RESUMEN
After a century of using the Bacillus Calmette-Guérin (BCG) vaccine, our understanding of its ability to provide protection against homologous (Mycobacterium tuberculosis) or heterologous (for example, influenza virus) infections remains limited. Here we show that systemic (intravenous) BCG vaccination provides significant protection against subsequent influenza A virus infection in mice. We further demonstrate that the BCG-mediated cross-protection against influenza A virus is largely due to the enrichment of conventional CD4+ effector CX3CR1hi memory αß T cells in the circulation and lung parenchyma. Importantly, pulmonary CX3CR1hi T cells limit early viral infection in an antigen-independent manner via potent interferon-γ production, which subsequently enhances long-term antimicrobial activity of alveolar macrophages. These results offer insight into the unknown mechanism by which BCG has persistently displayed broad protection against non-tuberculosis infections via cross-talk between adaptive and innate memory responses.
Asunto(s)
Vacuna BCG , Virus de la Influenza A , Infecciones por Orthomyxoviridae , Animales , Ratones , Administración Intravenosa , Vacuna BCG/inmunología , Células T de Memoria , Inmunidad Entrenada , Vacunación , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/prevención & controlRESUMEN
Infection or immunization can reprogram innate immune cells generating memory responses with broad protection against subsequent infection, a process referred to as "trained immunity." A new study by Stacy and colleagues demonstrates that, following acute infection, the commensal microbiota can also be "trained" to enhance colonization resistance against heterologous infection.
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Infecciones , Microbiota , Humanos , Inmunidad Innata , Inmunización , SimbiosisRESUMEN
A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or ß-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or ß-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.
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Células Madre Hematopoyéticas/microbiología , Inmunidad , Mycobacterium tuberculosis/fisiología , Mielopoyesis , Animales , Células de la Médula Ósea/metabolismo , Proliferación Celular , Susceptibilidad a Enfermedades , Homeostasis , Interferón Tipo I/metabolismo , Hierro/metabolismo , Cinética , Pulmón/microbiología , Pulmón/patología , Macrófagos/inmunología , Ratones Endogámicos C57BL , Células Mieloides/metabolismo , Necrosis , Transducción de Señal , Transcripción Genética , Tuberculosis/inmunología , Tuberculosis/microbiología , Tuberculosis/patologíaRESUMEN
Although the Bacille-Calmette-Guérin (BCG) vaccine is used to prevent tuberculosis, it also offers protection against a diverse range of non-mycobacterial infections. However, the underlying protective mechanisms in humans are not yet fully understood. Here, we surveyed at single-cell resolution the gene expression and chromatin landscape of human bone marrow, aspirated before and 90 days after BCG vaccination or placebo. We showed that BCG alters both the gene expression and epigenetic profiles of human hematopoietic stem and progenitor cells (HSPCs). Changes in gene expression occurred primarily within uncommitted stem cells. By contrast, changes in chromatin accessibility were most prevalent within differentiated progenitor cells at sites influenced by Kruppel-like factor (KLF) and early growth response (EGR) transcription factors and were highly correlated (r > 0.8) with the interleukin (IL)-1ß secretion capacity of paired peripheral blood mononuclear cells (PBMCs). Our findings shed light on BCG vaccination's profound and lasting effects on HSPCs and its influence on innate immune responses and trained immunity.
RESUMEN
The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for memory-like innate immune training. However, the underlying mechanisms and location for generating such innate memory responses in vivo remain unknown. Here, we show that access of Bacillus Calmette-Guérin (BCG) to the bone marrow (BM) changes the transcriptional landscape of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), leading to local cell expansion and enhanced myelopoiesis at the expense of lymphopoiesis. Importantly, BCG-educated HSCs generate epigenetically modified macrophages that provide significantly better protection against virulent M. tuberculosis infection than naïve macrophages. By using parabiotic and chimeric mice, as well as adoptive transfer approaches, we demonstrate that training of the monocyte/macrophage lineage via BCG-induced HSC reprogramming is sustainable in vivo. Our results indicate that targeting the HSC compartment provides a novel approach for vaccine development.
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Células Madre Hematopoyéticas/inmunología , Inmunidad Innata , Memoria Inmunológica , Mycobacterium bovis/inmunología , Transcriptoma , Animales , Línea Celular , Células Cultivadas , Epigénesis Genética , Hematopoyesis , Ratones , Ratones Endogámicos C57BL , Tuberculosis/inmunologíaRESUMEN
Pulmonary immunity requires tight regulation, as interstitial inflammation can compromise gas exchange and lead to respiratory failure. Here we found a greater number of aged CD11bhiL-selectinloCXCR4+ polymorphonuclear leukocytes (PMNs) in lung vasculature than in the peripheral circulation. Using pulmonary intravital microscopy, we observed lung PMNs physically interacting with B cells via ß2 integrins; this initiated neutrophil apoptosis, which led to macrophage-mediated clearance. Genetic deletion of B cells led to the accumulation of aged PMNs in the lungs without systemic inflammation, which caused pathological fibrotic interstitial lung disease that was attenuated by the adoptive transfer of B cells or depletion of PMNs. Thus, the lungs are an intermediary niche in the PMN lifecycle wherein aged PMNs are regulated by B cells, which restrains their potential to cause pulmonary pathology.
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Linfocitos B/inmunología , Enfermedades Pulmonares Intersticiales/patología , Neutrófilos/patología , Fibrosis Pulmonar/patología , Animales , Enfermedades Pulmonares Intersticiales/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fibrosis Pulmonar/inmunologíaRESUMEN
Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection. Here, we examined how chronic viral infections alter the pulmonary microenvironment to foster coinfection and worsen disease severity. We developed a coordinated system of chronic virus and Mtb infection that induced central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination, and heightened mortality. These disease states were not due to chronic virus-induced immunosuppression or exhaustion; rather, increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lymph node and subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17 differentiation and increasing pulmonary neutrophilia, which diminished long-term survival. Temporally restoring CD4 T cell induction overcame these diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function, and foster long-term coinfection.
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Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Mycobacterium tuberculosis/fisiología , Neutrófilos/inmunología , Células TH1/inmunología , Células Th17/inmunología , Tuberculosis/inmunología , Inmunidad Adaptativa , Animales , Enfermedad Crónica , Coinfección , Inmunidad Innata , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fagocitosis , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
Resident-tissue macrophages (RTMs) arise from embryonic precursors1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15-/- mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E2 production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.
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Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico , Autorrenovación de las Células , Macrófagos Alveolares , Neutrófilos , Animales , Ratones , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Lesión Pulmonar Aguda , Animales Recién Nacidos , Araquidonato 12-Lipooxigenasa/deficiencia , Araquidonato 15-Lipooxigenasa/deficiencia , COVID-19 , Virus de la Influenza A , Lipopolisacáridos , Pulmón/citología , Pulmón/virología , Macrófagos Alveolares/citología , Macrófagos Alveolares/metabolismo , Neutrófilos/metabolismo , Infecciones por Orthomyxoviridae , Prostaglandinas E , SARS-CoV-2 , Susceptibilidad a EnfermedadesAsunto(s)
Inmunidad Adaptativa , Tolerancia Inmunológica , Inmunidad Innata , Memoria Inmunológica , Inmunidad Adaptativa/inmunología , Animales , Vacuna BCG/inmunología , Diferenciación Celular , Humanos , Tolerancia Inmunológica/inmunología , Inmunidad Innata/inmunología , Memoria Inmunológica/inmunología , VacunaciónRESUMEN
The nervous and immune systems are intricately linked1. Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood2. Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues through skeletal-muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signalling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin-releasing hormone neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, therefore calibrating the ability of the immune system to respond to physical threats.
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Encéfalo , Miedo , Leucocitos , Neuronas Motoras , Vías Nerviosas , Estrés Psicológico , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Encéfalo/citología , Encéfalo/fisiología , COVID-19/inmunología , Quimiocinas/inmunología , Susceptibilidad a Enfermedades , Miedo/fisiología , Glucocorticoides/metabolismo , Humanos , Leucocitos/citología , Leucocitos/inmunología , Linfocitos/citología , Linfocitos/inmunología , Tejido Linfoide/citología , Tejido Linfoide/inmunología , Ratones , Monocitos/citología , Monocitos/inmunología , Neuronas Motoras/citología , Neuronas Motoras/fisiología , Neutrófilos/citología , Neutrófilos/inmunología , Optogenética , Infecciones por Orthomyxoviridae/inmunología , Núcleo Hipotalámico Paraventricular/fisiología , SARS-CoV-2/inmunología , Estrés Psicológico/inmunología , Estrés Psicológico/fisiopatologíaRESUMEN
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.
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Inmunidad Adaptativa , Células Madre Hematopoyéticas , Inmunidad Innata , Memoria Inmunológica , Animales , Humanos , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/inmunología , Transducción de Señal , Diferenciación Celular , Epigénesis Genética , Linaje de la Célula , Inmunidad EntrenadaRESUMEN
BACKGROUND: Viral infections can cause acute respiratory distress syndrome (ARDS), systemic inflammation, and secondary cardiovascular complications. Lung macrophage subsets change during ARDS, but the role of heart macrophages in cardiac injury during viral ARDS remains unknown. Here we investigate how immune signals typical for viral ARDS affect cardiac macrophage subsets, cardiovascular health, and systemic inflammation. METHODS: We assessed cardiac macrophage subsets using immunofluorescence histology of autopsy specimens from 21 patients with COVID-19 with SARS-CoV-2-associated ARDS and 33 patients who died from other causes. In mice, we compared cardiac immune cell dynamics after SARS-CoV-2 infection with ARDS induced by intratracheal instillation of Toll-like receptor ligands and an ACE2 (angiotensin-converting enzyme 2) inhibitor. RESULTS: In humans, SARS-CoV-2 increased total cardiac macrophage counts and led to a higher proportion of CCR2+ (C-C chemokine receptor type 2 positive) macrophages. In mice, SARS-CoV-2 and virus-free lung injury triggered profound remodeling of cardiac resident macrophages, recapitulating the clinical expansion of CCR2+ macrophages. Treating mice exposed to virus-like ARDS with a tumor necrosis factor α-neutralizing antibody reduced cardiac monocytes and inflammatory MHCIIlo CCR2+ macrophages while also preserving cardiac function. Virus-like ARDS elevated mortality in mice with pre-existing heart failure. CONCLUSIONS: Our data suggest that viral ARDS promotes cardiac inflammation by expanding the CCR2+ macrophage subset, and the associated cardiac phenotypes in mice can be elicited by activating the host immune system even without viral presence in the heart.
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COVID-19 , Cardiomiopatías , Síndrome de Dificultad Respiratoria , SARS-CoV-2 , COVID-19/inmunología , COVID-19/complicaciones , COVID-19/patología , Animales , Humanos , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/virología , Ratones , Masculino , Femenino , Cardiomiopatías/inmunología , Cardiomiopatías/etiología , Cardiomiopatías/patología , Cardiomiopatías/virología , Macrófagos/inmunología , Macrófagos/patología , Macrófagos/metabolismo , Inflamación/patología , Persona de Mediana Edad , Miocardio/patología , Miocardio/inmunología , Ratones Endogámicos C57BL , AncianoRESUMEN
Leukotrienes (LTs) are lipid mediators derived from the 5-lipoxygenase pathway of arachidonate metabolism. Though best known for their role in asthma, they have broad actions that touch on virtually every aspect of mammalian biology. In a Brief Review published in the journal in 2005, we presented the existing evidence supporting a role for LTs in host defense. In this updated Brief Review, we focus on selected advances since then. We detail new insights into mechanisms and regulation of LT biosynthesis; the protective roles of LTs in the host response to diverse classes of pathogens, with an emphasis on viruses, including SARS-CoV-2; the phagocyte signal transduction mechanisms by which LTs exert their antimicrobial actions; the capacity for overexuberant LT production to promote tissue damage; and roles of LTs in the noninfectious immune-relevant conditions neuroinflammation and cancer.
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COVID-19 , Animales , Humanos , Araquidonato 5-Lipooxigenasa/metabolismo , Eicosanoides , Inmunidad Innata , Leucotrienos , Mamíferos/metabolismo , SARS-CoV-2/metabolismoRESUMEN
Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.
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Proteínas Quinasas Activadas por AMP/metabolismo , Linfocitos T CD4-Positivos/fisiología , Linfocitos T CD8-positivos/fisiología , Subtipo H1N1 del Virus de la Influenza A/inmunología , Infecciones por Orthomyxoviridae/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Adaptación Fisiológica/inmunología , Animales , Células Cultivadas , Reprogramación Celular/genética , Reprogramación Celular/inmunología , Metabolismo Energético , Glucosa/metabolismo , Glutamina/metabolismo , Humanos , Inmunomodulación , Activación de Linfocitos/genética , Metabolómica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Orthomyxoviridae/inmunología , Biosíntesis de Proteínas/genéticaRESUMEN
Hematopoietic stem and progenitor cells (HSPCs) play a vital role in the host response to infection through the rapid and robust production of mature immune cells. These HSPC responses can be influenced, directly and indirectly, by pathogens as well. Infection with Mycobacterium tuberculosis (Mtb) can drive lymphopoiesis through modulation of type I interferon (IFN) signaling. We have previously found that the presence of a drug resistance (DR)-conferring mutation in Mtb drives altered host-pathogen interactions and heightened type I IFN production in vitro. But the impacts of this DR mutation on in vivo host responses to Mtb infection, particularly the hematopoietic compartment, remain unexplored. Using a mouse model, we show that, while drug-sensitive Mtb infection induces expansion of HSPC subsets and a skew toward lymphopoiesis, DR Mtb infection fails to induce an expansion of these subsets and an accumulation of mature granulocytes in the bone marrow. Using single-cell RNA sequencing, we show that the HSCs from DR Mtb-infected mice fail to upregulate pathways related to cytokine signaling across all profiled HSC subsets. Collectively, our studies report a novel finding of a chronic infection that fails to induce a potent hematopoietic response that can be further investigated to understand pathogen-host interaction at the level of hematopoiesis.
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Infecciones Bacterianas , Mycobacterium tuberculosis , Tuberculosis , Humanos , Médula Ósea , Células Madre Hematopoyéticas , Mycobacterium tuberculosis/fisiología , Hematopoyesis/fisiología , Infecciones Bacterianas/metabolismo , Células de la Médula ÓseaRESUMEN
Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.