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1.
Cells ; 10(3)2021 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806810

RESUMEN

As highlighted by the COVID-19 global pandemic, elderly individuals comprise the majority of cases of severe viral infection outcomes and death. A combined inability to control viral replication and exacerbated inflammatory immune activation in elderly patients causes irreparable immune-mediated tissue pathology in response to infection. Key to these responses are type I, II, and III interferons (IFNs), which are involved in inducing an antiviral response, as well as controlling and suppressing inflammation and immunopathology. IFNs support monocyte/macrophage-stimulated immune responses that clear infection and promote their immunosuppressive functions that prevent excess inflammation and immune-mediated pathology. The timing and magnitude of IFN responses to infection are critical towards their immunoregulatory functions and ability to prevent immunopathology. Aging is associated with multiple defects in the ability of macrophages and dendritic cells to produce IFNs in response to viral infection, leading to a dysregulation of inflammatory immune responses. Understanding the implications of aging on IFN-regulated inflammation will give critical insights on how to treat and prevent severe infection in vulnerable individuals. In this review, we describe the causes of impaired IFN production in aging, and the evidence to suggest that these impairments impact the regulation of the innate and adaptive immune response to infection, thereby causing disease pathology.


Asunto(s)
Inmunidad Adaptativa , Envejecimiento/inmunología , Inmunidad Innata , Interferones/fisiología , Replicación Viral/inmunología , Anciano , /virología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Interferón Tipo I/inmunología , Interferón Tipo I/uso terapéutico , Interferón gamma/inmunología , Interferón gamma/uso terapéutico , Interferones/inmunología , Interferones/uso terapéutico
2.
Cells ; 10(3)2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33808998

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation. Therefore, we attempt to connect various clues in this field by reviewing and discussing recent research on the role of the thymus and T cells in COVID-19 immunity during aging (a synergistic effect of diminished responses to pathogens and enhanced responses to self) impacting age-related clinical severity of COVID-19. We also address potential combinational strategies to rejuvenate multiple aging-impacted immune system checkpoints by revival of aged thymic function, boosting peripheral T cell responses, and alleviating chronic, basal inflammation to improve the efficiency of anti-SARS-CoV-2 immunity and vaccination in the elderly.


Asunto(s)
/inmunología , Senescencia Celular/inmunología , Linfocitos T/inmunología , Timo/inmunología , Anciano , Anciano de 80 o más Años , Envejecimiento/inmunología , Envejecimiento/patología , Autoinmunidad , /fisiopatología , Humanos , Inflamación/inmunología , Inflamación/patología , Timo/efectos de los fármacos , Timo/fisiopatología , Timo/virología
3.
Med Sci Monit ; 27: e930278, 2021 Apr 09.
Artículo en Inglés | MEDLINE | ID: mdl-33833211

RESUMEN

The high infectivity and severity of SARS-CoV-2 infection (COVID-19), and our limited understanding of the biology of the novel coronavirus, as well as the lack of an effective treatment for COVID-19, have created a global pandemic. Those most likely to become seriously ill with COVID-19 are adults, especially the elderly and those who are already weak or sick. At present, a specific drug for treatment of COVID-19 has not been developed. This, combined with the typical coexistence of a variety of chronic diseases in elderly patients, makes treatment challenging at present. In addition, for elderly patients, COVID-19 isolation measures during the epidemic can easily lead to psychological problems. Thus, how to manage elderly patients has become a focus of social attention in the current circumstances. This article reviews the effects of COVID-19 and makes management suggestions for elderly patients during this epidemic period. In addition to the elderly, critically ill people are also highly susceptible to this novel coronavirus. For elderly COVID-19 patients, antiviral therapy, immune regulation, and even auxiliary respiratory therapy can be given after a comprehensive evaluation of the disease. With the approval and use of COVID-19 vaccines, it is reasonable to expect that we can conquer SARS-CoV-2.


Asunto(s)
Antivirales/uso terapéutico , Enfermedad Crónica/epidemiología , Terapia Respiratoria/métodos , Factores de Edad , Anciano , Envejecimiento/inmunología , /epidemiología , /administración & dosificación , Terapia Combinada/métodos , Comorbilidad , Enfermedad Crítica/epidemiología , Susceptibilidad a Enfermedades , Humanos , Factores de Riesgo , /inmunología , Índice de Severidad de la Enfermedad
4.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-33800867

RESUMEN

During tissue injury events, the innate immune system responds immediately to alarms sent from the injured cells, and the adaptive immune system subsequently joins in the inflammatory reaction. The control mechanism of each immune reaction relies on the orchestration of different types of T cells and the activators, antigen-presenting cells, co-stimulatory molecules, and cytokines. Mitochondria are an intracellular signaling organelle and energy plant, which supply the energy requirement of the immune system and maintain the system activation with the production of reactive oxygen species (ROS). Extracellular mitochondria can elicit regenerative effects or serve as an activator of the immune cells to eliminate the damaged cells. Recent clarification of the cytosolic escape of mitochondrial DNA triggering innate immunity underscores the pivotal role of mitochondria in inflammation-related diseases. Human mesenchymal stem cells could transfer mitochondria through nanotubular structures to defective mitochondrial DNA cells. In recent years, mitochondrial therapy has shown promise in treating heart ischemic events, Parkinson's disease, and fulminating hepatitis. Taken together, these results emphasize the emerging role of mitochondria in immune-cell-mediated tissue regeneration and ageing.


Asunto(s)
Envejecimiento/inmunología , Células Presentadoras de Antígenos/inmunología , Subgrupos de Linfocitos B/inmunología , Mitocondrias/fisiología , Regeneración/inmunología , Subgrupos de Linfocitos T/inmunología , Inmunidad Adaptativa , Animales , Citocinas/fisiología , ADN/metabolismo , ADN Mitocondrial/metabolismo , Reposicionamiento de Medicamentos , Péptido 1 Similar al Glucagón/agonistas , Homeostasis , Humanos , Inmunidad Innata , Inflamación , Péptidos y Proteínas de Señalización Intercelular/fisiología , Lupus Eritematoso Sistémico/tratamiento farmacológico , Metformina/farmacología , Metformina/uso terapéutico , Mitocondrias/efectos de los fármacos , Proteínas Mitocondriales/fisiología , Especies Reactivas de Oxígeno/metabolismo , Inmunología del Trasplante , Heridas y Traumatismos/inmunología , Heridas y Traumatismos/fisiopatología
5.
Cell ; 184(8): 1990-2019, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33811810

RESUMEN

The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer. Here, we review the molecular and cellular aspects of lung aging, local stress response pathways, and how the aging process predisposes to the pathogenesis of pulmonary disease. We place these insights into context of the COVID-19 pandemic and discuss how innate and adaptive immunity within the lung is altered with age.


Asunto(s)
Envejecimiento , Senescencia Celular , Enfermedades Pulmonares , Pulmón , Inmunidad Adaptativa , Anciano , Envejecimiento/inmunología , Envejecimiento/patología , /patología , Humanos , Pulmón/inmunología , Pulmón/patología , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/patología , Estrés Oxidativo
6.
Int J Mol Sci ; 22(5)2021 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-33668122

RESUMEN

Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation induces the immunosuppressive tumor microenvironment, such as increasing the level of pro-inflammatory cytokines, chemokines, and immunosuppressive molecules, inducing immune checkpoint molecules and cytotoxic T-cell exhaustion, and accumulating regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). The suppression of antitumor immunity by inflammation is especially examined in the liver and colorectal cancer. In addition, chronic inflammation is induced during aging and causes age-related diseases, including cancer, by affecting immunity. Therefore, we also discuss the age-related diseases regulated by inflammation, especially in the liver and colon.


Asunto(s)
Envejecimiento/inmunología , Transformación Celular Neoplásica/inmunología , Neoplasias Gastrointestinales/inmunología , Inmunomodulación , Inflamación/inmunología , Neoplasias Hepáticas/inmunología , Envejecimiento/patología , Animales , Transformación Celular Neoplásica/patología , Neoplasias Gastrointestinales/patología , Humanos , Neoplasias Hepáticas/patología
7.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-33669239

RESUMEN

Irregular inflammatory responses are a major contributor to tissue dysfunction and inefficient repair. Skin has proven to be a powerful model to study mechanisms that regulate inflammation. In particular, skin wound healing is dependent on a rapid, robust immune response and subsequent dampening of inflammatory signaling. While injury-induced inflammation has historically been attributed to keratinocytes and immune cells, a vast body of evidence supports the ability of non-immune cells to coordinate inflammation in numerous tissues and diseases. In this review, we concentrate on the active participation of tissue-resident adipocytes and fibroblasts in pro-inflammatory signaling after injury, and how altered cellular communication from these cells can contribute to irregular inflammation associated with aberrant wound healing. Furthering our understanding of how tissue-resident mesenchymal cells contribute to inflammation will likely reveal new targets that can be manipulated to regulate inflammation and repair.


Asunto(s)
Adipocitos Blancos/inmunología , Dermis/citología , Dermis/lesiones , Fibroblastos/inmunología , Cicatrización de Heridas/inmunología , Envejecimiento/inmunología , Envejecimiento/metabolismo , Animales , Comunicación Celular/inmunología , Polaridad Celular/inmunología , Citocinas/metabolismo , Diabetes Mellitus/inmunología , Diabetes Mellitus/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Células Madre Mesenquimatosas/metabolismo , Transducción de Señal/inmunología
8.
J R Soc Interface ; 18(176): 20200982, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33726544

RESUMEN

Here, we report that COVID-19 hospitalization rates follow an exponential relationship with age, doubling for every 16 years of age or equivalently increasing by 4.5% per year of life (R2 = 0.98). This mirrors the well-studied exponential decline of both thymus volume and T-cell production, which halve every 16 years. COVID-19 can therefore be added to the list of other diseases with this property, including those caused by methicillin-resistant Staphylococcus aureus, MERS-CoV, West Nile virus, Streptococcus pneumoniae and certain cancers, such as chronic myeloid leukaemia and brain cancers. In addition, the incidence of severe disease and mortality due to COVID-19 are both higher in men, consistent with the degree to which thymic involution (and the decrease in T-cell production with age) is more severe in men compared to women. Since these properties are shared with some non-contagious diseases, we hypothesized that the age dependence does not come from social-mixing patterns, i.e. that the probability of hospitalization given infection rises exponentially, doubling every 16 years. A Bayesian analysis of daily hospitalizations, incorporating contact matrices, found that this relationship holds for every age group except for the under 20s. While older adults have fewer contacts than young adults, our analysis suggests that there is an approximate cancellation between the effects of fewer contacts for the elderly and higher infectiousness due to a higher probability of developing severe disease. Our model fitting suggests under 20s have 49-75% additional immune protection beyond that predicted by strong thymus function alone, consistent with increased juvenile cross-immunity from other viruses. We found no evidence for differences between age groups in susceptibility to infection or infectiousness to others (given disease state), i.e. the only important factor in the age dependence of hospitalization rates is the probability of hospitalization given infection. These findings suggest the existence of a T-cell exhaustion threshold, proportional to thymic output and that clonal expansion of peripheral T-cells does not affect disease risk. The strikingly simple inverse relationship between risk and thymic T-cell output adds to the evidence that thymic involution is an important factor in the decline of the immune system with age and may also be an important clue in understanding disease progression, not just for COVID-19 but other diseases as well.


Asunto(s)
Envejecimiento/inmunología , Hospitalización/estadística & datos numéricos , Linfocitos T/fisiología , Timo/citología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/patología , Teorema de Bayes , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto Joven
9.
PLoS Pathog ; 17(3): e1009420, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33770147

RESUMEN

To simultaneously determine clinical and immunological responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old females and males, 681 coronavirus disease 2019 (COVID-19) patients and 369 normal controls (NCs) were analyzed based on age and sex classifications using multiple linear regression analysis. Compared to the age-matched NCs, both young and old male and female non-comorbid COVID-19 patients had lower lymphocyte counts and alanine aminotransferase (ALT) concentration, and only young male and female patients had lower neutrophil counts. Compared to young patients, both old males and females had significantly higher plasma ALT and AST concentrations. Compared to young and old females, age-matched males had higher plasma ALT and AST concentrations, but only young males had higher C-reactive protein (CRP) concentration. Compared to females, old males, but not young males, showed higher incidence of critical illness. Compared to young patients, old females had more leukocyte and neutrophil counts above the normal upper limit and B cell count below the normal lower limit (NLL), while old males had more lymphocyte and natural killer (NK) cell counts below the NLL. No sex or age associations with B cell and NK cell counts were observed. However, there were age-dependent decreases in CD8+ T-cell counts in both male and female COVID-19 patients. Age was negatively associated with CD8+ T cell counts but positively associated with neutrophil count, CRP, ALT, and AST concentrations, and sex (females) was negatively associated with neutrophil count, CRP, ALT, and AST concentrations. The present study suggests that SARS-CoV-2 infection mainly induced 1) beneficial sex (female)-related differences regarding reduced COVID-19 disease severity and negative associations with inflammatory responses and liver damage, and 2) harmful age-related differences relating to negative associations with CD8+ T cell count and positive associations with inflammatory responses and liver damage. Thus, sex and age are biological variables that should be considered in the prevention and treatment of COVID-19.


Asunto(s)
Envejecimiento/inmunología , Linfocitos/inmunología , Caracteres Sexuales , Adolescente , Adulto , Factores de Edad , Anciano , Envejecimiento/patología , Femenino , Humanos , Recuento de Linfocitos , Linfocitos/patología , Masculino , Persona de Mediana Edad , Factores Sexuales
10.
Sci Immunol ; 6(57)2021 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-33653907

RESUMEN

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.


Asunto(s)
/inmunología , Activación de Linfocitos , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Envejecimiento/inmunología , Niño , Preescolar , Femenino , Citometría de Flujo , Humanos , Leucopenia/inmunología , Masculino , Adulto Joven
11.
Horm Mol Biol Clin Investig ; 42(1): 87-98, 2021 Feb 04.
Artículo en Inglés | MEDLINE | ID: mdl-33544506

RESUMEN

The COVID-19 pandemic has not only led to a worldwide socio-economic depression, but has also had the highest health impact on the geriatric population. Elderly population, due to various reasons such as low immunity, pre-existing co-morbidities such as hypertension, cardiovascular diseases or diabetes, are obviously predisposed to develop severe infections and exhibit a high mortality rate. This is because of many reasons which include the atypical presentation in the geriatric population which might have led to diagnostic delay. As per the WHO guidelines to perform RT-PCR only on the symptomatic individuals, a very small portion of individuals were tested, leaving a fraction of population undiagnosed. Therefore, there remained a chance that many asymptomatic individuals such caregivers, healthcare professionals, family members were undiagnosed and might have carried this virus to the geriatric patients. Also, many countries were not prepared to handle the burden on their healthcare system which included sudden increased demand of ICU beds, mechanical ventilation etc. As a result, they had to make decision on who to be admitted. Atypical presentation in geriatric population may include afebrile or low-grade fever, absence of cough, malaise, muscle pains, dyspnoea etc. Geriatric population shows a more severe type of pneumonia, significantly higher number of neutrophils and C-reactive protein, less lymphocytes and a higher proportion of multiple lobe involvement. Extreme social suppression during COVID-19 pandemic has increased the risk of mental and physical adverse effects that has made older adults more vulnerable to depression and anxiety.


Asunto(s)
Envejecimiento/fisiología , /patología , Factores de Edad , Anciano , Anciano de 80 o más Años , Envejecimiento/inmunología , /inmunología , Diagnóstico Tardío , Geriatría , Humanos , Persona de Mediana Edad , Pandemias , Pronóstico , Índice de Severidad de la Enfermedad
13.
J Allergy Clin Immunol Pract ; 9(2): 641-650, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33551039

RESUMEN

Maturation of the adaptive immune response is typically thought to improve outcome to virus infections. However, long-standing observations of natural infections with old viruses such as Epstein-Barr virus and newer observations of emerging viruses such as severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 suggest that immune immaturity may be beneficial for outcome. Mechanistic studies and studies of patients with inborn errors of immunity have revealed that immune dysregulation reflecting inappropriate antibody and T-cell responses plays a crucial role in causing bystander inflammation and more severe disease. Further evidence supports a role for innate immunity in normally regulating adaptive immune responses. Thus, changes in immune responses that normally occur with age may help explain an apparent protective role of immune immaturity during virus infections.


Asunto(s)
Envejecimiento/inmunología , Virosis/inmunología , Inmunidad Adaptativa , Animales , Humanos , Inmunidad Innata
14.
Nature ; 592(7853): 283-289, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33524990

RESUMEN

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD-foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD-foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD 'down', one-RBD 'up' state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses. Prime-boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2-18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA1-3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).


Asunto(s)
/inmunología , /prevención & control , Modelos Animales de Enfermedad , /inmunología , Envejecimiento/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Antígenos Virales/química , Antígenos Virales/genética , Antígenos Virales/inmunología , /terapia , /administración & dosificación , /genética , Línea Celular , Ensayos Clínicos como Asunto , Femenino , Humanos , Inmunización Pasiva , Internacionalidad , Macaca mulatta/inmunología , Macaca mulatta/virología , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Multimerización de Proteína , ARN Viral/análisis , Sistema Respiratorio/inmunología , Sistema Respiratorio/virología , /genética , Solubilidad , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Linfocitos T/inmunología , Vacunación , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/química , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología
15.
Nature ; 590(7844): 29-31, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33469204
16.
Elife ; 92020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33317695

RESUMEN

Vaccines are powerful tools to develop immune memory to infectious diseases and prevent excess mortality. In older adults, however vaccines are generally less efficacious and the molecular mechanisms that underpin this remain largely unknown. Autophagy, a process known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show that autophagy is specifically induced in vaccine-induced antigen-specific CD8+ T cells in healthy human volunteers. In addition, reduced IFNγ secretion by RSV-induced T cells in older vaccinees correlates with low autophagy levels. We demonstrate that levels of the endogenous autophagy-inducing metabolite spermidine fall in human T cells with age. Spermidine supplementation in T cells from old donors recovers their autophagy level and function, similar to young donors' cells, in which spermidine biosynthesis has been inhibited. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. In summary, we have provided evidence for the importance of autophagy in vaccine immunogenicity in older humans and uncovered two novel drug targets that may increase vaccination efficiency in the aging context.


Asunto(s)
Envejecimiento/inmunología , Autofagia/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra Virus Sincitial Respiratorio/inmunología , Espermidina/farmacología , Adyuvantes Inmunológicos/farmacología , Adulto , Anciano , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Línea Celular Tumoral , Humanos , Memoria Inmunológica/inmunología , Interferón gamma/sangre , Células Jurkat , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Factores de Iniciación de Péptidos/metabolismo , Proteínas de Unión al ARN/metabolismo , Virus Sincitiales Respiratorios/inmunología , Espermidina/sangre , Vacunación , Adulto Joven
17.
Proc Natl Acad Sci U S A ; 117(52): 33561-33569, 2020 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-33376222

RESUMEN

Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.


Asunto(s)
Envejecimiento/inmunología , Interacciones Huésped-Patógeno/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Proteínas Asociadas a Microtúbulos/metabolismo , Fagocitosis , Streptococcus pneumoniae/inmunología , Animales , Autofagia , Proteínas Bacterianas/metabolismo , Lípidos/química , Macrófagos/ultraestructura , Masculino , Ratones , Ratones Endogámicos C57BL , Viabilidad Microbiana , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Streptococcus pneumoniae/ultraestructura , Estreptolisinas/metabolismo
18.
PLoS One ; 15(12): e0240773, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33378402

RESUMEN

Infectious diseases are a threat to elderly individuals, whose immune systems weaken with age. Among the various infectious diseases, Clostridium difficile infection is associated with a high rate of mortality in elderly individuals and is a serious health problem worldwide, owing to the increasing infection rates. Probiotic use has been proposed as an effective countermeasure for C. difficile infection. The aim of this study was to evaluate the effects of heat-killed Enterococcus faecalis T-110 on intestinal immunity, intestinal flora, and intestinal infections, especially C. difficile infections, in naturally ageing animals, for extrapolating the results to elderly human subjects. Twenty female hamsters were randomly distributed into two groups. Group 1 was fed a basal diet and group 2 was fed a basal diet supplemented with heat-killed E. faecalis for 7 days. Heat-killed E. faecalis T-110 improved the gut immunity and microflora, especially Clostridium perfringens and C. difficile, in naturally aged hamsters. Therefore, heat-killed E. faecalis T-110 use may be a countermeasure against age-related immune dysfunction and intestinal infections, especially C. difficile infection, in elderly humans. However, further investigation in this regard is needed in humans.


Asunto(s)
Envejecimiento/inmunología , Infecciones por Clostridium/prevención & control , Diarrea/prevención & control , Enterococcus faecalis/inmunología , Probióticos/administración & dosificación , Factores de Edad , Anciano , Animales , /aislamiento & purificación , Infecciones por Clostridium/inmunología , Infecciones por Clostridium/microbiología , Clostridium perfringens/inmunología , Clostridium perfringens/aislamiento & purificación , Cricetinae , Diarrea/inmunología , Diarrea/microbiología , Modelos Animales de Enfermedad , Heces/microbiología , Femenino , Microbioma Gastrointestinal/inmunología , Calor , Humanos , Tolerancia Inmunológica/fisiología , Inmunidad Mucosa , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología
20.
Aging Cell ; 19(10): e13230, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33006233

RESUMEN

COVID-19 is an ongoing pandemic caused by the SARS-CoV-2 coronavirus that poses one of the greatest challenges to public health in recent years. SARS-CoV-2 is known to preferentially target older subjects and those with pre-existing conditions, but the reason for this age dependence is unclear. Here, we found that the case fatality rate for COVID-19 grows exponentially with age in all countries tested, with the doubling time approaching that of all-cause human mortality. In addition, men and those with multiple age-related diseases are characterized by increased mortality. Moreover, similar mortality patterns were found for all-cause pneumonia. We further report that the gene expression of ACE2, the SARS-CoV-2 receptor, grows in the lung with age, except for subjects on a ventilator. Together, our findings establish COVID-19 as an emergent disease of aging, and age and age-related diseases as its major risk factors. In turn, this suggests that COVID-19, and deadly respiratory diseases in general, may be targeted, in addition to antiviral approaches, by approaches that target the aging process.


Asunto(s)
Envejecimiento/inmunología , Infecciones por Coronavirus/mortalidad , Neumonía Viral/mortalidad , Factores de Edad , Anciano , Betacoronavirus , Femenino , Salud Global , Humanos , Masculino , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Factores Sexuales
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