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2.
Nat Immunol ; 22(9): 1127-1139, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34413521

RESUMO

Follicular helper T (TFH) cells are a specialized subset of CD4+ T cells that essentially support germinal center responses where high-affinity and long-lived humoral immunity is generated. The regulation of TFH cell survival remains unclear. Here we report that TFH cells show intensified lipid peroxidation and altered mitochondrial morphology, resembling the features of ferroptosis, a form of programmed cell death that is driven by iron-dependent accumulation of lipid peroxidation. Glutathione peroxidase 4 (GPX4) is the major lipid peroxidation scavenger and is necessary for TFH cell survival. The deletion of GPX4 in T cells selectively abrogated TFH cells and germinal center responses in immunized mice. Selenium supplementation enhanced GPX4 expression in T cells, increased TFH cell numbers and promoted antibody responses in immunized mice and young adults after influenza vaccination. Our findings reveal the central role of the selenium-GPX4-ferroptosis axis in regulating TFH homeostasis, which can be targeted to enhance TFH cell function in infection and following vaccination.


Assuntos
Ferroptose/fisiologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Selênio/farmacologia , Células T Auxiliares Foliculares/fisiologia , Adolescente , Adulto , Animais , Sobrevivência Celular/imunologia , Criança , Feminino , Centro Germinativo/citologia , Centro Germinativo/imunologia , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Imunidade Humoral/imunologia , Vacinas contra Influenza/imunologia , Peroxidação de Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/fisiologia , Ovalbumina , Células T Auxiliares Foliculares/imunologia , Vacinação , Adulto Jovem
3.
Comput Inform Nurs ; 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34347639

RESUMO

This article describes the development process and application of the Pediatric Nursing-Clinical Decision Support System for Hyperthermia. Firstly, we formed the Pediatric Nursing-Knowledge Base for Hyperthermia, which combines publicly available clinical practice guidelines and nursing routines of hyperthermia management. Then, following the nursing process framework, the system was developed using clinical decision support technology. Finally, a pre- and post-test were adopted to examine the effectiveness, usability, and feasibility before (1st to 31st of August 2018) and after (1st to 31st of December 2019) using the system. Its effectiveness was examined by analysis of nursing records' quality, including completeness of nursing assessment, timeliness of nursing diagnosis, individualization of nursing interventions, and timeliness of nursing evaluation. Its usability and feasibility were assessed using the Clinical Nursing Information System Effectiveness Evaluation Scale. There was a significant difference between the two groups in effectiveness, usability, and feasibility. Although the system was developed specifically for our hospital workflow and processes, the Pediatric Nursing-Knowledge Base for Hyperthermia and workflow for hyperthermia management in this study can be used as a reference to other hospitals.

4.
Front Cell Dev Biol ; 9: 678377, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34169075

RESUMO

Schistosoma japonicum infection showed protective effects against allergic airway inflammation (AAI). However, controversial findings exist especially regarding the timing of the helminth infection and the underlying mechanisms. Most previous studies focused on understanding the preventive effect of S. japonicum infection on asthma (infection before allergen sensitization), whereas the protective effects of S. japonicum infection (allergen sensitization before infection) on asthma were rarely investigated. In this study, we investigated the protective effects of S. japonicum infection on AAI using a mouse model of OVA-induced asthma. To explore how the timing of S. japonicum infection influences its protective effect, the mice were percutaneously infected with cercaria of S. japonicum at either 1 day (infection at lung-stage during AAI) or 14 days before ovalbumin (OVA) challenge (infection at post-lung-stage during AAI). We found that lung-stage S. japonicum infection significantly ameliorated OVA-induced AAI, whereas post-lung-stage infection did not. Mechanistically, lung-stage S. japonicum infection significantly upregulated the frequency of regulatory T cells (Treg cells), especially OVA-specific Treg cells, in lung tissue, which negatively correlated with the level of OVA-specific immunoglobulin E (IgE). Depletion of Treg cells in vivo partially counteracted the protective effect of lung-stage S. japonicum infection on asthma. Furthermore, transcriptomic analysis of lung tissue showed that lung-stage S. japonicum infection during AAI shaped the microenvironment to favor Treg induction. In conclusion, our data showed that lung-stage S. japonicum infection could relieve OVA-induced asthma in a mouse model. The protective effect was mediated by the upregulated OVA-specific Treg cells, which suppressed IgE production. Our results may facilitate the discovery of a novel therapy for AAI.

5.
Nat Commun ; 12(1): 3073, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34031386

RESUMO

Follicular helper T (TFH) cells control antibody responses by supporting antibody affinity maturation and memory formation. Inadequate TFH function has been found in individuals with ineffective responses to vaccines, but the mechanism underlying TFH regulation in vaccination is not understood. Here, we report that lower serum levels of the metabolic hormone leptin associate with reduced vaccine responses to influenza or hepatitis B virus vaccines in healthy populations. Leptin promotes mouse and human TFH differentiation and IL-21 production via STAT3 and mTOR pathways. Leptin receptor deficiency impairs TFH generation and antibody responses in immunisation and infection. Similarly, leptin deficiency induced by fasting reduces influenza vaccination-mediated protection for the subsequent infection challenge, which is mostly rescued by leptin replacement. Our results identify leptin as a regulator of TFH cell differentiation and function and indicate low levels of leptin as a risk factor for vaccine failure.


Assuntos
Formação de Anticorpos/imunologia , Vacinas contra Influenza/imunologia , Leptina/metabolismo , Animais , Anticorpos Antivirais/imunologia , Diferenciação Celular , Feminino , Homeostase , Humanos , Imunização , Influenza Humana/prevenção & controle , Leptina/deficiência , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Vacinação/métodos
6.
Virol Sin ; 36(4): 784-795, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33723807

RESUMO

Raising a heterologous tier 2 neutralizing antibody (nAb) response remains a daunting task for HIV vaccine development. In this study, we explored the utility of diverse HIV-1 envelope (Env) immunogens in a sequential immunization scheme as a solution to this task. This exploration stemmed from the rationale that gp145, a membrane-bound truncation form of HIV Env, may facilitate the focusing of induced antibody response on neutralizing epitopes when sequentially combined with the soluble gp140 form as immunogens in a prime-boost mode. We first showed that gp140 DNA prime-gp145 Tiantan vaccinia (TV) boost likely represents a general format for inducing potent nAb response in mice. However, when examined in rhesus macaque, this modality showed little effectiveness. To improve the efficacy, we extended the original modality by adding a strong protein boost, namely native-like SOSIP.664 trimer displayed on ferritin-based nanoparticle (NP), which was generated by a newly developed click approach. The resulting three-immunization regimen succeeded in eliciting tier-2 nAb response with substantial breadth when implemented in rhesus macaque over a short 8-week schedule. Importantly, the elicited nAb response was able to effectively contain viremia upon a heterologous SHIV challenge. Collectively, our studies highlighted that diversification of Env immunogens, in both types and formulations, under the framework of a sequential immunization scheme might open new opportunity toward HIV vaccine development.


Assuntos
Vacinas contra a AIDS , Infecções por HIV , HIV-1 , Animais , Anticorpos Neutralizantes , Anticorpos Anti-HIV , Infecções por HIV/prevenção & controle , Imunização , Macaca mulatta , Camundongos , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
7.
Clin Transl Immunology ; 10(2): e1251, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33614032

RESUMO

Objectives: We aimed to gain an understanding of the paradox of the immunity in COVID-19 patients with T cells showing both functional defects and hyperactivation and enhanced proliferation. Methods: A total of 280 hospitalised patients with COVID-19 were evaluated for cytokine profiles and clinical features including viral shedding. A mouse model of acute infection by lymphocytic choriomeningitis virus (LCMV) was applied to dissect the relationship between immunological, virological and pathological features. The results from the mouse model were validated by published data set of single-cell RNA sequencing (scRNA-seq) of immune cells in bronchoalveolar lavage fluid (BALF) of COVID-19 patients. Results: The levels of soluble CD25 (sCD25), IL-6, IL-8, IL-10 and TNF-α were higher in severe COVID-19 patients than non-severe cases, but only sCD25 was identified as an independent risk factor for disease severity by multivariable binary logistic regression analysis and showed a positive association with the duration of viral shedding. In agreement with the clinical observation, LCMV-infected mice with high levels of sCD25 demonstrated insufficient anti-viral response and delayed viral clearance. The elevation of sCD25 in mice was mainly contributed by the expansion of CD25+CD8+ T cells that also expressed the highest level of PD-1 with pro-inflammatory potential. The counterpart human CD25+PD-1+ T cells were expanded in BALF of COVID-19 patients with severe disease compared to those with modest disease. Conclusion: These results suggest that high levels of sCD25 in COVID-19 patients probably result from insufficient anti-viral immunity and indicate an expansion of pro-inflammatory T cells that contribute to disease severity.

8.
J Leukoc Biol ; 109(1): 91-97, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32930458

RESUMO

Regulatory T cell can protect against severe forms of coronaviral infections attributable to host inflammatory responses. But its role in the pathogenesis of COVID-19 is still unclear. In this study, frequencies of total and multiple subsets of lymphocytes in peripheral blood of COVID-19 patients and discharged individuals were analyzed using a multicolor flow cytometry assay. Plasma concentration of IL-10 was measured using a microsphere-based immunoassay kit. Comparing to healthy controls, the frequencies of total lymphocytes and T cells decreased significantly in both acutely infected COVID-19 patients and discharged individuals. The frequencies of total lymphocytes correlated negatively with the frequencies of CD3- CD56+ NK cells. The frequencies of regulatory CD8+ CD25+ T cells correlated with CD4+ /CD8+ T cell ratios positively, while the frequencies of regulatory CD4+ CD25+ CD127- T cells correlated negatively with CD4+ /CD8+ T cell ratios. Ratios of CD4+ /CD8+ T cells increased significantly in patients beyond age of 45 years. And accordingly, the frequencies of regulatory CD8+ CD25+ T cells were also found significantly increased in these patients. Collectively, the results suggest that regulatory CD4+ and CD8+ T cells may play distinct roles in the pathogenesis of COVID-19. Moreover, the data indicate that NK cells might contribute to the COVID-19 associated lymphopenia.


Assuntos
Linfócitos T CD8-Positivos , COVID-19 , SARS-CoV-2 , Linfócitos T Reguladores , Adulto , Idoso , Antígenos CD/sangue , Antígenos CD/imunologia , Relação CD4-CD8 , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , COVID-19/sangue , COVID-19/imunologia , COVID-19/patologia , Feminino , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
9.
Cytokine ; 138: 155365, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33246770

RESUMO

The hyper-inflammatory response is thought to be a major cause of acute respiratory distress syndrome (ARDS) in patients with COVID-19. Although multiple cytokines are reportedly associated with disease severity, the key mediators of SARS-CoV-2 induced cytokine storm and their predictive values have not been fully elucidated. The present study analyzed maximal and early (within 10 days after disease onset) concentrations of 12-plex cytokines in plasma. We found consistently elevated plasma levels of IL-6, IL-8 and IL-5 in patients who were deceased compared with those who had mild/moderate or severe disease. The early plasma concentrations of IFN-a and IL-2 positively correlated with the length of the disease course. Moreover, correlation network analysis showed that IL-6, IL-8, and IL-5 located at the center of an inter-correlated cytokine network. These findings suggested that IL-8, IL-6, IL-5 might play central roles in cytokine storms associated with COVID-19 and that the early detection of multiple plasma cytokines might help to predict the prognosis of this disease.


Assuntos
COVID-19/patologia , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , Síndrome do Desconforto Respiratório/patologia , SARS-CoV-2/imunologia , Idoso , Correlação de Dados , Feminino , Humanos , Interferon-alfa/sangue , Interleucina-2/sangue , Interleucina-5/sangue , Interleucina-6/sangue , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença
10.
J Clin Invest ; 130(12): 6429-6442, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32853182

RESUMO

After over 3 decades of research, an effective anti-HIV vaccine remains elusive. The recently halted HVTN702 clinical trial not only further stresses the challenge to develop an effective HIV vaccine but also emphasizes that unconventional and novel vaccine strategies are urgently needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provided greater than 80% protection to Mauritian cynomolgus macaques against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses correlated with vaccine efficacy. The PCS vaccine did not induce immune activation or inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune microenvironment generated by the PCS vaccine was predictive of vaccine efficacy. Our study demonstrates, for the first time to our knowledge, that a vaccine which targets only viral maturation, but lacks full-length Env and Gag immunogens, can prevent intravaginal infection in a stringent macaque/SIV challenge model. Targeting HIV maturation thus offers a potentially novel approach to developing an effective HIV vaccine.


Assuntos
Vacinas contra a SAIDS , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Vacinas contra a AIDS/genética , Vacinas contra a AIDS/imunologia , Administração Intravaginal , Animais , Feminino , Infecções por HIV/genética , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Macaca fascicularis , Vacinas contra a SAIDS/genética , Vacinas contra a SAIDS/farmacologia , Síndrome de Imunodeficiência Adquirida dos Símios/genética , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/imunologia
11.
Hum Vaccin Immunother ; 16(3): 595-601, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-31486333

RESUMO

Background We conducted a matched case-control study in China during the 2013/14-2015/16 influenza seasons to estimate influenza vaccine effectiveness (VE) by dose among children aged 6 months to 8 years.Methods Cases were laboratory-confirmed influenza infections identified through the influenza-like illness sentinel surveillance network in Guangzhou. Age- and sex-matched community controls were randomly selected through the expanded immunization program database. We defined priming as receipt of ≥1 dose of influenza vaccine during the immediate prior season.Results In total, 4,185 case-control pairs were analyzed. Among children 6-35 months, VE for current season dose(s) across the three seasons during 2013/14-2015/16 were 59% (95% Confidence Interval: 44-71%), 12% (-11%,30%), 54% (32-69%); among unprimed children 6-35 months, VE for 1 vs 2 current season doses were 45% (8-67%) vs 65% (46-78%), -2% (-53%,32%) vs 19% (-11%,40%), and 37% (-24%,68%) vs 61% (32-78%). Among children aged 3-8 years, VE for current season dose(s) across study seasons were 62% (36-78%), 43% (22-58%), 32% (1-53%). VE for unprimed children receiving 1 dose only in current season was insignificant or lower than among all children.Conclusion Findings support utility of providing second dose ("booster dose") of seasonal influenza vaccine to unprimed children aged 6-35 months, and the need to study further dose effect of a booster dose among unprimed children aged 3-8 years in China.


Assuntos
Vacinas contra Influenza , Influenza Humana , Estudos de Casos e Controles , Criança , China/epidemiologia , Humanos , Lactente , Vírus da Influenza A Subtipo H3N2 , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Laboratórios , Estações do Ano , Vacinação
12.
Cytokine ; 125: 154814, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450102

RESUMO

Enhancement of the magnitude or affinity of protective antibodies (Abs) induced by vaccine adjuvant is highly desirable to prevent challenging pathogens such as HIV-1. IL-21 plays a crucial role in germinal center reactions during humoral immune responses. However, the effect of IL-21 as a vaccine adjuvant on the quantity and quality of antigen-specific Abs elicited by DNA prime and MVA boost vaccine, a commonly used vaccine strategy, remains unknown. To close this knowledge gap, female adult B6N mice were primed with DNA vaccine twice (days 0, 14, 100 µg, I.M.) and boosted with MVA vaccine (day 28, 2 × 107 pfu, I.M.) with or without an IL-21 DNA adjuvant (days 3, 17, 31, 40 µg, I.M.), in which HIV-1 gag was expressed as a model antigen. With the addition of an IL-21 adjuvant, we found significantly increased avidity of antigen-specific Abs at multiple time points in a longitudinal follow up. Collectively, our results suggest that an IL-21 immune adjuvant can significantly increase Ab quality induced by heterologous DNA-MVA prime-boost vaccine strategy.


Assuntos
Adjuvantes Imunológicos , HIV-1/imunologia , Interleucinas/administração & dosagem , Vacinação/métodos , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Animais , Afinidade de Anticorpos/imunologia , Linfócitos B/metabolismo , Medula Óssea/imunologia , Feminino , Expressão Gênica , Células HEK293 , HIV-1/genética , Humanos , Imunidade Humoral , Imunoglobulina G/imunologia , Interferon gama/metabolismo , Interleucinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes , Baço/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia
14.
PLoS One ; 13(8): e0202997, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30153293

RESUMO

HIV mutates rapidly and infects CD4+ T cells, especially when they are activated. A vaccine targeting conserved, essential viral elements while limiting CD4+ T cell activation could be effective. Learning from natural immunity observed in a group of highly HIV-1 exposed seronegative Kenyan female sex workers, we are testing a novel candidate HIV vaccine targeting the 12 viral protease cleavage sites (PCSs) (the PCS vaccine), in comparison with a vaccine targeting full-length Gag and Env (the Gag/Env vaccine) in a Mauritian cynomolgus macaque/SIV model. In this study we evaluated these vaccines for induction of mucosal antibodies to SIV immunogens at the female genital tract. Bio-Plex and Western blot analyses of cervicovaginal lavage samples showed that both the PCS and Gag/Env vaccines can elicit mucosal IgG antibody responses to SIV immunogens. Significantly higher increase of anti-PCS antibodies was induced by the PCS vaccine than by the Gag/Env vaccine (p<0.0001). The effect of the mucosal antibody responses in protection from repeated low dose pathogenic SIVmac251 challenges is being evaluated.


Assuntos
Produtos do Gene env/imunologia , Produtos do Gene gag/imunologia , Peptídeo Hidrolases/metabolismo , Proteólise , Vacinas contra a SAIDS/imunologia , Vírus da Imunodeficiência Símia/enzimologia , Vírus da Imunodeficiência Símia/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Antivirais/imunologia , Sítios de Ligação , Reações Cruzadas , Feminino , Produtos do Gene env/química , Produtos do Gene env/metabolismo , Produtos do Gene gag/química , Produtos do Gene gag/metabolismo , Imunização , Macaca fascicularis
15.
ACS Synth Biol ; 7(6): 1612-1617, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29787233

RESUMO

Large efforts have been devoted to genetic code engineering in the past decade, aiming for unnatural amino acid mutagenesis. Recently, an increasing number of studies were reported to employ quadruplet codons to encode unnatural amino acids. We and others have demonstrated that the quadruplet decoding efficiency could be significantly enhanced by an extensive engineering of tRNAs bearing an extra nucleotide in their anticodon loops. In this work, we report the identification of tRNA mutants derived from directed evolution to efficiently decode a UAGA quadruplet codon in mammalian cells. Intriguingly, the trend of quadruplet codon decoding efficiency among the tested tRNA variants in mammalian cells was largely the same as that in E. coli. We subsequently demonstrate the utility of quadruplet codon decoding by the construction of the first HIV-1 mutant that lacks any in-frame amber nonsense codons and can be precisely activated by the decoding of a genomically embedded UAGA codon with an unnatural amino acid. Such conditionally activatable HIV-1 mutant can likely facilitate both fundamental investigations of HIV-1 as well as vaccine developments. The use of quadruplet codon, instead of an amber nonsense codon, to control HIV-1 replication has the advantage in that the correction of a frameshift caused by a quadruplet codon is much less likely than the reversion of an amber codon back into a sense codon in HIV-1.


Assuntos
Códon , Engenharia Genética/métodos , HIV-1/fisiologia , Replicação Viral/genética , Códon sem Sentido , Evolução Molecular Direcionada/métodos , Proteínas de Fluorescência Verde/genética , Células HEK293 , HIV-1/genética , Humanos , Microrganismos Geneticamente Modificados , Mutação , RNA de Transferência/genética
16.
Sci Transl Med ; 10(437)2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29669853

RESUMO

The persistence of HIV reservoirs, including latently infected, resting CD4+ T cells, is the major obstacle to cure HIV infection. CD32a expression was recently reported to mark CD4+ T cells harboring a replication-competent HIV reservoir during antiretroviral therapy (ART) suppression. We aimed to determine whether CD32 expression marks HIV latently or transcriptionally active infected CD4+ T cells. Using peripheral blood and lymphoid tissue of ART-treated HIV+ or SIV+ subjects, we found that most of the circulating memory CD32+ CD4+ T cells expressed markers of activation, including CD69, HLA-DR, CD25, CD38, and Ki67, and bore a TH2 phenotype as defined by CXCR3, CCR4, and CCR6. CD32 expression did not selectively enrich for HIV- or SIV-infected CD4+ T cells in peripheral blood or lymphoid tissue; isolated CD32+ resting CD4+ T cells accounted for less than 3% of the total HIV DNA in CD4+ T cells. Cell-associated HIV DNA and RNA loads in CD4+ T cells positively correlated with the frequency of CD32+ CD69+ CD4+ T cells but not with CD32 expression on resting CD4+ T cells. Using RNA fluorescence in situ hybridization, CD32 coexpression with HIV RNA or p24 was detected after in vitro HIV infection (peripheral blood mononuclear cell and tissue) and in vivo within lymph node tissue from HIV-infected individuals. Together, these results indicate that CD32 is not a marker of resting CD4+ T cells or of enriched HIV DNA-positive cells after ART; rather, CD32 is predominately expressed on a subset of activated CD4+ T cells enriched for transcriptionally active HIV after long-term ART.


Assuntos
Infecções por HIV/metabolismo , Receptores de IgG/metabolismo , Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/metabolismo , Infecções por HIV/tratamento farmacológico , Humanos , Técnicas In Vitro , Linfócitos/metabolismo , Receptores CCR4/metabolismo , Receptores CCR6/metabolismo , Receptores CXCR3/metabolismo
17.
Front Microbiol ; 9: 557, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29651274

RESUMO

Characterizing the transmitted/founder (T/F) viruses of multi-variant SIV infection may shed new light on the understanding of mucosal transmission. We intrarectally inoculated six Chinese rhesus macaques with a single high dose of SIVmac251 (3.1 × 104 TCID50) and obtained 985 full-length env sequences from multiple tissues at 6 and 10 days post-infection by single genome amplification (SGA). All 6 monkeys were infected with a range of 2 to 8 T/F viruses and the dominant variants from the inoculum were still dominant in different tissues from each monkey. Interestingly, our data showed that a cluster of rare T/F viruses was unequally represented in different tissues. This cluster of rare T/F viruses phylogenetically related to the non-dominant SIV variants in the inoculum and was not detected in any rectum tissues, but could be identified in the descending colon, jejunum, spleen, or plasma. In 2 out of 6 macaques, identical SIVmac251 variants belonging to this cluster were detected simultaneously in descending colon/jejunum and the inoculum. We also demonstrated that the average CG dinucleotide frequency of these rare T/F viruses found in tissues, as well as non-dominant variants in the inoculum, was significantly higher than the dominant T/F viruses in tissues and the inoculum. Collectively, these findings suggest that descending colon/jejunum might be more susceptible than rectum to SIV in the very early phase of infection. And host CG suppression, which was previously shown to inhibit HIV replication in vitro, may also contribute to the bottleneck selection during in vivo transmission.

18.
J Immunol ; 200(9): 3180-3187, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29610141

RESUMO

Individuals with chronic HIV-1 infection have an increased prevalence of autoreactive Abs. Many of the isolated HIV broadly neutralizing Abs from these individuals are also autoreactive. However, the underlying mechanism(s) that produce these autoreactive broadly neutralizing Abs remains largely unknown. The highly regulated coordination among B cells, T follicular helper (TFH) cells, and T follicular regulatory (TFR) cells in germinal centers (GCs) of peripheral lymphatic tissues (LTs) is essential for defense against pathogens while also restricting autoreactive responses. We hypothesized that an altered ratio of TFH/TFR cells in the GC contributes to the increased prevalence of autoreactive Abs in chronic HIV infection. We tested this hypothesis using a rhesus macaque (RM) SIV model. We measured the frequency of TFH cells, TFR cells, and GC B cells in LTs and anti-dsDNA and anti-phospholipid Abs from Indian RMs, with and without SIV infection. We found that the frequency of anti-dsDNA and anti-phospholipid Abs was much higher in chronically infected RMs (83.3% [5/6] and 66.7% [4/6]) than in acutely infected RMs (33.3% [2/6] and 18.6% [1/6]) and uninfected RMs (0% [0/6] and 18.6% [1/6]). The increased ratio of TFH/TFR cells in SIV infection correlated with anti-dsDNA and anti-phospholipid autoreactive Ab levels, whereas the frequency of TFR cells alone did not correlate with the levels of autoreactive Abs. Our results provide direct evidence that the ratio of TFH/TFR cells in LTs is critical for regulating autoreactive Ab production in chronic SIV infection and possibly, by extension, in chronic HIV-1 infection.


Assuntos
Autoanticorpos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Centro Germinativo/imunologia , Macaca mulatta , Vírus da Imunodeficiência Símia/imunologia
19.
J Virol ; 92(11)2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29514906

RESUMO

Two lineages of influenza D virus (IDV) have been found to infect cattle and promote bovine respiratory disease complex, one of the most commonly diagnosed causes of morbidity and mortality within the cattle industry. Furthermore, IDV can infect other economically important domestic livestock, including pigs, and has the potential to infect humans, which necessitates the need for an efficacious vaccine. In this study, we designed a DNA vaccine expressing consensus hemagglutinin-esterase fusion (HEF) protein (FluD-Vax) and tested its protective efficacy against two lineages of IDV (D/OK and D/660) in guinea pigs. Animals that received FluD-Vax (n = 12) developed appreciable titers of neutralizing antibodies against IDV lineage representatives, D/OK and D/660. Importantly, vaccinated animals were protected against intranasal challenge with IDV [3 × 105 50% tissue culture infective dose(s) (TCID50)] D/OK (n = 6) or D/600 (n = 6), based on the absence of viral RNA in necropsied tissues (5 and 7 days postchallenge) using quantitative reverse transcription-PCR and in situ hybridization. In contrast, animals that received a sham DNA vaccine (n = 12) had no detectable neutralizing antibodies against IDV, and viral RNA was readily detectable in respiratory tract tissues after intranasal challenge (3 × 105 TCID50) with IDV D/OK (n = 6) or D/660 (n = 6). Using a TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling) assay, we found that IDV D/OK and D/600 infections induced apoptosis in epithelial cells lining alveoli and bronchioles, as well as nonepithelial cells in lung tissues. Our results demonstrate for the first time that the consensus IDV HEF DNA vaccine can elicit complete protection against infection from two lineages of IDV in the guinea pig model.IMPORTANCE Influenza D virus (IDV) infection has been associated with bovine respiratory disease complex, one of the most devastating diseases of the cattle population. Moreover, with broad host range and high environmental stability, IDV has the potential to further gain virulence or even infect humans. An efficacious vaccine is needed to prevent infection and stop potential cross-species transmission. In this study, we designed a DNA vaccine encoding the consensus hemagglutinin-esterase fusion (HEF) protein of two lineages of IDV (D/OK and D/660) and tested its efficacy in a guinea pig model. Our results showed that the consensus DNA vaccine elicited high-titer neutralizing antibodies and achieved sterilizing protection against two lineage-representative IDV intranasal infections. To our knowledge, this is the first study showing that a DNA vaccine expressing consensus HEF is efficacious in preventing different lineages of IDV infections.


Assuntos
Hemaglutininas Virais/imunologia , Vacinas contra Influenza/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/veterinária , Thogotovirus/imunologia , Vacinas de DNA/imunologia , Proteínas Virais de Fusão/imunologia , Animais , Apoptose/imunologia , Feminino , Cobaias , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/virologia , Estudo de Prova de Conceito
20.
Nat Commun ; 9(1): 824, 2018 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-29483513

RESUMO

Severe influenza A virus (IAV) infection is associated with immune dysfunction. Here, we show circulating CD8+ T-cell profiles from patients hospitalized with avian H7N9, seasonal IAV, and influenza vaccinees. Patient survival reflects an early, transient prevalence of highly activated CD38+HLA-DR+PD-1+ CD8+ T cells, whereas the prolonged persistence of this set is found in ultimately fatal cases. Single-cell T cell receptor (TCR)-αß analyses of activated CD38+HLA-DR+CD8+ T cells show similar TCRαß diversity but differential clonal expansion kinetics in surviving and fatal H7N9 patients. Delayed clonal expansion associated with an early dichotomy at a transcriptome level (as detected by single-cell RNAseq) is found in CD38+HLA-DR+CD8+ T cells from patients who succumbed to the disease, suggesting a divergent differentiation pathway of CD38+HLA-DR+CD8+ T cells from the outset during fatal disease. Our study proposes that effective expansion of cross-reactive influenza-specific TCRαß clonotypes with appropriate transcriptome signatures is needed for early protection against severe influenza disease.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Seleção Clonal Mediada por Antígeno/genética , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Influenza Humana/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Subpopulações de Linfócitos T/imunologia , Transcriptoma/imunologia , ADP-Ribosil Ciclase 1/genética , ADP-Ribosil Ciclase 1/imunologia , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , Estudos de Coortes , Estado Terminal , Regulação da Expressão Gênica , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Hospitalização , Humanos , Subtipo H7N9 do Vírus da Influenza A/imunologia , Influenza Humana/genética , Influenza Humana/mortalidade , Influenza Humana/virologia , Ativação Linfocitária , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Análise de Sobrevida , Subpopulações de Linfócitos T/patologia , Subpopulações de Linfócitos T/virologia
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