereby triggering elevated responsiveness against secondary stimuli. BM progenitors can respond to microbial and sterile signals, thereby possibly acquiring trained immunity‐mediated long‐lasting alterations that may shape the fate and function of their progeny, for example, neutrophils. Neutrophils, the most abundant innate immune cell population, are produced in the BM from committed progenitor cells in a process designated granulopoiesis. Neutrophils are the first responders against infectious or inflammatory challenges and have versatile functions in immunity. Together with other innate immune cells, neutrophils are effectors of peripheral trained immunity. However, given the short lifetime of neutrophils, their ability to acquire immunological memory may lie in the central training of their BM progenitors resulting in generation of reprogrammed, that is, "trained", neutrophils. Although trained immunity may have beneficial effects in infection or cancer, it may also mediate detrimental outcomes in chronic inflammation. Here, we review the emerging research area of trained immunity with a particular emphasis on the role of neutrophils and granulopoiesis. [ABSTRACT FROM AUTHOR]

Summary: Neutrophils are a critical element of host defense and are rapidly recruited to inflammatory sites. Such sites are frequently limited in oxygen and/or nutrient availability, presenting a metabolic challenge for infiltrating cells. Long believed to be uniquely dependent on glycolysis, it is now clear that neutrophils possess far greater metabolic plasticity than previously thought, with the capacity to generate energy stores and utilize extracellular proteins to fuel central carbon metabolism and biosynthetic activity. Out‐with cellular energetics, metabolic programs have also been implicated in the production of neutrophils and their progenitors in the bone marrow compartment, activation of neutrophil antimicrobial responses, inflammatory and cell survival signaling cascades, and training of the innate immune response. Thus, understanding the mechanisms by which metabolic processes sustain changes in neutrophil effector functions and how these are subverted in disease states provides exciting new avenues for the treatment of dysfunctional neutrophilic inflammation which are lacking in clinical practice to date. [ABSTRACT FROM AUTHOR]

Innate immune cells experience long lasting metabolic and epigenetic changes after an encounter with specific stimuli. This facilitates enhanced immune responses upon secondary exposition to both the same and unrelated pathogens, a process termed trained immunity. Trained immunity‐based vaccines (TIbV) are vaccines able to induce innate immune memory, thus conferring heterologous protection against a broad range of pathogens. While trained immunity has been well documented in the context of infections and multiple immune‐mediated diseases, the role of innate immune memory and its contribution to the initiation and maintenance of chronic allergic diseases remains poorly understood. Over the last years, different studies attempting to uncover the role of trained immunity in allergy have emerged. Exposition to environmental factors impacting allergy development such as allergens or viruses induces the reprogramming of innate immune cells to acquire a more pro‐inflammatory phenotype in the context of asthma or food allergy. Several studies have convincingly demonstrated that prevention of viral infections using TIbV contributes to reduce wheezing attacks in children, which represent a high‐risk factor for asthma development later in life. Innate immune cells trained with specific stimuli might also acquire anti‐inflammatory features and promote tolerance, which may have important implications for chronic inflammatory diseases such as allergies. Recent findings showed that allergoid‐mannan conjugates, which are next generation vaccines for allergen‐specific immunotherapy (AIT), are able to reprogram monocytes into tolerogenic dendritic cells by mechanisms depending on metabolic and epigenetic rewiring. A better understanding of the underlying mechanisms of trained immunity in allergy will pave the way for the design of novel trained immunity‐based allergen vaccines as potential alternative strategies for the prevention and treatment of allergic diseases. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is characterized by chronic skeletal muscle necrosis, leading to muscle regeneration failure and fibrosis. Although macrophages (MPs) are normally essential for muscle regeneration, dysregulated MP function promotes pathological muscle remodelling. Infiltrating MPs can be predominantly pro-inflammatory (M1 biased), anti-inflammatory (M2 biased) or of a mixed phenotype and can originate from the adult bone marrow (monocyte dependent) or embryonic precursors (monocyte independent). In mdx mice (genetic model of DMD) lacking either Toll-like receptor (Tlr) 2 or Tlr4, it is found that MP infiltration of dystrophic muscle is significantly reduced and that the MP phenotype is shifted toward a more anti-inflammatory profile. This is accompanied by significant improvements in muscle histology and force production. Lack of the chemokine receptor CCR2, which impedes monocyte release from the bone marrow, leads to similar beneficial effects in mdx mice. Evidence was also found for Tlr4-regulated induction of trained innate immunity in MPs cultured from the bone marrow of mdx mice before their entry into the muscle. These MPs exhibit epigenetic and metabolic alterations, accompanied by non-specific hyper-responsiveness to multiple stimuli, which is manifested by potentiated upregulation of both pro- and anti-inflammatory genes. In summary, exaggerated recruitment of monocyte-derived MPs and signs of trained innate immunity at the level of the bone marrow are features of the immunophenotype associated with dystrophic muscle disease. These phenomena are regulated by Toll-like receptors that bind endogenous damage-associated molecular pattern (DAMP) molecules, suggesting that DAMP release from dystrophic muscles modulates MP plasticity at the bone marrow level through Toll-like receptor-driven mechanisms. [ABSTRACT FROM AUTHOR]

Background: Infectious disease has a significant impact on livestock production. Availability of alternatives to antibiotics to prevent and treat disease is required to reduce reliance on antibiotics while not impacting animal welfare. Innate immune stimulants, such as mycobacterium cell wall fractions (MCWF), are used as alternatives to antibiotics for the treatment and prevention of infectious disease in a number of species including cattle, horses and dogs. This study aimed to evaluate the safety of Amplimune®, an MCWF‐based immune stimulant, for weaner Angus cattle. Methods: On day −1 and 0, sixty mixed‐sex Angus weaner cattle were transported for 6 h before being inducted and housed in a large single pen, simulating feedlot induction conditions. The cattle were assigned to one of six treatment groups (n = 10 per group): 2 mL Amplimune intramuscularly (2IM); 2 mL Amplimune subcutaneously (2SC); 5 mL Amplimune intramuscularly (5IM); 5 mL Amplimune subcutaneously (5SC); 5 mL saline intramuscularly (SalIM) and 5 mL saline subcutaneously (SalSC) on day 0 following transportation. Body temperature, body weight, concentrations of circulating pro‐inflammatory cytokines (TNFα, IL‐1β, IL‐6 and IL‐12) and haematology parameters were measured at various times up to 96 h post‐treatment. Results: No adverse effects from Amplimune treatment were observed. Amplimune induced an increase in circulating cytokine TNFα concentrations, total white blood cell count and lymphocyte counts indicative of activation of the innate immune system without causing an excessive inflammatory response. Conclusions: Results confirm that Amplimune can be safely administered to beef cattle at the dose rates and via the routes of administration investigated here. [ABSTRACT FROM AUTHOR]

Periodontitis is bidirectionally associated with systemic inflammatory disorders. The prevalence and severity of this oral disease and linked comorbidities increases with aging. Here, we review two newly emerged concepts, trained innate immunity (TII) and clonal hematopoiesis of indeterminate potential (CHIP), which together support a potential hypothesis on how periodontitis affects and is affected by comorbidities and why the susceptibility to periodontitis and comorbidities increases with aging. Given that chronic diseases are largely triggered by the action of inflammatory immune cells, modulation of their bone marrow precursors, the hematopoietic stem and progenitor cells (HSPCs), may affect multiple disorders that emerge as comorbidities. Such alterations in HSPCs can be mediated by TII and/or CHIP, two non-mutually exclusive processes sharing a bias for enhanced myelopoiesis and production of innate immune cells with heightened proinflammatory potential. TII is a state of elevated immune responsiveness based on innate immune (epigenetic) memory. Systemic inflammation can initiate TII in the bone marrow via sustained rewiring of HSPCs, which thereby display a skewing toward the myeloid lineage, resulting in generation of hyper-reactive or "trained" myeloid cells. CHIP arises from aging-related somatic mutations in HSPCs, which confer a survival and proliferation advantage to the mutant HSPCs and give rise to an outsized fraction of hyper-inflammatory mutant myeloid cells in the circulation and tissues. This review discusses emerging evidence that supports the notion that TII and CHIP may underlie a causal and age-related association between periodontitis and comorbidities. A holistic mechanistic understanding of the periodontitis-systemic disease connection may offer novel diagnostic and therapeutic targets for treating inflammatory comorbidities. [ABSTRACT FROM AUTHOR]

During the last 15 years, a significant amount of data related to the crustacean immune system has been generated, mainly led by the advances made in the field of transcriptomic analysis through massive mRNA sequencing technology. In order to shed new light on the genes and metabolic pathways associated with the immune system in shrimp species, we have carried out a meta‐analysis using the current literature and the Sequence Read Archive (SRA) database of the National Center for Biotechnology Information (NCBI), which has 1195 published transcriptomic data sets until 31 December 2020, from different tissues and 14 Penaeus species. The transcriptomic analyses published so far have explored the effects of the challenge from viral and bacterial pathogens, as well as abiotic stressors, such as ammonia, temperature, salinity, oxygen deprivation and pH. They have also explored the effect of dietary factors and beneficial microbes (pre‐ and probiotics) in the immune response. In order to harness the vast amount of information available, multidisciplinary efforts have to generate better genomic tools to overcome the complexity of the genome and to implement the knowledge gained into commercial applications for the improvement of the culture conditions, adaptation of more sustainable feeds and producing strains showing more resilience/tolerance to diseases. [ABSTRACT FROM AUTHOR]

Traditionally, immune memory is regarded as an exclusive hallmark of adaptive immunity. However, a growing body of evidence suggesting that innate immune cells show adaptive characteristics has challenged this dogma. In the past decade, trained immunity, a de facto innate immune memory, has been defined as a long‐term functional reprogramming of cells of the innate immune system: the reprogramming is evoked by endogenous or exogenous insults, the cells return to a nonactivated state and subsequently show altered inflammatory responses against a second challenge. Trained immunity became regarded as a mechanism selected in evolution to protect against infection; however, a maladaptive effect might result in hyperinflammation. This dual effect is consistent with the Yin‐Yang theory in traditional Chinese philosophy, in which Yang represents active, positive, and aggressive factors, whereas Yin represents passive, negative, and inhibitory factors. In this review, we give a brief overview of history and latest progress about trained immunity, including experimental models, inductors, molecular mechanisms, clinical application and so on. Moreover, this is the first time to put forward the theory of Yin‐Yang balance to understand trained immunity. We envision that more efforts will be focused on developing novel immunotherapies targeting trained immunity in the coming years. [ABSTRACT FROM AUTHOR]

Innate immune cells are able to build memory characteristics via a process termed "trained immunity." Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro‐induced trained immunity responses were assessed in two independent population‐based cohorts of healthy individuals, the 300 Bacillus Calmette‐Guérin (300BCG; n = 267) and 200 Functional Genomics (200FG; n = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta‐analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K‐Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec‐5 and Siglec‐14). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions. [ABSTRACT FROM AUTHOR]

BCG turns 100 this year and while it might not be the perfect vaccine, it has certainly contributed significantly towards eradication and prevention of spread of tuberculosis (TB). The search for newer and better vaccines for TB is an ongoing endeavor and latest results from trials of candidate TB vaccines such as M72AS01 look promising. However, recent encouraging data from BCG revaccination trials in adults combined with studies on mucosal and intravenous routes of BCG vaccination in non‐human primate models have renewed interest in BCG for TB prevention. In addition, several well‐demonstrated non‐specific effects of BCG, for example, prevention of viral and respiratory infections, give BCG an added advantage. Also, BCG vaccination is currently being widely tested in human clinical trials to determine whether it protects against SARS‐CoV‐2 infection and/or death with detailed analyses and outcomes from several ongoing trials across the world awaited. Through this review, we attempt to bring together information on various aspects of the BCG‐induced immune response, its efficacy in TB control, comparison with other candidate TB vaccines and strategies to improve its efficiency including revaccination and alternate routes of administration. Finally, we discuss the future relevance of BCG use especially in light of its several heterologous benefits. [ABSTRACT FROM AUTHOR]

SARS‐CoV‐2 triggers a dysregulated innate immune system activation. As the mevalonate pathway (MVP) prevents the activation of inflammasomes and cytokine release and regulates endosomal transport, compromised signaling could be associated with the pathobiology of COVID‐19. Prior transcriptomic studies of host cells in response to SARS‐CoV‐2 infection have not reported to date the effects of SARS‐CoV‐2 on the MVP. In this study, we accessed public data sets to report in silico investigations into gene expression. In addition, we proposed candidate genes that are thought to have a direct association with the pathogenesis of COVID‐19, and which may be dependent on signals derived from the MVP. Our results revealed dysregulation of genes involved in the MVP. These results were not found when investigating the gene expression data from host cells infected with H3N2 influenza virus, H1N1 influenza virus, or respiratory syncytial virus. Our manually curated gene set showed significant gene expression variability in A549 cells infected with SARS‐CoV‐2, as per Blanco‐Melo et al. data set (GSE147507). In light of the present findings, SARS‐CoV‐2 could hijack the MVP, leading to hyperinflammatory responses. Prompt reconstitution of this pathway with available agents should be considered in future studies. [ABSTRACT FROM AUTHOR]

Trained immunity is characterized by long‐term functional reprogramming of innate immune cells following challenge with pathogens or microbial ligands during infection or vaccination. This cellular reprogramming leads to increased responsiveness upon restimulation, and is mediated through epigenetic and metabolic modifications. In this review, we describe how molecular mechanisms underlying trained immunity, for example, induced by β‐glucan or Bacille Calmette‐Guérin (BCG) vaccination, can be investigated by using and integrating different layers of information including genome, epigenome, transcriptome, proteome, metabolome, microbiome, immune cell phenotyping, and function. We also describe the most commonly used experimental and computational techniques. Finally, we provide a number of examples of how a systems biology approach was applied to study trained immunity to understand interindividual variation or the complex interplay between molecular layers. In conclusion, trained immunity represents an opportunity for regulating innate immune function, and understanding the complex interplay of mechanisms that mediate trained immunity might enable us to employ it as a clinical tool in the future. [ABSTRACT FROM AUTHOR]

As the number of infections and mortalities from the SARS‐CoV‐2 pandemic continues to rise, the development of an effective therapy against COVID‐19 becomes ever more urgent. A few reports showing a positive correlation between BCG vaccination and reduced COVID‐19 mortality have ushered in some hope. BCG has been suggested to confer a broad level of nonspecific protection against several pathogens, mainly via eliciting "trained immunity" in innate immune cells. Secondly, BCG has also been proven to provide benefits in autoimmune diseases by inducing tolerogenicity. Being an acute inflammatory disease, COVID‐19 requires a therapy that induces early priming of anti‐viral immune responses and regulates aberrant hyperactivity of innate‐immune cells. Here, we hypothesize that BCG can offer reliable spatiotemporal protection from COVID‐19 by triggering trained immunity and tolerogenesis, through multiple cellular pathways. We propose further research on BCG‐mediated immunoprotection, especially in vulnerable individuals, as a strategy to halt the progress of the SARS‐CoV‐2 pandemic. Also see the video abstract here https://youtu.be/P2D2RXfq6Vg. [ABSTRACT FROM AUTHOR]

The novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has kept the whole world in tenterhooks due to its severe life‐threatening infectious disease, COVID‐19. The virus is distinct from its cousins, SARS‐CoV and MERS‐CoV in terms of severity of the infection. The obligated killing properties of the SARS‐CoV‐2 virus is mediated by its unique structure. Efforts for developing vaccines for COVID‐19 are ongoing, but it is unlikely to be available in the immediate future. Due to the absence of precise treatment, the investigators are discovering other effective, protective, and healing choices. However, the lower than a predictable number of SARS‐CoV‐2 cases in countries with fragile health systems is mystifying. Recently, there has been a buzz about the protective effect of Bacille Calmette‐Guérin (BCG) vaccine in COVID‐19 through long‐term boosting of trained immunity. Based on epidemiological correlations, we link up that BCG vaccination adopted by different countries might influence the SARS‐CoV‐2 transmission patterns and/or COVID‐19 associated mortality through the vaccine's capacity to confer heterologous protection. A number of clinical studies are underway to investigate this possibility but even if they prove effective‐many questions will remain. Moreover, responsible stewardship of the BCG vaccine in the context of the COVID‐19 epidemic is directly needed. [ABSTRACT FROM AUTHOR]

Background: Milder symptoms were observed in children with COVID‐19. However, whether this also holds true for neonates is not known. Methods: The clinical data of a total of 3213 patients aged 2 years or below, including 749 neonates, in Brazil nationwide were studied. Comparisons were made between neonate and infant patients by conducting statistical tests. Results: Neonates appeared to bear more severe clinical courses. In addition to higher case fatality rates, newborns with COVID‐19 had much shorter time from symptom onset to death and longer time from symptom onset to discharge. Dyspnoea, sore throat and cough were more prominent in neonate patients, suggestive of both upper and lower respiratory tract infection, as opposed to upper respiratory tract symptoms mostly observed in children. Conclusion: Findings suggested that trained immunity provides a possible explanation because the innate immune system in newborns is not "well‐trained" while that in adult tends to hyperactive. [ABSTRACT FROM AUTHOR]

Objectives: Histone methyltransferase G9a, also known as Euchromatic Histone Lysine Methyltransferase 2 (EHMT2), mediates H3K9 methylation which is associated with transcriptional repression. It possesses immunomodulatory effects and is overexpressed in multiple types of cancer. In this study, we investigated the role of G9a in the induction of trained immunity, a de facto innate immune memory, and its effects in non‐muscle‐invasive bladder cancer (NMIBC) patients treated with intravesical Bacillus Calmette‐Guérin (BCG). Methods: EHMT2 expression was assessed upon induction of trained immunity by RNA sequencing and Western blotting. G9a inhibitor BIX‐01294 was used to investigate the effect on trained immunity responses in vitro. Subsequent cytokine production was measured by ELISA, epigenetic modifications were measured by ChIP‐qPCR, Seahorse technology was used to measure metabolic changes, and a luminescence assay was used to measure ROS release. RNA sequencing was performed on BIX‐01294‐treated monocytes ex vivo. Results: The expression of EHMT2 mRNA and protein decreased in monocytes during induction of trained immunity. G9a inhibition by BIX‐01294 induced trained immunity and amplified trained immunity responses evoked by various microbial ligands in vitro. This was accompanied by decreased H3K9me2 at the promoters of pro‐inflammatory genes. G9a inhibition was also associated with amplified ex vivo trained immunity responses in circulating monocytes of NMIBC patients. Additionally, altered RNA expression of inflammatory genes in monocytes of NMIBC patients was observed upon ex vivo G9a inhibition. Furthermore, intravesical BCG therapy decreased H3K9me2 at the promoter of pro‐inflammatory genes. Conclusion: Inhibition of G9a is important in the induction of trained immunity, and G9a may represent a novel therapeutic target in NMIBC patients. [ABSTRACT FROM AUTHOR]

Summary: In the face of ineffective vaccines, increasing antibiotic resistance and the decline in new antibacterial drugs in the pipeline, tuberculosis (TB) still remains pandemic. Exposure to Mycobacterium tuberculosis (Mtb), which causes TB, results in either direct elimination of the pathogen, most likely by the innate immune system, or infection and containment that requires both innate and adaptive immunity to form the granuloma. Host defence strategies against infectious diseases are comprised of both host resistance, which is the ability of the host to prevent invasion or to eliminate the pathogen, and disease tolerance, which is defined by limiting the collateral tissue damage. In this review, we aim to examine the metabolic demands of the immune cells involved in both host resistance and disease tolerance, chiefly the macrophage and T‐lymphocyte. We will further discuss how baseline metabolic heterogeneity and inflammation‐driven metabolic reprogramming during infection are linked to their key immune functions containing mycobacterial growth and instructing protective immunity. Targeting key players in immune cellular metabolism may provide a novel opportunity for treatments at different stages of TB disease. [ABSTRACT FROM AUTHOR]

Background: Bovine respiratory disease (BRD) is a major problem affecting beef cattle after arrival to feedlots. Alternatives to antibiotics are needed for prevention. Hypothesis: Stimulation of pulmonary innate immune responses at the time of arrival to a feedlot reduces the occurrence and severity of BRD. Animals Sixty beef steers at high risk of BRD. Methods: Randomized, double‐blinded, placebo‐controlled study. Calves received saline or a lysate of Staphylococcus aureus and Escherichia coli by aerosol, at 16 hours after feedlot arrival. Calves were monitored for 28 days for disease outcomes and levels of Mycoplasma bovis and Mannheimia haemolytica in nasal swabs. Results: Death from M bovis pneumonia was significantly greater in lysate‐treated animals (6/29, 24%) compared to controls (1/29, 3%; odds ratio = 10.2; 95% confidence interval [CI] = 1.1‐96.0; P =.04). By 28 days after arrival, 29/29 lysate‐treated calves had ultrasonographic pulmonary consolidation compared to 24/29 control calves (P =.05). Lysate‐treated calves had lower weight gain compared to control calves (−8.8 kg, 95% CI = −17.1 to −0.5; P =.04), and higher body temperatures on days 4, 7, and 21 (0.19°C; 95% CI = 0.01‐0.37; P =.04). Nasal M bovis numbers increased over time and were higher in lysate‐treated calves (0.76 log CFU, 95% CI = 0.3‐1.2; P =.001). Conclusions and Clinical Importance: Aerosol administration of a bacterial lysate exacerbated BRD in healthy high‐risk beef calves, suggesting that respiratory tract inflammation adversely affects how calves respond to subsequent natural infection with M bovis and other respiratory pathogens. [ABSTRACT FROM AUTHOR]

COVID‐19 is a severe health problem in many countries and has altered day‐to‐day life in the whole world. This infection is caused by the SARS‐CoV‐2 virus, and depending on age, sex and health status of the patient, it can present with variety of clinical symptoms such as mild infection, a very severe form or even asymptomatic course of the disease. Similarly to other viruses, innate immune response plays a vital role in protection against COVID‐19. However, dysregulation of innate immunity could have a significant influence on the severity of the disease. Despite various efforts, there is no effective vaccine against the disease so far. Recent data have demonstrated that the Bacillus Calmette–Guérin (BCG) vaccine could reduce disease severity and the burden of several infectious diseases in addition to targeting its primary focus tuberculosis. There is growing evidence for the concept of beneficial non‐specific boosting of immune responses by BCG or other microbial compounds termed trained immunity, which may protect against COVID‐19. In this manuscript, we review data on how the development of innate immune memory due to microbial compounds specifically BCG can result in protection against SARS‐CoV‐2 infection. We also discuss possible mechanisms, challenges and perspectives of using innate immunity as an approach to reduce COVID‐19 severity. [ABSTRACT FROM AUTHOR]

Bone marrow haematopoietic stem and progenitor cells (HSPCs) express pattern recognition receptors such as Toll‐like receptors (TLRs) to sense microbial products and activation of these innate immune receptors induces cytokine expression and redirects bone marrow haematopoiesis towards the increased production of myeloid cells. Secreted cytokines by HSPCs in response to TLR ligands can act in an autocrine or paracrine manner to regulate haematopoiesis. Moreover, tonic activation of HSPCs by microbiota‐derived compounds might educate HSPCs to produce superior myeloid cells equipped with innate memory responses to combat pathogens. While haematopoietic stem cell activation through TLRs meets the increased demand for blood leucocytes to protect the host against infection, persistent exposure to inflammatory cytokines or microbial products might impair their function and even induce malignant transformation. This review highlights the potential outcomes of HSPCs in response to TLR ligands. [ABSTRACT FROM AUTHOR]