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Purpose: To analyze the interfering effect of plasma from COVID-19 convalescent adults vaccinated or not with intradermal Bacillus Calmette-Guérin (BCG) on human macrophages. Methods: The BATTLE clinical trial (NCT04369794) was initiated in the 2020 SARS-CoV-2 pandemic to study the safety and efficacy of BCG revaccination of COVID-19 convalescent adults. We measured the expression induction of eleven COVID-19-related genes in human macrophages cultured in plasma taken from 22 BCG vaccinated and 17 placebo patients at baseline and 45 days post-intervention. Subgroup analysis was based on gender, age, job type (healthcare worker [HCW] vs non-HCW), and the presence of anosmia/dysgeusia. Results: Compared to plasma from placebo counterparts, the plasma of BCG vaccinated patients increased the expression induction of interferon (IFN)ß-1b (p = 0.042) in human macrophages. This increase was more pronounced in females and in healthcare workers (HCW) (p = 0.007 and 0.001, respectively). Interferon-induced transmembrane protein 3 (IFITM3) expression induction was increased by plasma from BCG vaccinated females, young age group, and HCWs (p = 0.004, 0.011, and 0.040, respectively). Interleukin (IL)-10 induction increased by the plasma of young BCG recipients (p = 0.008). Induction of IL-6 expression increased by non-HCW BCG recipients plasma but decreased by HCW BCG recipients plasma (p = 0.005). Baseline plasma of patients who presented with anosmia/dysgeusia at the time of admission induced lower angiotensin-converting enzyme 2 (ACE2) compared to those without the symptom (0.76 vs 0.97, p = 0.004). ACE2 expression induction significantly increased by plasma of BCG recipients if they had anosmia/dysgeusia on admission (p = 0.028). Conclusion: The expressions of IFNß-1b, IFITM3, IL-6, and IL-10 in human macrophages incubated with the plasma of COVID-19 convalescent patients were modulated by BCG. These modulations depended on subject-specific characteristics, including gender, age, clinical presentation (anosmia/dysgeusia), job type, and previous exposure to mycobacteria.
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Introduction: Innate immune training is a metabolic, functional, and epigenetic long-term reprogramming of innate cells triggered by different stimuli. This imprinting also reaches hematopoietic precursors in the bone marrow to sustain a memory-like phenotype. Dendritic cells (DCs) can exhibit memory-like responses, enhanced upon subsequent exposure to a pathogen; however, whether this imprinting is lineage and stimulus-restricted is still being determined. Nevertheless, the functional consequences of DCs training on the adaptive and protective immune response against non-infectious diseases remain unresolved. Methods: We evaluated the effect of the nontoxic cholera B subunit (CTB), LPS and LTA in the induction of trained immunity in murine DCs revealed by TNFa and LDH expression, through confocal microscopy. Additionally, we obtained bone marrow DCs (BMDCs) from mice treated with CTB, LPS, and LTA and evaluated training features in DCs and their antigen-presenting cell capability using multiparametric cytometry. Finally, we design an experimental melanoma mouse model to demonstrate protection induced by CTB-trained DCs in vivo. Results: CTB-trained DCs exhibit increased expression of TNFa, and metabolic reprogramming indicated by LDH expression. Moreover, CTB training has an imprint on DC precursors, increasing the number and antigen-presenting function in BMDCs. We found that training by CTB stimulates the recruitment of DC precursors and DCs infiltration at the skin and lymph nodes. Interestingly, training-induced by CTB promotes a highly co-stimulatory phenotype in tumor-infiltrating DCs (CD86+) and a heightened functionality of exhausted CD8 T cells (Ki67+, GZMB+), which were associated with a protective response against melanoma challenge in vivo. Conclusion: Our work indicates that CTB can induce innate immune training on DCs, which turns into an efficient adaptive immune response in the melanoma model and might be a potential immunotherapeutic approach for tumor growth control.
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Linfócitos T CD8-Positivos , Toxina da Cólera , Células Dendríticas , Melanoma Experimental , Camundongos Endogâmicos C57BL , Animais , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Camundongos , Linfócitos T CD8-Positivos/imunologia , Toxina da Cólera/imunologia , Toxina da Cólera/farmacologia , Melanoma Experimental/imunologia , Imunidade Inata , Feminino , Memória Imunológica , Imunidade TreinadaRESUMO
Whether specific immune protection after initial pathogen exposure (immune memory) occurs in invertebrates has long been uncertain. The absence of antibodies, B-cells and T-cells, and the short lifespans of invertebrates led to the hypothesis that immune memory does not occur in these organisms. However, research in the past two decades has supported the existence of immune memory in several invertebrate groups, including Ctenophora, Cnidaria, Nematoda, Mollusca and Arthropoda. Interestingly, some studies have demonstrated immune memory that is specific to the parasite strain. Nonetheless, other work does not provide support for immune memory in invertebrates or offers only partial support. Moreover, the expected biphasic immune response, a characteristic of adaptive immune memory in vertebrates, varies within and between invertebrate species. This variation may be attributed to the influence of biotic or abiotic factors, particularly parasites, on the outcome of immune memory. Despite its critical importance for survival, the role of phenotypic plasticity in immune memory has not been systematically examined in the past two decades. Additionally, the features of immune responses occurring in diverse environments have yet to be fully characterized.
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Artrópodes , Memória Imunológica , Animais , Invertebrados , Adaptação Fisiológica , AnticorposRESUMO
Innate immune cells can undergo long-term functional reprogramming after certain infections, a process called trained immunity (TI). Here, we focus on antigens of Leishmania braziliensis, which induced anti-tumor effects via trained immunity in human monocytes. We reveal that monocytes exposed to promastigote antigens of L. braziliensis develop an enhanced response to subsequent exposure to Toll-like receptor (TLR)2 or TLR4 ligands. Mechanistically, the induction of TI in monocytes by L. braziliensis is mediated by multiple pattern recognition receptors, changes in metabolism, and increased deposition of H3K4me3 at the promoter regions of immune genes. The administration of L. braziliensis exerts potent anti-tumor capabilities by delaying tumor growth and prolonging survival of mice with non-Hodgkin lymphoma. Our work reveals mechanisms of TI induced by L. braziliensis in vitro and identifies its potential for cancer immunotherapy.
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Leishmania braziliensis , Leishmaniose Cutânea , Neoplasias , Humanos , Camundongos , Animais , MonócitosRESUMO
The bacillus Calmette-Guérin (BCG) is an attenuated bacterium derived from virulent Mycobacterium bovis. It is the only licensed vaccine used for preventing severe forms of tuberculosis in children. Besides its specific effects against tuberculosis, BCG administration is also associated with beneficial non-specific effects (NSEs) following heterologous stimuli in humans and mice. The NSEs from BCG could be related to both adaptive and innate immune responses. The latter is also known as trained immunity (TI), a recently described biological feature of innate cells that enables functional improvement based on metabolic and epigenetic reprogramming. Currently, the mechanisms related to BCG-mediated TI are the focus of intense research, but many gaps are still in need of elucidation. This review discusses the present understanding of TI induced by BCG, exploring signaling pathways that are crucial to a trained phenotype in hematopoietic stem cells and monocytes/macrophages lineage. It focuses on BCG-mediated TI mechanisms, including the metabolic-epigenetic axis and the inflammasome pathway in these cells against intracellular pathogens. Moreover, this study explores the TI in different immune cell types, its ability to protect against various intracellular infections, and the integration of trained innate memory with adaptive memory to shape next-generation vaccines.
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Background: Trained immunity is the enhanced innate immune response resulting from exposure to pathogens or vaccines against an unrelated pathogen stimulus. Certain vaccines induce a memory like response in monocytes and NK cells, leading to modulation in cytokine production, metabolic changes, and modifications in histone patterns. Here, we hypothesized that vaccination against SARS-CoV-2 could induce the training of monocytes in addition to stimulating the adaptive immune response. Methods: Therefore, we aimed to investigate the immunophenotyping, cytokine and metabolic profile of monocytes from individuals who were completely immunized with two doses of inactivated COVID-19 vaccine or non-replicating viral vector vaccine. Subsequently, we investigated the epigenetic mechanisms underlying monocyte immune training. As a model of inflammatorychallenge, to understand if the monocytes were trained by vaccination and how they were trained, cells were stimulated in vitro with the endotoxin LPS, an unrelated stimulus that would provoke the effects of training. Results: When challenged in vitro, monocytes from vaccinated individuals produced less TNF-α and those who received inactivated vaccine produced less IL-6, whereas vaccination with non-replicating viral vector vaccine induced more IL-10. Inactivated vaccine increased classical monocyte frequency, and both groups showed higher CD163 expression, a hallmark of trained immunity. We observed increased expression of genes involved in glycolysis and reduced IRG1 expression in vaccinated subjects, a gene associated with the tolerance phenotype in monocytes. We observed that both vaccines reduced the chromatin accessibility of genes associated with the inflammatory response, the inactivated COVID-19 vaccine trained monocytes to a regulatory phenotype mediated by histone modifications in the IL6 and IL10 genes, while the non-replicating viral vector COVID-19 vaccine trained monocytes to a regulatory phenotype, mediated by histone modifications in the IL6, IL10, TNF, and CCL2 genes. Conclusions: Our findings support the recognized importance of adopting vaccination against SARS CoV-2, which has been shown to be effective in enhancing the adaptive immune response against the virus and reducing mortality and morbidity rates. Here, we provide evidence that vaccination also modulates the innate immune response by controlling the detrimental inflammatory response to unrelated pathogen stimulation.
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COVID-19 , Vacinas Virais , Humanos , Monócitos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , COVID-19/prevenção & controle , COVID-19/metabolismo , Vacinas contra COVID-19 , SARS-CoV-2 , Citocinas/metabolismo , Vacinação , Fenótipo , Vacinas de Produtos Inativados/metabolismo , Epigênese GenéticaRESUMO
Abstract Objectives: Since the beginning of its use for the prevention of tuberculosis (TB) in 1921, other uses of BCG (Bacillus Calmette-Guérin) have been proposed, particularly in the treatment of malignant solid tumors, multiple sclerosis, and other autoimmune diseases. Its beneficial impact on other infections, by nontuberculous mycobacteria, and by viruses, has been more often studied in recent years, especially after the introduction of the concept of trained immunity. The present study's objective was to review the possible indications of BCG and the immunological rationale for these indications. Data source: Non-systematic review carried out in the PubMed, SciELO and Google Scholar databases, using the following search terms: "BCG" and "history", "efficacy", "use", "cancer", "trained immunity", "other infections", "autoimmune diseases". Data synthesis: There is epidemiological evidence that BCG can reduce overall child morbidity/mortality beyond what would be expected from TB control. BCG is able to promote cross-immunity with nontuberculous mycobacteria and other bacteria. BCG promotes in vitro changes that increase innate immune response to other infections, mainly viral ones, through mechanisms known as trained immunity. Effects on cancer, except bladder cancer, and on autoimmune and allergic diseases are debatable. Conclusions: Despite evidence obtained from in vitro studies, and some epidemiological and clinical evidence, more robust evidence of in vivo efficacy is still needed to justify the use of BCG in clinical practice, in addition to what is recommended by the National Immunization Program for TB prevention and bladder cancer treatment.
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Recently, it has been described that innate immune cells such as monocytes, macrophages, and natural killer cells can develop a non-specific immune response induced by different stimuli, including lipopolysaccharides, Mycobacterium bovis Bacillus Calmette-Guérin, and oxidized low-density lipoprotein. This non-specific immune response has been named "trained immunity," whose mechanism is essential for host defense and vaccine response, promoting better infection control. However, limited information about trained immunity in other non-infectious diseases, such as autoimmune illness, has been reported. The complexity of autoimmune pathology arises from dysfunctions in the innate and adaptive immune systems, triggering different clinical outcomes depending on the disease. Nevertheless, T and B cell function dysregulation is the most common characteristic associated with autoimmunity by promoting the escape from central and peripheral tolerance. Despite the importance of adaptative immunity to autoimmune diseases, the innate immune system also plays a prominent and understudied role in these pathologies. Accordingly, epigenetic and metabolic changes associated with innate immune cells that undergo a trained process are possible new therapeutic targets for autoimmune diseases. Even so, trained immunity can be beneficial or harmful in autoimmune diseases depending on several factors associated with the stimuli. Here, we reviewed the role of trained immunity over the innate immune system and the possible role of these changes in common autoimmune diseases, including Systemic Lupus Erythematosus, Rheumatoid Arthritis, Multiple Sclerosis, and Type 1 Diabetes.
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Doenças Autoimunes , Imunidade Inata , Humanos , Autoimunidade , Imunidade Treinada , Macrófagos , Imunidade AdaptativaRESUMO
OBJECTIVES: Since the beginning of its use for the prevention of tuberculosis (TB) in 1921, other uses of BCG (Bacillus Calmette-Guérin) have been proposed, particularly in the treatment of malignant solid tumors, multiple sclerosis, and other autoimmune diseases. Its beneficial impact on other infections, by nontuberculous mycobacteria, and by viruses, has been more often studied in recent years, especially after the introduction of the concept of trained immunity. The present study's objective was to review the possible indications of BCG and the immunological rationale for these indications. DATA SOURCE: Non-systematic review carried out in the PubMed, SciELO and Google Scholar databases, using the following search terms: "BCG" and "history", "efficacy", "use", "cancer", "trained immunity", "other infections", "autoimmune diseases". DATA SYNTHESIS: There is epidemiological evidence that BCG can reduce overall child morbidity/mortality beyond what would be expected from TB control. BCG is able to promote cross-immunity with nontuberculous mycobacteria and other bacteria. BCG promotes in vitro changes that increase innate immune response to other infections, mainly viral ones, through mechanisms known as trained immunity. Effects on cancer, except bladder cancer, and on autoimmune and allergic diseases are debatable. CONCLUSIONS: Despite evidence obtained from in vitro studies, and some epidemiological and clinical evidence, more robust evidence of in vivo efficacy is still needed to justify the use of BCG in clinical practice, in addition to what is recommended by the National Immunization Program for TB prevention and bladder cancer treatment.
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Tuberculose , Neoplasias da Bexiga Urinária , Criança , Humanos , Vacina BCG/uso terapêutico , Tuberculose/prevenção & controle , Imunidade Inata , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
Invertebrates' immune priming or innate immune memory is an analogous response to the vertebrates' adaptive memory. We investigated if honey bees have immune memory. We compared survival and immune response between bees that were: 1) manipulated (Naïve), 2) challenged twice with the same pathogen Escherichia coli (Memory), 3) challenged twice with different pathogens (Staphylococcus aureus versus E. coli, Micrococcus lysodeikticus versus E. coli), or 4) with PBS (the diluent of bacteria) versus E. coli (heterologous challenge; Control). Results indicate better survival in the Memory than the Control group, and the Memory group showed a similar survival than Naïve insects. The Memory group had higher lytic activity but lower prophenoloxidase, phenoloxidase activity, and hemocyte count than the Control and Naïve groups. No differences were found in relative expression of defensin-1. This first demonstration of immune memory opens the questions about its molecular mechanisms and whether, immune memory could be used against natural parasites that affect honey bees, hence, if they could be "vaccinated" against some natural parasites.
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Escherichia coli , Monofenol Mono-Oxigenase , Animais , Abelhas , Defensinas , Escherichia coli/metabolismo , Hemócitos/metabolismo , Memória Imunológica , Monofenol Mono-Oxigenase/metabolismoRESUMO
Introduction: It is well established that moderate physical activity can improve the immune status, rather excess or high-intensity physical exercise can cause damage to the immune system. In addition, muscle injuries resulting from increased frequency and intensity of exercises compromise innate immune activity and may decrease tissue regeneration. Thus, ß-glucans, a natural compound, may represent an important substance with strong immunomodulatory properties acting as an immunostimulant therapy known as "trained immunity". This immune stimulating therapeutic is an immunological memory phenomenon linked to the innate immune system, triggering cellular changes at epigenetic, transcriptional, and functional levels, to regulate the immune system and recover its homeostasis with clinical benefits. Conclusion: This narrative review works with the current evidence regarding ß-glucans as a possible alternative therapy for wound healing and its safety and efficacy in the treatment of muscle injuries and physical recovery including other chronic conditions and diseases.
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The Bacille Calmette-Guérin (BCG) is a potent immunomodulator. It was initially used by oral administration, but it is mostly used subcutaneously nowadays. This study shows that oral BCG vaccination modifies the immune response to a second non-related antigen (Ovalbumin) systemic immunization. Airway Ovalbumin challenge six months after the systemic intraperitoneal immunization resulted in a potent γδ+ T cell response in the lungs biased to IFN-γ and IL-17 production ex vivo and a mixed TH1, TH2, and TH17 T cells upon further stimulation with anti-CD3 mAb in vitro. Higher percentages of CD4+ T cells accompanied the augmented T cell response in oral BCG vaccinated mice. Also, the proportion of Foxp3+ Tregs was diminished compared to PBS-gavaged and OVA-immunized mice. The anti-OVA-specific antibody response was also influenced by oral exposure to BCG so that these mice produced more IgG2a and less IgE detected in the sera. These results suggest that oral BCG vaccination can modify future immune responses to vaccines and improve immunity to pathogen infections, especially in the mucosal interfaces.
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Vacina BCG , Interleucina-17 , Animais , Vacina BCG/farmacologia , Fatores de Transcrição Forkhead , Imunidade , Imunoglobulina E , Imunoglobulina G , Interferon gama , Potenciação de Longa Duração , Camundongos , Ovalbumina , Vacinação/métodosRESUMO
Background:Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine mainly administered to newborns and used for over 100 years to prevent the disease caused by Mycobacterium tuberculosis (M. tb). This vaccine can induce immune response polarization towards a Th1 profile, which is desired for counteracting M. tb, other mycobacteria, and unrelated intracellular pathogens. The vaccine BCG has been used as a vector to express recombinant proteins and has been shown to protect against several diseases, particularly respiratory viruses. Methods: BCG was used to develop recombinant vaccines expressing either the Nucleoprotein from SARS-CoV-2 or Andes orthohantavirus. Mice were immunized with these vaccines with the aim of evaluating the safety and immunogenicity parameters. Results: Immunization with two doses of 1 × 108 CFU or one dose of 1 × 105 CFU of these BCGs was safe in mice. A statistically significant cellular immune response was induced by both formulations, characterized as the activation of CD4+ and CD8+ T cells. Stimulation with unrelated antigens resulted in increased expression of activation markers by T cells and secretion of IL-2 and IFN-γ, while increased secretion of IL-6 was found for both recombinant vaccines; all of these parameters related to a trained immunity profile. The humoral immune response elicited by both vaccines was modest, but further exposure to antigens could increase this response. Conclusions: The BCG vaccine is a promising platform for developing vaccines against different pathogens, inducing a marked antigen-specific immune response.
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A dysregulated immune response toward self-antigens characterizes autoimmune and autoinflammatory (AIF) disorders. Autoantibodies or autoreactive T cells contribute to autoimmune diseases, while autoinflammation results from a hyper-functional innate immune system. Aside from their differences, many studies suggest that monocytes and macrophages (Mo/Ma) significantly contribute to the development of both types of disease. Mo/Ma are innate immune cells that promote an immune-modulatory, pro-inflammatory, or repair response depending on the microenvironment. However, understanding the contribution of these cells to different immune disorders has been difficult due to their high functional and phenotypic plasticity. Several factors can influence the function of Mo/Ma under the landscape of autoimmune/autoinflammatory diseases, such as genetic predisposition, epigenetic changes, or infections. For instance, some vaccines and microorganisms can induce epigenetic changes in Mo/Ma, modifying their functional responses. This phenomenon is known as trained immunity. Trained immunity can be mediated by Mo/Ma and NK cells independently of T and B cell function. It is defined as the altered innate immune response to the same or different microorganisms during a second encounter. The improvement in cell function is related to epigenetic and metabolic changes that modify gene expression. Although the benefits of immune training have been highlighted in a vaccination context, the effects of this type of immune response on autoimmunity and chronic inflammation still remain controversial. Induction of trained immunity reprograms cellular metabolism in hematopoietic stem cells (HSCs), transmitting a memory-like phenotype to the cells. Thus, trained Mo/Ma derived from HSCs typically present a metabolic shift toward glycolysis, which leads to the modification of the chromatin architecture. During trained immunity, the epigenetic changes facilitate the specific gene expression after secondary challenge with other stimuli. Consequently, the enhanced pro-inflammatory response could contribute to developing or maintaining autoimmune/autoinflammatory diseases. However, the prediction of the outcome is not simple, and other studies propose that trained immunity can induce a beneficial response both in AIF and autoimmune conditions by inducing anti-inflammatory responses. This article describes the metabolic and epigenetic mechanisms involved in trained immunity that affect Mo/Ma, contraposing the controversial evidence on how it may impact autoimmune/autoinflammation conditions.
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Doenças Autoimunes , Doenças Hereditárias Autoinflamatórias , Autoimunidade , Humanos , Imunidade Inata , Células Matadoras NaturaisRESUMO
Interleukin-32 (IL-32) has several immune regulatory properties, which have driven its investigation in the context of various diseases. IL-32 expression is reported to be induced in the lesions of patients with American tegumentary leishmaniasis (ATL) by the New World Leishmania spp. that are responsible for causing ATL and visceral leishmaniasis (VL). IL-32 expression may elevate the inflammatory process through the induction of pro-inflammatory cytokines and also via mechanisms directed to kill the parasites. The genetic variants of IL-32 might be associated with the resistance or susceptibility to ATL, while different isoforms of IL-32 could be associated with distinct T helper lymphocyte profiles. IL-32 also determines the transcriptional profile in the bone marrow progenitor cells to mediate the trained immunity induced by ß-glucan and BCG, thereby contributing to the resistance against Leishmania. IL-32γ is essential for the vitamin D-dependent microbicidal pathway for parasite control. In this context, the present review report briefly discusses the data retrieved from the studies conducted on IL-32 in leishmaniasis in humans and mice to highlight the current challenges to understanding the role of IL-32 in leishmaniasis.
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Leishmania , Leishmaniose Cutânea , Leishmaniose Visceral , Animais , Citocinas/metabolismo , Humanos , Interleucinas/metabolismo , Leishmania/metabolismo , CamundongosRESUMO
BCG has shown the ability to induce protection against unrelated pathogens, which likely depends on an immune mechanism known as innate immune memory or trained immunity. In this study, we evaluated the induction of innate memory by a recombinant BCG strain expressing the genetically detoxified S1 subunit of the pertussis toxin (rBCG-S1PT). In vitro pre-exposure of naïve murine macrophages to rBCG-S1PT increased their innate/inflammatory response (IL-6, TNF-α, and IL-10) to a subsequent challenge with unrelated pathogens, as compared to pre-exposure to wild-type BCG. Following LPS challenge, mice immunized with rBCG-S1PT produced higher levels of IFN-γ, while the release of other inflammatory cytokines was comparable to that measured after BCG immunization. SCID mice previously immunized with rBCG-S1PT and challenged with pathogenic Candida albicans displayed a similar survival curve as BCG-immunized mice but a lower CFU burden in the kidneys, suggesting an innate memory-dependent control of C. albicans infection. This study highlights the potential of recombinant BCG to increase innate immune memory and, ultimately, non-specific protection, more effectively than wild-type BCG. To our knowledge, this is the first report describing the potential of a recombinant BCG strain to strengthen innate immune memory responses.
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BCG has shown the ability to induce protection against unrelated pathogens, which likely depends on an immune mechanism known as innate immune memory or trained immunity. In this study, we evaluated the induction of innate memory by a recombinant BCG strain expressing the genetically detoxified S1 subunit of the pertussis toxin (rBCG-S1PT). In vitro pre-exposure of naïve murine macrophages to rBCG-S1PT increased their innate/inflammatory response (IL-6, TNF-α, and IL-10) to a subsequent challenge with unrelated pathogens, as compared to pre-exposure to wild-type BCG. Following LPS challenge, mice immunized with rBCG-S1PT produced higher levels of IFN-γ, while the release of other inflammatory cytokines was comparable to that measured after BCG immunization. SCID mice previously immunized with rBCG-S1PT and challenged with pathogenic Candida albicans displayed a similar survival curve as BCG-immunized mice but a lower CFU burden in the kidneys, suggesting an innate memory-dependent control of C. albicans infection. This study highlights the potential of recombinant BCG to increase innate immune memory and, ultimately, non-specific protection, more effectively than wild-type BCG. To our knowledge, this is the first report describing the potential of a recombinant BCG strain to strengthen innate immune memory responses.
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The induction of trained immunity represents an emerging concept defined as the ability of innate immune cells to acquire a memory phenotype, which is a typical hallmark of the adaptive response. Key points modulated during the establishment of trained immunity include epigenetic, metabolic and functional changes in different innate-immune and non-immune cells. Regarding to epigenetic changes, it has been described that long non-coding RNAs (LncRNAs) act as molecular scaffolds to allow the assembly of chromatin-remodeling complexes that catalyze epigenetic changes on chromatin. On the other hand, relevant metabolic changes that occur during this process include increased glycolytic rate and the accumulation of metabolites from the tricarboxylic acid (TCA) cycle, which subsequently regulate the activity of histone-modifying enzymes that ultimately drive epigenetic changes. Functional consequences of established trained immunity include enhanced cytokine production, increased antigen presentation and augmented antimicrobial responses. In this article, we will discuss the current knowledge regarding the ability of different cell subsets to acquire a trained immune phenotype and the molecular mechanisms involved in triggering such a response. This knowledge will be helpful for the development of broad-spectrum therapies against infectious diseases based on the modulation of epigenetic and metabolic cues regulating the development of trained immunity.
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Interações Hospedeiro-Patógeno/imunologia , Imunidade Celular , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Imunidade Adaptativa/fisiologia , Animais , Vacina BCG/imunologia , Brônquios/citologia , Brônquios/imunologia , Citocinas/fisiologia , Metabolismo Energético , Epigênese Genética , Células Epiteliais/imunologia , Trato Gastrointestinal/citologia , Trato Gastrointestinal/imunologia , Células-Tronco Hematopoéticas/imunologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/fisiologia , Humanos , Imunidade Celular/genética , Imunidade Celular/fisiologia , Imunidade Inata/genética , Imunidade Inata/fisiologia , Memória Imunológica/genética , Memória Imunológica/fisiologia , Linfócitos/imunologia , Camundongos , Células Mieloides/imunologia , NAD/fisiologia , Pele/citologia , Pele/imunologiaRESUMO
Bacillus Calmette-Guérin (BCG), an attenuated vaccine from Mycobacterium bovis, was initially developed as an agent for vaccination against tuberculosis. BCG proved to be the first successful immunotherapy against established human bladder cancer and other neoplasms. The use of BCG has been shown to induce a long-lasting antitumor response over all other forms of treatment against intermediate, non-invasive muscle bladder cancer Several types of tumors may now be treated by releasing the immune response through the blockade of checkpoint inhibitory molecules, such as CTLA-4 and PD-1. In addition, Toll-Like Receptor (TLR) agonists and BCG are used to potentiate the immune response against tumors. Studies concerning TLR-ligands combined with BCG to treat melanoma have demonstrated efficacy in treating mice and patients This review addresses several interventions using BCG on neoplasms, such as Leukemia, Bladder Cancer, Lung Cancer, and Melanoma, describing treatments and antitumor responses promoted by this attenuated bacillus. Of essential importance, BCG is described recently to participate in an adequate microbiome, establishing an effective response during cell-target therapy when combined with anti-PD-1 antibody, which stimulates T cell responses against the melanoma. Finally, trained immunity is discussed, and reprogramming events to shape innate immune responses are addressed.