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1.
J Immunol ; 204(6): 1661-1673, 2020 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-32060136

RESUMEN

The seasonal influenza vaccine is an important public health tool but is only effective in a subset of individuals. The identification of molecular signatures provides a mechanism to understand the drivers of vaccine-induced immunity. Most previously reported molecular signatures of human influenza vaccination were derived from a single age group or season, ignoring the effects of immunosenescence or vaccine composition. Thus, it remains unclear how immune signatures of vaccine response change with age across multiple seasons. In this study we profile the transcriptional landscape of young and older adults over five consecutive vaccination seasons to identify shared signatures of vaccine response as well as marked seasonal differences. Along with substantial variability in vaccine-induced signatures across seasons, we uncovered a common transcriptional signature 28 days postvaccination in both young and older adults. However, gene expression patterns associated with vaccine-induced Ab responses were distinct in young and older adults; for example, increased expression of killer cell lectin-like receptor B1 (KLRB1; CD161) 28 days postvaccination positively and negatively predicted vaccine-induced Ab responses in young and older adults, respectively. These findings contribute new insights for developing more effective influenza vaccines, particularly in older adults.


Asunto(s)
Anticuerpos Antivirales/sangre , Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Adulto , Factores de Edad , Anciano , Envejecimiento/inmunología , Anticuerpos Antivirales/inmunología , Estudios de Cohortes , Femenino , Perfilación de la Expresión Génica , Pruebas de Inhibición de Hemaglutinación , Humanos , Inmunogenicidad Vacunal/genética , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/inmunología , Gripe Humana/virología , Masculino , Subfamilia B de Receptores Similares a Lectina de Células NK/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Estaciones del Año , Transcriptoma/inmunología , Vacunación , Vacunas de Productos Inactivados/administración & dosificación , Vacunas de Productos Inactivados/inmunología , Adulto Joven
2.
Aging (Albany NY) ; 15(16): 7866-7908, 2023 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-37606991

RESUMEN

Dectin-1 is an innate immune receptor that recognizes and binds ß-1, 3/1, 6 glucans on fungi. We evaluated Dectin-1 function in myeloid cells in a cohort of HIV-positive and HIV-negative young and older adults. Stimulation of monocytes with ß-D-glucans induced a pro-inflammatory phenotype in monocytes of HIV-infected individuals that was characterized by increased levels of IL-12, TNF-α, and IL-6, with some age-associated cytokine increases also noted. Dendritic cells showed a striking HIV-associated increase in IFN-α production. These increases in cytokine production paralleled increases in Dectin-1 surface expression in both monocytes and dendritic cells that were noted with both HIV and aging. Differential gene expression analysis showed that HIV-positive older adults had a distinct gene signature compared to other cohorts characterized by a robust TNF-α and coagulation response (increased at baseline), a persistent IFN-α and IFN-γ response, and an activated dendritic cell signature/M1 macrophage signature upon Dectin-1 stimulation. Dectin-1 stimulation induced a strong upregulation of MTORC1 signaling in all cohorts, although increased in the HIV-Older cohort (stimulation and baseline). Overall, our study demonstrates that the HIV Aging population has a distinct immune signature in response to Dectin-1 stimulation. This signature may contribute to the pro-inflammatory environment that is associated with HIV and aging.


Asunto(s)
Infecciones por VIH , Factor de Necrosis Tumoral alfa , Humanos , Citocinas , Glucanos
3.
Biochemistry ; 50(32): 6763-73, 2011 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-21688771

RESUMEN

The role of the extracellular loop region of a short-wavelength sensitive pigment, Xenopus violet cone opsin, is investigated via computational modeling, mutagenesis, and spectroscopy. The computational models predict a complex H-bonding network that stabilizes and connects the EC2-EC3 loop and the N-terminus. Mutations that are predicted to disrupt the H-bonding network are shown to produce visual pigments that do not stably bind chromophore and exhibit properties of a misfolded protein. The potential role of a disulfide bond between two conserved Cys residues, Cys(105) in TM3 and Cys(182) in EC2, is necessary for proper folding and trafficking in VCOP. Lastly, certain residues in the EC2 loop are predicted to stabilize the formation of two antiparallel ß-strands joined by a hairpin turn, which interact with the chromophore via H-bonding or van der Waals interactions. Mutations of conserved residues result in a decrease in the level of chromophore binding. These results demonstrate that the extracellular loops are crucial for the formation of this cone visual pigment. Moreover, there are significant differences in the structure and function of this region in VCOP compared to that in rhodopsin.


Asunto(s)
Secuencia Conservada , Pigmentos Retinianos/química , Secuencia de Aminoácidos , Disulfuros/química , Enlace de Hidrógeno , Modelos Moleculares , Simulación de Dinámica Molecular , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Pigmentos Retinianos/genética , Homología de Secuencia de Aminoácido , Espectrofotometría Ultravioleta
4.
Front Genet ; 15: 1396535, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38660674
5.
J Gerontol A Biol Sci Med Sci ; 74(6): 794-801, 2019 05 16.
Artículo en Inglés | MEDLINE | ID: mdl-30239628

RESUMEN

Both aging and HIV infection are associated with an enhanced pro-inflammatory environment that contributes to impaired immune responses and is mediated in part by innate immune pattern-recognition receptors. MINCLE is a C-type lectin receptor that recognizes trehalose-6,6'-dimycolate or "cord factor," the most abundant glycolipid in Mycobacterium tuberculosis. Here, we evaluated MINCLE function in monocytes in a cohort of HIV-infected and uninfected young (21-35 years) and older adults (≥60 years) via stimulation of peripheral blood mononuclear cells with trehalose-6,6-dibehenate, a synthetic analog of trehalose-6,6'-dimycolate and measurement of cytokine production (interleukin [IL]-10, IL-12, IL-6, tumor necrosis factor-α) by multicolor flow cytometry. Our studies show an age- and HIV-associated increase in cytokine multifunctionality of monocytes both at the population and single cell level that was dominated by IL-12, IL-10, and IL-6. These findings provide insight into the host response to M. tuberculosis and possible sources for the pro-inflammatory environment seen in aging and HIV infection.


Asunto(s)
Envejecimiento/inmunología , Infecciones por VIH/inmunología , Lectinas Tipo C/metabolismo , Monocitos/metabolismo , Receptores Inmunológicos/metabolismo , Adulto , Estudios de Cohortes , Citocinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
6.
J Am Geriatr Soc ; 63(4): 776-81, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25851728

RESUMEN

Advances in bacterial deoxyribonucleic acid sequencing allow for characterization of the human commensal bacterial community (microbiota) and its corresponding genome (microbiome). Surveys of healthy adults reveal that a signature composite of bacteria characterizes each unique body habitat (e.g., gut, skin, oral cavity, vagina). A myriad of clinical changes, including a basal proinflammatory state (inflamm-aging), that directly interface with the microbiota of older adults and enhance susceptibility to disease accompany aging. Studies in older adults demonstrate that the gut microbiota correlates with diet, location of residence (e.g., community dwelling, long-term care settings), and basal level of inflammation. Links exist between the microbiota and a variety of clinical problems plaguing older adults, including physical frailty, Clostridium difficile colitis, vulvovaginal atrophy, colorectal carcinoma, and atherosclerotic disease. Manipulation of the microbiota and microbiome of older adults holds promise as an innovative strategy to influence the development of comorbidities associated with aging.


Asunto(s)
Envejecimiento/fisiología , Microbiota/fisiología , Anciano , Clostridioides difficile , Colitis/microbiología , Susceptibilidad a Enfermedades/microbiología , Anciano Frágil , Tracto Gastrointestinal/microbiología , Humanos , Inflamación/microbiología , Características de la Residencia
7.
Curr Opin Immunol ; 29: 127-36, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24997358

RESUMEN

HIV infection is associated with a chronic inflammatory state arising from multiple factors, including innate immune recognition of HIV, increased microbial translocation, and release of endogenous ligands from damaged cells (such as CD4 T cells). In many respects, this heightened pro-inflammatory environment resembles that associated with aging in the absence of HIV infection, and evidence of dysregulated innate immune responses can be found in not only older HIV-negative adults, but also adults with HIV infection. While the study of innate immune aging in HIV infection is still in its early stages, it seems likely that at least additive, or potentially synergistic effects of aging and HIV infection will be found.


Asunto(s)
Envejecimiento/inmunología , Infecciones por VIH/inmunología , Inmunidad Innata , Células Dendríticas/inmunología , Humanos , Inflamación/inmunología , Receptores Toll-Like/inmunología
8.
Infect Control Hosp Epidemiol ; 35(7): 810-7, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24915208

RESUMEN

OBJECTIVE: We describe the efficacy of enhanced infection control measures, including those recommended in the Centers for Disease Control and Prevention's 2012 carbapenem-resistant Enterobacteriaceae (CRE) toolkit, to control concurrent outbreaks of carbapenemase-producing Enterobacteriaceae (CPE) and extensively drug-resistant Acinetobacter baumannii (XDR-AB). DESIGN: Before-after intervention study. SETTING: Fifteen-bed surgical trauma intensive care unit (ICU). METHODS: We investigated the impact of enhanced infection control measures in response to clusters of CPE and XDR-AB infections in an ICU from April 2009 to March 2010. Polymerase chain reaction was used to detect the presence of blaKPC and resistance plasmids in CRE. Pulsed-field gel electrophoresis was performed to assess XDR-AB clonality. Enhanced infection-control measures were implemented in response to ongoing transmission of CPE and a new outbreak of XDR-AB. Efficacy was evaluated by comparing the incidence rate (IR) of CPE and XDR-AB before and after the implementation of these measures. RESULTS: The IR of CPE for the 12 months before the implementation of enhanced measures was 7.77 cases per 1,000 patient-days, whereas the IR of XDR-AB for the 3 months before implementation was 6.79 cases per 1,000 patient-days. All examined CPE shared endemic blaKPC resistance plasmids, and 6 of the 7 XDR-AB isolates were clonal. Following institution of enhanced infection control measures, the CPE IR decreased to 1.22 cases per 1,000 patient-days (P = .001), and no more cases of XDR-AB were identified. CONCLUSIONS: Use of infection control measures described in the Centers for Disease Control and Prevention's 2012 CRE toolkit was associated with a reduction in the IR of CPE and an interruption in XDR-AB transmission.


Asunto(s)
Infecciones por Acinetobacter/prevención & control , Acinetobacter baumannii/efectos de los fármacos , Carbapenémicos/farmacología , Infección Hospitalaria/prevención & control , Infecciones por Enterobacteriaceae/prevención & control , Enterobacteriaceae/efectos de los fármacos , Control de Infecciones/métodos , Centros Médicos Académicos , Acinetobacter baumannii/aislamiento & purificación , Centers for Disease Control and Prevention, U.S. , Farmacorresistencia Bacteriana Múltiple , Enterobacteriaceae/aislamiento & purificación , Humanos , Unidades de Cuidados Intensivos , Evaluación de Resultado en la Atención de Salud , Estados Unidos , Virginia
9.
BMJ Case Rep ; 20132013 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-24248316

RESUMEN

A 56-year-old Hispanic man with no significant medical problems presented with a 2-month history of a non-healing right forearm lesion that progressed despite several courses of empiric antibiotics. The patient underwent incision and drainage. Warthin-Starry stain with immunohistochemistry testing diagnosed bacillary angiomatosis secondary to Bartonella quintana. Subsequently, the patient was diagnosed with HIV, with a CD4 count of 68 cells/mm(3), and a HIV viral load of 47, 914 copies/mL. The patient was treated with doxycycline and started on antiretroviral therapy. The lesion has resolved and he has had no recurrence after 16 months of treatment.


Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Angiomatosis Bacilar/etiología , Antibacterianos/uso terapéutico , Infecciones por Bartonella/etiología , Bartonella quintana/aislamiento & purificación , Doxiciclina/uso terapéutico , Infecciones por VIH/diagnóstico , Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Angiomatosis Bacilar/diagnóstico , Infecciones por Bartonella/tratamiento farmacológico , Recuento de Linfocito CD4 , Antebrazo/patología , Infecciones por VIH/complicaciones , Humanos , Huésped Inmunocomprometido , Masculino , Persona de Mediana Edad
10.
J Virol ; 81(2): 977-90, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17079291

RESUMEN

The transcription factors ATF-2 and c-Jun are important for transactivation of varicella-zoster virus (VZV) genes. c-Jun is activated by the c-Jun N-terminal kinase (JNK), a member of the mitogen-activated protein kinase pathway that responds to stress and cytokines. To study the effects of VZV on this pathway, confluent human foreskin fibroblasts were infected with cell-associated VZV for 1 to 4 days. Immunoblots showed that phosphorylated JNK and c-Jun levels increased in VZV-infected cells, and kinase assays determined that phospho-JNK was active. Phospho-JNK was detected after 24 h, and levels rose steadily over 4 days in parallel with accumulation of VZV antigen. The two main activators of JNK are MKK4 and MKK7, and levels of their active, phosphorylated forms also increased. The competitive inhibitor of JNK, SP600125, caused a dose-dependent reduction in VZV yield (50% effective concentration, congruent with 8 microM). Specificity was verified by immunoblotting; phospho-c-Jun was eliminated by 18 microM SP600125 in VZV-infected cells. Immunofluorescent confocal microscopy showed that phospho-c-Jun and most of phospho-JNK were in the nuclei of VZV-infected cells; some phospho-JNK was in the cytoplasm. MKK4, MKK7, JNK, and phospho-JNK were detected by immunoblotting in purified preparations of VZV virions, but c-Jun was absent. JNK was located in the virion tegument, as determined by biochemical fractionation and immunogold transmission electron microscopy. Overall, these results demonstrate the importance of the JNK pathway for VZV replication and advance the idea that JNK is a useful drug target against VZV.


Asunto(s)
Fibroblastos/virología , Herpesvirus Humano 3/patogenicidad , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Línea Celular , Activación Enzimática , Humanos , MAP Quinasa Quinasa 4/metabolismo , MAP Quinasa Quinasa 7/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Virión/metabolismo
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