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1.
Sci Rep ; 9(1): 15560, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31664157

RESUMO

Since ID93/GLA-SE was developed as a targeted BCG-prime booster vaccine, in the present study, we evaluated the protective efficacy of ID93/GLA-SE as a boost to a BCG-prime against the hypervirulent Mycobacterium tuberculosis (Mtb) K challenge to provide further information on the development and application of this vaccine candidate. Boosting BCG with the ID93/GLA-SE vaccine significantly reduced bacterial burden at 16 weeks post-challenge while the BCG vaccine alone did not confer significant protection against Mtb K. The pathological analysis of the lung from the challenged mice also showed the remarkably protective boosting effect of ID93/GLA-SE on BCG-immunised animals. Moreover, qualitative and quantitative analysis of the immune responses following ID93/GLA-SE-immunisation demonstrated that ID93/GLA-SE was able to elicit robust and sustained Th1-biased antigen-specific multifunctional CD4+ T-cell responses up to 16 weeks post-challenge as well as a high magnitude of an antigen-specific IgG response. Our findings demonstrate that the ID93/GLA-SE vaccine candidate given as a BCG-prime boost regimen confers a high level of long-term protection against the hypervirulent Mtb Beijing infection. These findings will provide further and more feasible validation for the potential utility of this vaccine candidate particularly in East-Asian countries, with the predominance of the Beijing genotype, after BCG vaccination.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31527037

RESUMO

Globally, more people die annually from tuberculosis than from any other single infectious agent. Unfortunately, there is no commercially-available vaccine that is sufficiently effective at preventing acquisition of pulmonary tuberculosis in adults. In this study, pre-exposure prophylactic pulmonary delivery of active aerosolized anti-tuberculosis bacteriophage D29 was evaluated as an option for protection against Mycobacterium tuberculosis infection. An average bacteriophage concentration of approximately 1 PFU/alveolus was achieved in the lungs of mice using a nose-only inhalation device optimized with a dose simulation technique and adapted for use with a vibrating mesh nebulizer. Within 30 minutes of bacteriophage delivery, the mice received either a low dose (∼50-100 CFU), or an ultra-low dose (∼5-10 CFU), of M. tuberculosis H37Rv aerosol to the lungs. A prophylactic effect was observed with bacteriophage aerosol pre-treatment significantly decreasing M. tuberculosis burden in mouse lungs 24 hours and 3 weeks post-challenge (p < 0.05). These novel results indicate that a sufficient dose of nebulized mycobacteriophage aerosol to the lungs may be a valuable intervention to provide extra protection to health care professionals and other individuals at risk of exposure to M. tuberculosis.

3.
Viruses ; 11(3)2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875748

RESUMO

Bats are increasingly implicated as hosts of highly pathogenic viruses. The underlying virus⁻host interactions and cellular mechanisms that promote co-existence remain ill-defined, but physiological traits such as flight and longevity are proposed to drive these adaptations. Autophagy is a cellular homeostatic process that regulates ageing, metabolism, and intrinsic immune defense. We quantified basal and stimulated autophagic responses in black flying fox cells, and demonstrated that although black flying fox cells are susceptible to Australian bat lyssavirus (ABLV) infection, viral replication is dampened in these bat cells. Black flying fox cells tolerated prolonged ABLV infection with less cell death relative to comparable human cells, suggesting post-entry mechanisms interference with virus replication. An elevated basal autophagic level was observed and autophagy was induced in response to high virus doses. Pharmacological stimulation of the autophagy pathway reduced virus replication, indicating autophagy acts as an anti-viral mechanism. Enhancement of basal and virus-induced autophagy in bat cells connects related reports that long-lived species possess homeostatic processes that dampen oxidative stress and macromolecule damage. Exemplifying the potential that evolved cellular homeostatic adaptations like autophagy may secondarily act as anti-viral mechanisms, enabling bats to serve as natural hosts to an assortment of pathogenic viruses. Furthermore, our data suggest autophagy-inducing drugs may provide a novel therapeutic strategy for combating lyssavirus infection.


Assuntos
Autofagia , Quirópteros/virologia , Interações entre Hospedeiro e Microrganismos , Lyssavirus/fisiologia , Replicação Viral , Animais , Encéfalo/citologia , Encéfalo/virologia , Células Cultivadas , Rim/citologia , Rim/virologia
4.
PLoS Negl Trop Dis ; 13(2): e0007083, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30763316

RESUMO

Seemingly innocuous nontuberculous mycobacteria (NTM) species, classified by their slow or rapid growth rates, can cause a wide range of illnesses, from skin ulceration to severe pulmonary and disseminated disease. Despite their worldwide prevalence and significant disease burden, NTM do not garner the same financial or research focus as Mycobacterium tuberculosis. In this review, we outline the most abundant of over 170 NTM species and inadequacies of diagnostics and treatments and weigh the advantages and disadvantages of currently available in vivo animal models of NTM. In order to effectively combat this group of mycobacteria, more research focused on appropriate animal models of infection, screening of chemotherapeutic compounds, and development of anti-NTM vaccines and diagnostics is urgently needed.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Micobactéria não Tuberculosa/tratamento farmacológico , Infecções por Micobactéria não Tuberculosa/prevenção & controle , Humanos , Infecções por Micobactéria não Tuberculosa/diagnóstico
5.
Eur J Immunol ; 49(2): 266-276, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30548475

RESUMO

Influenza A annually infects 5-10% of the world's human population resulting in one million deaths. Influenza causes annual epidemics and reinfects previously exposed individuals because of antigenic drift in the glycoprotein hemagglutinin. Due to antigenic drift, the immune system is simultaneously exposed to novel and conserved parts of the influenza virus via vaccination and/or infection throughout life. Preexisting immunity has long been known to augment subsequent hemagglutination inhibitory antibody (hAb) responses. However, the preexisting immunological contributors that influence hAb responses are not understood. Therefore, we adapted and developed sequential infection and immunization mouse models using drifted influenza strains to show that MHC Class II haplotype and T-cell reactivity influences subsequent hAb responses. We found that CB6F1 mice infected with A/CA followed by immunization with A/PR8 have increased hAb responses to A/PR8 compared to C57BL/6 mice. Increased hAb responses in CB6F1 mice were CD4+  T-cell and B-cell dependent and corresponded to increased germinal center A/PR8-specific B and T-follicular helper cells. These results suggest conserved MHC Class II restricted epitopes within HA are essential for B cells to respond to drifting influenza and could be leveraged to boost hAb responses.

6.
Vaccines (Basel) ; 6(2)2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29795025

RESUMO

It is estimated that one third of the world's population is infected with Mycobacterium tuberculosis (Mtb). This astounding statistic, in combination with costly and lengthy treatment regimens make the development of therapeutic vaccines paramount for controlling the global burden of tuberculosis. Unlike prophylactic vaccination, therapeutic immunization relies on the natural pulmonary infection with Mtb as the mucosal prime that directs boost responses back to the lung. The purpose of this work was to determine the protection and safety profile over time following therapeutic administration of our lead Mtb vaccine candidate, ID93 with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion (GLA-SE)), in combination with rifampicin, isoniazid, and pyrazinamide (RHZ) drug treatment. We assessed the host inflammatory immune responses and lung pathology 7⁻22 weeks post infection, and determined the therapeutic efficacy of combined treatment by enumeration of the bacterial load and survival in the SWR/J mouse model. We show that drug treatment alone, or with immunotherapy, tempered the inflammatory responses measured in brochoalveolar lavage fluid and plasma compared to untreated cohorts. RHZ combined with therapeutic immunizations significantly enhanced TH1-type cytokine responses in the lung over time, corresponding to decreased pulmonary pathology evidenced by a significant decrease in the percentage of lung lesions and destructive lung inflammation. These data suggest that bacterial burden assessment alone may miss important correlates of lung architecture that directly contribute to therapeutic vaccine efficacy in the preclinical mouse model. We also confirmed our previous finding that in combination with antibiotics therapeutic immunizations provide an additive survival advantage. Moreover, therapeutic immunizations with ID93/GLA-SE induced differential T cell immune responses over the course of infection that correlated with periods of enhanced bacterial control over that of drug treatment alone. Here we advance the immunotherapy model and investigate reliable correlates of protection and Mtb control.

7.
Front Immunol ; 9: 295, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29515589

RESUMO

Elderly people are at high risk for influenza-related morbidity and mortality due to progressive immunosenescence. While toll-like receptor (TLR) agonist containing adjuvants, and other adjuvants, have been shown to enhance influenza vaccine-induced protective responses, the mechanisms underlying how these adjuvanted vaccines could benefit the elderly remain elusive. Here, we show that a split H1N1 influenza vaccine (sH1N1) combined with a TLR4 agonist, glucopyranosyl lipid adjuvant formulated in a stable oil-in-water emulsion (GLA-SE), boosts IgG2c:IgG1 ratios, enhances hemagglutination inhibition (HAI) titers, and increases protection in aged mice. We find that all adjuvanted sH1N1 vaccines tested were able to protect both young and aged mice from lethal A/H1N1/California/4/2009 virus challenge after two immunizations compared to vaccine alone. We show that GLA-SE combined with sH1N1, however, also provides enhanced protection from morbidity in aged mice given one immunization (based on change in weight percentage). While the GLA-SE-adjuvanted sH1N1 vaccine promotes the generation of cytokine-producing T helper 1 cells, germinal center B cells, and long-lived bone marrow plasma cells in young mice, these responses were muted in aged mice. Differential in vitro responses, dependent on age, were also observed from mouse-derived bone marrow-derived dendritic cells and lung homogenates following stimulation with adjuvants, including GLA-SE. Besides enhanced HAI titers, additional protective factors elicited with sH1N1 + GLA-SE in young mice were observed, including (a) rapid reduction of viral titers in the lung, (b) prevention of excessive lung inflammation, and (c) homeostatic maintenance of alveolar macrophages (AMs) following H1N1 infection. Collectively, our results provide insight into mechanisms of adjuvant-mediated immune protection in the young and elderly.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Células Dendríticas/imunologia , Vírus da Influenza A Subtipo H1N1/fisiologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Infecções por Orthomyxoviridae/imunologia , Idoso , Animais , Anticorpos Antivirais/sangue , Células Cultivadas , Células Dendríticas/virologia , Feminino , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Humanos , Imunidade , Imunização , Lipídeo A/farmacologia , Lipídeo A/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Receptor 4 Toll-Like/agonistas
9.
Cancer Lett ; 408: 190-196, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28866092

RESUMO

An effective adaptive immune response hinges on the rapid clonal expansion of T cells in response to antigen. The sensitivity of these T cells to programmed cell death (i.e. apoptosis) is carefully calibrated at various stages to ensure a robust yet measured reaction that resolves without inflicting unintended damage to host tissues. To meet bioenergetic demands associated with vigorous proliferation, acquisition of effector functions, and memory formation, T cells also undergo dynamic changes in their metabolism at every stage of this response. In this review, we focus on relatively recent studies that illuminate intimate links between metabolic programs and apoptosis sensitivity in T cells. We then examine how these connections ultimately influence T cell survival and function within the metabolically taxing environs of the tumor microenvironment.


Assuntos
Apoptose , Reprogramação Celular , Metabolismo Energético , Memória Imunológica , Linfócitos T/imunologia , Animais , Diferenciação Celular , Humanos , Transdução de Sinais , Linfócitos T/metabolismo
10.
Cell Death Discov ; 3: 17031, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28580175

RESUMO

CD8+ central memory (CM) and effector memory (EM) T-cell subsets exhibit well-established differences in proliferative and protective capacity after infectious challenge. However, their relative sensitivity to apoptosis has been largely overlooked, despite the importance of programmed cell death in regulating effector T-cell homeostasis. Here we demonstrate that primary human effector T cells derived from the CD8+ EM subset exhibit significantly higher sensitivity to cytokine withdrawal-induced cell death (CWID), a critical intrinsic apoptosis program responsible for culling cells once an infection is cleared and interleukin-2 (IL-2) levels diminish. Interestingly, we found no differences in the expression of IL-2 or IL-2 receptor components in cells originating from either subset. Relative to CM-derived effectors, however, EM-derived T cells displayed more mitochondrial instability and greater caspase activity. Indeed, we found that heightened CWID sensitivity in EM-derived effectors coincided with higher expression of the pro-apoptotic Bcl-2 family protein BIM, both at steady state and with de novo induction following withdrawal of exogenous IL-2. These data point to 'imprinted' differences in BIM protein regulation, preserved by CD8+ CM and EM progeny, which govern their relative sensitivity to CWID. In addition, we detected a burst of autophagy after IL-2 withdrawal, which was better maintained in CM-derived T cells. Both subsets showed increased, equivalent CWID sensitivity upon treatment with autophagy inhibitors, suggesting sustained autophagy could preferentially protect CM-derived T cells from apoptosis. These findings offer new insight into how CM CD8+ T cells display superior effector cell expansion and more persistent memory responses in vivo relative to EM-derived T cells, based in part on decreased CWID sensitivity.

11.
J Immunol ; 198(1): 147-155, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27852741

RESUMO

Restimulation-induced cell death (RICD) regulates immune responses by restraining effector T cell expansion and limiting nonspecific damage to the host. RICD is triggered by re-engagement of the TCR on a cycling effector T cell, resulting in apoptosis. It remains unclear how RICD sensitivity is calibrated in T cells derived from different individuals or subsets. In this study we show that aerobic glycolysis strongly correlates with RICD sensitivity in human CD8+ effector T cells. Reducing glycolytic activity or glucose availability rendered effector T cells significantly less sensitive to RICD. We found that active glycolysis specifically facilitates the induction of proapoptotic Fas ligand upon TCR restimulation, accounting for enhanced RICD sensitivity in highly glycolytic T cells. Collectively, these data indicate that RICD susceptibility is linked to metabolic reprogramming, and that switching back to metabolic quiescence may help shield T cells from RICD as they transition into the memory pool.


Assuntos
Apoptose/imunologia , Linfócitos T CD8-Positivos/metabolismo , Glicólise/imunologia , Western Blotting , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Reação em Cadeia da Polimerase em Tempo Real
12.
Sci Transl Med ; 8(321): 321ra7, 2016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-26764158

RESUMO

X-linked lymphoproliferative disease (XLP-1) is an often-fatal primary immunodeficiency associated with the exuberant expansion of activated CD8(+) T cells after Epstein-Barr virus (EBV) infection. XLP-1 is caused by defects in signaling lymphocytic activation molecule (SLAM)-associated protein (SAP), an adaptor protein that modulates T cell receptor (TCR)-induced signaling. SAP-deficient T cells exhibit impaired TCR restimulation-induced cell death (RICD) and diminished TCR-induced inhibition of diacylglycerol kinase α (DGKα), leading to increased diacylglycerol metabolism and decreased signaling through Ras and PKCθ (protein kinase Cθ). We show that down-regulation of DGKα activity in SAP-deficient T cells restores diacylglycerol signaling at the immune synapse and rescues RICD via induction of the proapoptotic proteins NUR77 and NOR1. Pharmacological inhibition of DGKα prevents the excessive CD8(+) T cell expansion and interferon-γ production that occur in SAP-deficient mice after lymphocytic choriomeningitis virus infection without impairing lytic activity. Collectively, these data highlight DGKα as a viable therapeutic target to reverse the life-threatening EBV-associated immunopathology that occurs in XLP-1 patients.


Assuntos
Diacilglicerol Quinase/antagonistas & inibidores , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Morte Celular/efeitos dos fármacos , Citocinas/biossíntese , Diacilglicerol Quinase/metabolismo , Inativação Gênica/efeitos dos fármacos , Humanos , Sinapses Imunológicas/efeitos dos fármacos , Sinapses Imunológicas/metabolismo , Ativação Linfocitária , Contagem de Linfócitos , Transtornos Linfoproliferativos/tratamento farmacológico , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinonas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/deficiência , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/metabolismo , Tiazóis/farmacologia , Proteínas ras/metabolismo
13.
J Immunol ; 192(9): 4202-9, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24688028

RESUMO

Upon TCR restimulation, activated, cycling T cells can undergo a self-regulatory form of apoptosis known as restimulation-induced cell death (RICD). We previously demonstrated that RICD is impaired in T cells from patients with X-linked lymphoproliferative disease, which lack SLAM-associated protein (SAP) expression. Both SAP and the specific SLAM receptor NK, T, and B cell Ag (NTB-A) are required for RICD, but the mechanism by which these molecules promote a strong, proapoptotic signal through the TCR remains unclear. In this article, we show that the Src-family kinase LCK, but not FYN, associates with NTB-A in activated human T cells. This association increased after TCR restimulation in a SAP-dependent manner, requiring both immunoreceptor tyrosine-based switch motifs in the NTB-A cytoplasmic tail. Both NTB-A-associated LCK phosphorylation and kinase activity were enhanced in restimulated T cells, amplifying proximal TCR signaling. In contrast, TCR-induced LCK association with NTB-A, as well as phosphorylation and kinase activity, was reduced in T cells from patients with X-linked lymphoproliferative disease or normal T cells transfected with SAP-specific small interfering RNA, consistent with RICD resistance. Collectively, our data reveal how SAP nucleates a previously unknown signaling complex involving NTB-A and LCK to potentiate RICD of activated human T cells.


Assuntos
Antígenos CD/imunologia , Apoptose/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/imunologia , Receptores de Superfície Celular/imunologia , Linfócitos T/imunologia , Antígenos CD/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Immunoblotting , Imunoprecipitação , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação Linfocitária/imunologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , RNA Interferente Pequeno , Receptores de Superfície Celular/metabolismo , Transdução de Sinais/imunologia , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Família de Moléculas de Sinalização da Ativação Linfocitária , Membro 1 da Família de Moléculas de Sinalização da Ativação Linfocitária , Linfócitos T/citologia , Transfecção
14.
Clin Microbiol Rev ; 26(3): 381-421, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23824365

RESUMO

SUMMARY Filarial worms cause highly morbid diseases such as elephantiasis and river blindness. Since the 1940s, researchers have conducted vaccine trials in 27 different animal models of filariasis. Although no vaccine trial in a permissive model of filariasis has provided sterilizing immunity, great strides have been made toward developing vaccines that could block transmission, decrease pathological sequelae, or decrease susceptibility to infection. In this review, we have organized, to the best of our ability, all published filaria vaccine trials and reviewed them in the context of the animal models used. Additionally, we provide information on the life cycle, disease phenotype, concomitant immunity, and natural immunity during primary and secondary infections for 24 different filaria models.


Assuntos
Filariose/prevenção & controle , Filarioidea/imunologia , Vacinas/farmacologia , Animais , Modelos Animais de Doenças , Vacinas/química
15.
J Med Entomol ; 50(6): 1315-23, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24843938

RESUMO

Canine heartworm is one of the most serious infections primarily affecting domestic dogs but will also infect cats and wild canids. To evaluate the potential of mosquitoes as vectors of dog heartworm, Dirofilaria immitis (Leidy) in San Joaquin County, CA, we collected mosquitoes in 2011 and analyzed for infection with heartworm by using polymerase chain reaction. Of 3,000 mosquito pools (total number of specimens = 36,554), D. immitis DNA was detected in 97 pools of seven species, and the overall minimum infection rate (MIR) for all mosquito species was 2.69: Culex pipiens L. (n = 40; MIR = 3.66), Culex tarsalis Coquillett (n = 25; MIR = 1.89), Culiseta incidens (Thomson) (n = 11; MIR = 2.81), Aedes vexans (Meigen) (n = 7; MIR = 2.18), Aedes melanimon Dyar (n = 5; MIR = 4.64), Culex erythrothorax Dyar (n = 5; MIR = 3.96), and Culiseta inornata (Williston) (n = 4; MIR = 2.65). Cx. pipiens and Cx. tarsalis had the highest number of D. immitis infections and collectively accounted for 67% of all positive pools. Ae. melanimon, Ae. vexans, and Cx. erythrothorax were found to be infected with D. immitis only in rural and agriculture areas, whereas infections in other species were identified in rural and agriculture areas, and urban and residential settings. The majority of positive pools were identified from June through November and peaked during August through October. This is the first report of D. immitis infection in Ae. melanimon, Cx. erythrothorax, Cx. tarsalis, Cs. incidens, and Cs. inornata. The frequent detection of D. immitis in field-collected Cx. pipiens and Cx. tarsalis in concert with their seasonal abundance and widespread distribution suggest a central role for these species in dog heartworm transmission. Other species, including Ae. vexans, Ae. melanimon, Cs. incidens, Cs. inornata, and Cx. erythrothorax, may play a secondary role in transmission.


Assuntos
Doenças do Gato/epidemiologia , Culicidae/parasitologia , Dirofilaria immitis/fisiologia , Dirofilariose/epidemiologia , Doenças do Cão/epidemiologia , Insetos Vetores/parasitologia , Aedes/parasitologia , Animais , California/epidemiologia , Doenças do Gato/parasitologia , Doenças do Gato/transmissão , Gatos , Culex/parasitologia , Dirofilaria immitis/isolamento & purificação , Doenças do Cão/parasitologia , Doenças do Cão/transmissão , Cães , Feminino , Larva/fisiologia , Prevalência , Reação em Cadeia da Polimerase Via Transcriptase Reversa/veterinária , Especificidade da Espécie
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