RESUMEN
Influenza viral infections often lead to increased mortality in older people. However, the mechanisms by which aging impacts immunity to influenza lung infection remain unclear. We employed a murine model of influenza infection to identify these mechanisms. With aging, we found reduced numbers of alveolar macrophages, cells essential for lung homeostasis. We also determined that these macrophages are critical for influenza-induced mortality with aging. Furthermore, aging vastly alters the transcriptional profile and specifically downregulates cell cycling pathways in alveolar macrophages. Aging impairs the ability of alveolar macrophages to limit lung damage during influenza infection. Moreover, aging decreases alveolar macrophage phagocytosis of apoptotic neutrophils, downregulates the scavenging receptor CD204, and induces retention of neutrophils during influenza infection. Thus, aging induces defective phagocytosis by alveolar macrophages and increases lung damage. These findings indicate that therapies that enhance the function of alveolar macrophages may improve outcomes in older people infected with respiratory viruses.
Asunto(s)
Envejecimiento , Gripe Humana/mortalidad , Macrófagos Alveolares/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/mortalidad , Fagocitosis , Animales , Ciclo Celular , Modelos Animales de Enfermedad , Humanos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana/inmunología , Gripe Humana/virología , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Macrófagos Alveolares/metabolismo , Ratones , Neutrófilos/inmunología , Neutrófilos/patología , Neutrófilos/virología , Infecciones por Orthomyxoviridae/virología , Receptores Depuradores de Clase A/genética , Receptores Depuradores de Clase A/metabolismoRESUMEN
The emergence of resistance to multiple antimicrobial agents by pathogenic bacteria has become a significant global public health threat. Multi-drug-resistant (MDR) Gram-negative bacteria have become particularly problematic, as no new classes of small-molecule antibiotics for Gram-negative bacteria have emerged in over two decades. We have developed a combinatorial screening process for identifying mixed ligand monolayer/gold nanoparticle conjugates (2.4 nm diameter) with antibiotic activity. The method previously led to the discovery of several conjugates with potent activity against the Gram-negative bacterium Escherichia coli. Here we show that these conjugates are also active against MDR E. coli and MDR Klebsiella pneumoniae. Moreover, we have shown that resistance to these nanoparticles develops significantly more slowly than to a commercial small-molecule drug. These results, combined with their relatively low toxicity to mammalian cells and biocompatibility in vivo, suggest that gold nanoparticles may be viable new candidates for the treatment of MDR Gram-negative bacterial infections.
Asunto(s)
Antibacterianos/farmacología , Materiales Biocompatibles/farmacología , Escherichia coli/efectos de los fármacos , Oro/farmacología , Klebsiella pneumoniae/efectos de los fármacos , Nanopartículas del Metal/química , Antibacterianos/síntesis química , Antibacterianos/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Relación Dosis-Respuesta a Droga , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Oro/química , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
The elderly exhibit increased mortality to influenza viral infection for unclear reasons. Mice are frequently used to model how aging impacts disease. Several studies have shown that aged mice exhibit an increased mortality to influenza virus, but two recent studies demonstrated the opposite. These two studies administered the virus intranasally in 20 µL, whereas the other studies used a viral inoculum in at least 30 µL. To determine whether the volume of the inoculum could explain the conflicting reports, we infected young and aged mice via intranasal instillation of 40 µL or 20 µL containing 1 x 104 plaque-forming units (PFU) of H1N1 influenza virus. We found that intranasal administration of 40 µL but not 20 µL of inoculum resulted in age-dependent mortality in mice. Compared to aged mice infected with 40 µL inoculum, those infected with 20 µL inoculum showed reduced levels of live virus and IFN-ß in the lung 3 days postinfection. Furthermore, aged mice administered 40 µL of Evans blue intranasally displayed increased dye retention in their bronchoalveolar lavage fluid compared to those administered 20 µL of Evans blue. Our data demonstrate that the inoculating volume of virus is critical for adequate delivery of influenza virus to the lung and thus for efficient infection of aged mice. These findings shed light on discrepant results in the literature regarding aged mice and influenza infection, and establish that mice can be used to examine how aging impacts the response to this biomedically important infection.
Asunto(s)
Líquido del Lavado Bronquioalveolar/virología , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Infecciones por Orthomyxoviridae/virología , Administración Intranasal , Factores de Edad , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/patología , Análisis de SupervivenciaRESUMEN
Neutrophils clear viruses, but excessive neutrophil responses induce tissue injury and worsen disease. Aging increases mortality to influenza infection; however, whether this is due to impaired viral clearance or a pathological host immune response is unknown. Here we show that aged mice have higher levels of lung neutrophils than younger mice after influenza viral infection. Depleting neutrophils after, but not before, infection substantially improves the survival of aged mice without altering viral clearance. Aged alveolar epithelial cells (AECs) have a higher frequency of senescence and secrete higher levels of the neutrophil-attracting chemokines CXCL1 and CXCL2 during influenza infection. These chemokines are required for age-enhanced neutrophil chemotaxis in vitro. Our work suggests that aging increases mortality from influenza in part because senescent AECs secrete more chemokines, leading to excessive neutrophil recruitment. Therapies that mitigate this pathological immune response in the elderly might improve outcomes of influenza and other respiratory infections.
Asunto(s)
Envejecimiento/fisiología , Células Epiteliales/fisiología , Gripe Humana/inmunología , Pulmón/patología , Neutrófilos/inmunología , Animales , Recuento de Células , Senescencia Celular , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/metabolismo , Quimiotaxis , Células Epiteliales/virología , Humanos , Gripe Humana/mortalidad , Ratones , Ratones Endogámicos C57BL , Mortalidad , Neutrófilos/virología , Análisis de SupervivenciaRESUMEN
Influenza-associated mortality continues to occur annually despite available antiviral therapies. New therapies that improve host immunity could reduce influenza virus disease burden. Targeting macrophage migration inhibitory factor (MIF) has improved the outcomes of certain inflammatory diseases, but its role in influenza viral infection is unclear. Here, we showed that, during influenza viral infection, Mif-deficient mice have less inflammation, viral load, and mortality compared with WT control mice; conversely, Tg mice, overexpressing Mif in alveolar epithelial cells, had higher inflammation, viral load, and mortality. Antibody-mediated blockade of MIF in WT mice during influenza viral infection improved their survival. Mif-deficient murine lungs showed reduced levels of parkin, a mitophagy protein that negatively regulates antiviral signaling, prior to infection and augmented antiviral type I/III IFN levels in the airspaces after infection as compared with WT lungs. Additionally, in vitro assays with human lung epithelial cells showed that treatment with recombinant human MIF increased the percentage of influenza virus-infected cells. In conclusion, our study reveals that MIF impairs antiviral host immunity and increases inflammation during influenza infection and suggests that targeting MIF could be therapeutically beneficial during influenza viral infection.
Asunto(s)
Antivirales/farmacología , Subtipo H1N1 del Virus de la Influenza A/patogenicidad , Gripe Humana/mortalidad , Oxidorreductasas Intramoleculares/inmunología , Factores Inhibidores de la Migración de Macrófagos/inmunología , Células Epiteliales Alveolares/inmunología , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Células Epiteliales Alveolares/virología , Animales , Antivirales/uso terapéutico , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H1N1 del Virus de la Influenza A/aislamiento & purificación , Gripe Humana/tratamiento farmacológico , Gripe Humana/inmunología , Gripe Humana/virología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/metabolismo , Pulmón/inmunología , Pulmón/patología , Factores Inhibidores de la Migración de Macrófagos/antagonistas & inhibidores , Factores Inhibidores de la Migración de Macrófagos/genética , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Cultivo Primario de Células , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismo , Análisis de Supervivencia , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/inmunología , Ubiquitina-Proteína Ligasas/metabolismo , Carga ViralRESUMEN
An increasing number of older people receive organ transplants for various end-stage conditions. Although organ transplantation is an effective therapy for older patients (i.e., older than 65 years of age), such as in end-stage renal disease, this therapy has not been optimized for older patients because of our lack of understanding of the effect of aging and the immune response to organ transplantation. Here, we provide an overview of the impact of aging on both the allograft and the recipient and its effect on the immune response to organ transplantation. We describe what has been determined to date, discuss existing gaps in our knowledge, and make suggestions on necessary future studies to optimize organ transplantation for older people.
Asunto(s)
Envejecimiento/inmunología , Fallo Renal Crónico/terapia , Trasplante de Riñón , Inmunología del Trasplante , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Fallo Renal Crónico/inmunología , MasculinoRESUMEN
BACKGROUND: Antiretroviral therapy (ART) has improved lifespan and quality of life of patients infected with the HIV-1. However, ART has several potential limitations, including the development of drug resistance and suboptimal penetration to selected anatomic compartments. Improving the delivery of antiretroviral molecules could overcome several of the limitations of current ART. RESULTS & CONCLUSION: Two to ten nanometer diameter inorganic gold crystals serve as a base scaffold to combine molecules with an array of properties in its surface. We show entry into different cell types, antiviral activity of an HIV integrase inhibitor conjugated in a gold nanoparticle and penetration into the brain in vivo without toxicity. Herein, gold nanoparticles prove to be a promising tool to use in HIV therapy.
Asunto(s)
Fármacos Anti-VIH/química , Portadores de Fármacos/química , Oro/química , VIH-1/fisiología , Nanopartículas del Metal/química , Animales , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/síntesis química , Encéfalo/metabolismo , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Proteína p24 del Núcleo del VIH/antagonistas & inhibidores , Proteína p24 del Núcleo del VIH/metabolismo , Infecciones por VIH/tratamiento farmacológico , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Macrófagos/citología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Nanopartículas del Metal/toxicidad , Nanopartículas del Metal/ultraestructura , Ratones , Ratones Endogámicos BALB C , Raltegravir Potásico/administración & dosificación , Raltegravir Potásico/síntesis química , Raltegravir Potásico/química , Distribución Tisular , Replicación Viral/efectos de los fármacosRESUMEN
The use of gold nanoparticles as imaging agents and therapeutic delivery systems is growing rapidly. However, a significant limitation of gold nanoparticles currently is their low absorption efficiencies in the gastrointestinal (GI) tract following oral administration. In an attempt to identify ligands that facilitate gold nanoparticle absorption in the GI tract, we have studied the oral bioavailability of 2.0 nm diameter gold nanoparticles modified with the small molecules p-mercaptobenzoic acid and glutathione, and polyethylene glycols (PEG) of different lengths and charge (neutral and anionic). We show that GI absorption of gold nanoparticles modified with the small molecules tested was undetectable. However, the absorption of PEGs depended upon PEG length, with the shortest PEG studied yielding gold nanoparticle absorptions that are orders-of-magnitude larger than observed previously. As the oral route is the most convenient one for administering drugs and diagnostic reagents, these results suggest that short-chain PEGs may be useful in the design of gold nanoparticles for the diagnosis and treatment of disease.