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1.
Front Psychiatry ; 15: 1265722, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38559394

RESUMEN

Objectives: Although sexual minorities have reported higher levels of suicidal ideation than heterosexuals across cultures, the role of various psychosocial factors underlying this disparity among young men has been understudied, particularly in China. This study examined the multiple mediating effects of psychosocial factors between sexual orientation and suicidal ideation in Chinese sexual minority and heterosexual young men. Methods: 302 Chinese cisgender men who identified as gay or bisexual, and 250 cisgender heterosexual men (n=552, aged 18-39 years) completed an online questionnaire measuring perceived social support, self-esteem, depressive symptoms, and suicidal ideation. Results: Young sexual minority men reported significantly higher suicidal ideation and lower social support than their heterosexual peers. Structural equation modelling revealed two multiple indirect pathways. One pathway indicated that sexual orientation was indirectly related to suicidal ideation via family support and depressive symptoms. Another pathway indicated that sexual orientation was indirectly related to suicidal ideation via support from friends, self-esteem, and depressive symptoms. Conclusions: This study is among the first to examine the potentially cascading relationships between sexual orientation and psychosocial factors with suicidal ideation in a Chinese sample of young men. The findings highlight several promising psychosocial targets (i.e., improving family/friend support and increasing self-esteem) for suicide interventions among sexual minority males in China.

2.
J Nanobiotechnology ; 22(1): 15, 2024 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-38166929

RESUMEN

Embryonic stem cell (ESC)-derived epitopes can act as therapeutic tumor vaccines against different types of tumors Jin (Adv Healthc Mater 2023). However, these epitopes have poor immunogenicity and stimulate insufficient CD8+ T cell responses, which motivated us to develop a new method to deliver and enhance their effectiveness. Bacterial outer membrane vesicles (OMVs) can serve as immunoadjuvants and act as a delivery vector for tumor antigens. In the current study, we engineered a new OMV platform for the co-delivery of ESC-derived tumor antigens and immune checkpoint inhibitors (PD-L1 antibody). An engineered Staphylococcal Protein A (SpA) was created to non-specifically bind to anti-PD-L1 antibody. SpyCatcher (SpC) and SpA were fused into the cell outer membrane protein OmpA to capture SpyTag-attached peptides and PD-L1 antibody, respectively. The modified OMV was able to efficiently conjugate with ESC-derived TAAs and PD-L1 antibody (SpC-OMVs + SpT-peptides + anti-PD-L1), increasing the residence time of TAAs in the body. The results showed that the combination therapy of ESC-based TAAs and PD-L1 antibody delivered by OMV had significant inhibitory effects in mouse tumor model. Specifically, it was effective in reducing tumor growth by enhancing IFN-γ-CD8+ T cell responses and increasing the number of CD8+ memory cells and antigen-specific T cells. Overall, the new OMV delivery system is a versatile platform that can enhance the immune responses of ESC-based TAA cancer vaccines.


Asunto(s)
Vacunas contra el Cáncer , Neoplasias , Animales , Ratones , Antígeno B7-H1/metabolismo , Neoplasias/terapia , Anticuerpos , Antígenos de Neoplasias , Proteínas de la Membrana , Inmunidad , Péptidos , Epítopos
3.
EBioMedicine ; 99: 104916, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38101297

RESUMEN

BACKGROUND: Earlier Omicron subvariants including BA.1, BA.2, and BA.5 emerged in waves, with a subvariant replacing the previous one every few months. More recently, the post-BA.2/5 subvariants have acquired convergent substitutions in spike that facilitated their escape from humoral immunity and gained ACE2 binding capacity. However, the intrinsic pathogenicity and replication fitness of the evaluated post-BA.2/5 subvariants are not fully understood. METHODS: We systemically investigated the replication fitness and intrinsic pathogenicity of representative post-BA.2/5 subvariants (BL.1, BQ.1, BQ.1.1, XBB.1, CH.1.1, and XBB.1.5) in weanling (3-4 weeks), adult (8-10 weeks), and aged (10-12 months) mice. In addition, to better model Omicron replication in the human nasal epithelium, we further investigated the replication capacity of the post-BA.2/5 subvariants in human primary nasal epithelial cells. FINDINGS: We found that the evaluated post-BA.2/5 subvariants are consistently attenuated in mouse lungs but not in nasal turbinates when compared with their ancestral subvariants BA.2/5. Further investigations in primary human nasal epithelial cells revealed a gained replication fitness of XBB.1 and XBB.1.5 when compared to BA.2 and BA.5.2. INTERPRETATION: Our study revealed that the post-BA.2/5 subvariants are attenuated in lungs while increased in replication fitness in the nasal epithelium, indicating rapid adaptation of the circulating Omicron subvariants in the human populations. FUNDING: The full list of funding can be found at the Acknowledgements section.


Asunto(s)
COVID-19 , SARS-CoV-2 , Adulto , Humanos , Animales , Ratones , Virulencia , Células Epiteliales , Mucosa Nasal
4.
EBioMedicine ; 95: 104753, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37579626

RESUMEN

BACKGROUND: Among the Omicron sublineages that have emerged, BA.1, BA.2, BA.5, and their related sublineages have resulted in the largest number of infections. While recent studies demonstrated that all Omicron sublineages robustly escape neutralizing antibody response, it remains unclear on whether these Omicron sublineages share any pattern of evolutionary trajectory on their replication efficiency and intrinsic pathogenicity along the respiratory tract. METHODS: We compared the virological features, replication capacity of dominant Omicron sublineages BA.1, BA.2 and BA.5 in the human nasal epithelium, and characterized their pathogenicity in K18-hACE2, A129, young C57BL/6, and aged C57BL/6 mice. FINDINGS: We found that BA.5 replicated most robustly, followed by BA.2 and BA.1, in the differentiated human nasal epithelium. Consistently, BA.5 infection resulted in higher viral gene copies, infectious viral titres and more abundant viral antigen expression in the nasal turbinates of the infected K18-hACE2 transgenic mice. In contrast, the Omicron sublineages are continuously attenuated in lungs of infected K18-hACE2 and C57BL/6 mice, leading to decreased pathogenicity. Nevertheless, lung manifestations remain severe in Omicron sublineages-infected A129 and aged C57BL/6 mice. INTERPRETATION: Our results suggested that the Omicron sublineages might be gaining intrinsic replication fitness in the upper respiratory tract, therefore highlighting the importance of global surveillance of the emergence of hyper-transmissive Omicron sublineages. On the contrary, replication and intrinsic pathogenicity of Omicron is suggested to be further attenuated in the lower respiratory tract. Effective vaccination and other precautions should be in place to prevent severe infections in the immunocompromised populations at risk. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.


Asunto(s)
COVID-19 , Ratones , Animales , Humanos , Anciano , Ratones Endogámicos C57BL , SARS-CoV-2 , Virulencia , Anticuerpos Neutralizantes , Ratones Transgénicos , Anticuerpos Antivirales
5.
Cell Host Microbe ; 31(8): 1301-1316.e8, 2023 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-37527659

RESUMEN

Current COVID-19 vaccines are highly effective against symptomatic disease, but repeated booster doses using vaccines based on the ancestral strain offer limited additional protection against SARS-CoV-2 variants of concern (VOCs). To address this, we used antigenic distance to in silico select optimized booster vaccine seed strains effective against both current and future VOCs. Our model suggests that a SARS-CoV-1-based booster vaccine has the potential to cover a broader range of VOCs. Candidate vaccines including the spike protein from ancestral SARS-CoV-2, Delta, Omicron (BA.1), SARS-CoV-1, or MERS-CoV were experimentally evaluated in mice following two doses of the BNT162b2 vaccine. The SARS-CoV-1-based booster vaccine outperformed other candidates in terms of neutralizing antibody breadth and duration, as well as protective activity against Omicron (BA.2) challenge. This study suggests a unique strategy for selecting booster vaccines based on antigenic distance, which may be useful in designing future booster vaccines as new SARS-CoV-2 variants emerge.


Asunto(s)
COVID-19 , Animales , Humanos , Ratones , COVID-19/prevención & control , SARS-CoV-2 , Vacunas contra la COVID-19 , Vacuna BNT162 , Anticuerpos Neutralizantes , Anticuerpos Antivirales
6.
Nat Commun ; 14(1): 3440, 2023 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-37301910

RESUMEN

The overall success of worldwide mass vaccination in limiting the negative effect of the COVID-19 pandemics is inevitable, however, recent SARS-CoV-2 variants of concern, especially Omicron and its sub-lineages, efficiently evade humoral immunity mounted upon vaccination or previous infection. Thus, it is an important question whether these variants, or vaccines against them, induce anti-viral cellular immunity. Here we show that the mRNA vaccine BNT162b2 induces robust protective immunity in K18-hACE2 transgenic B-cell deficient (µMT) mice. We further demonstrate that the protection is attributed to cellular immunity depending on robust IFN-γ production. Viral challenge with SARS-CoV-2 Omicron BA.1 and BA.5.2 sub-variants induce boosted cellular responses in vaccinated µMT mice, which highlights the significance of cellular immunity against the ever-emerging SARS-CoV-2 variants evading antibody-mediated immunity. Our work, by providing evidence that BNT162b2 can induce significant protective immunity in mice that are unable to produce antibodies, thus highlights the importance of cellular immunity in the protection against SARS-CoV-2.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Inmunidad Celular , Animales , Humanos , Ratones , Anticuerpos , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacuna BNT162 , COVID-19/prevención & control , Interferón gamma , SARS-CoV-2 , Vacunas contra la COVID-19/inmunología
7.
Adv Healthc Mater ; 12(9): e2202691, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36510117

RESUMEN

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) share many cellular and molecular features with cancer cells. Taking advantage of these similarities, stem cells are effective vaccines against cancers in animal models. However, the molecular basis is not well understood, which hinders the development of effective cancer vaccines. Here, prophylactic and therapeutic bladder cancer vaccines composed of allogeneic ESCs and CpG with or without granulocyte macrophage colony stimulating factor are tested. The ESC-based cancer vaccines are able to induce specific antitumor immunity including stimulating cytotoxic CD8+ T cells and memory CD4+ T cells, reducing myeloid-derived suppressor cells, and preventing bladder cancer growth in mouse models. Furthermore, several genes that are overexpressed in both ESCs and tumors are identified. An epitope-based vaccine designed with shared overexpressed proteins induces specific antitumor immunity and reduces bladder cancer growth. Functional epitopes underlying the action of stem cell-based vaccines against bladder cancer are identified and it is confirmed that ESC-based anticancer vaccines have great potential. A systematic approach is provided here to developing novel effective epitope-based cancer vaccines in the future.


Asunto(s)
Vacunas contra el Cáncer , Neoplasias de la Vejiga Urinaria , Ratones , Animales , Linfocitos T CD8-positivos , Epítopos , Neoplasias de la Vejiga Urinaria/terapia , Células Madre Embrionarias
8.
Front Psychiatry ; 13: 1009810, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36532171

RESUMEN

Introduction: COVID-19 related stress might vary with the pandemic changes, as well as other associated factors. This study aimed to compare the stress level during the first wave of the pandemic outbreak and 1 year later in China, and to explore the differential roles of social support and perceptions of this disease in affecting pandemic-related stress over time. Methods: COVID-19 related stress, social support, and perceptions of the pandemic (perceived threat, perceived protection, and perceived controllability) were measured using the Impact of Event Scale-Revised for COVID-19, the Multidimensional Scale of Perceived Social Support, and the Self-Compiled Scale of COVID-19 Related Perception, respectively. Using an online survey, two independent samples were collected during the first wave of the COVID-19 outbreak (Time 1: March 2020, N = 430) and 1 year later (Time 2: April 2021, N = 512). Results: Levels of COVID-19 related stress and social support were lower at Time 2. Furthermore, at both Time 1 and Time 2, more social support was associated with less stress. Perceived protection and controllability of COVID-19 also mediated the relationship between social support and COVID-19 at both time points. However, the perceived threat of COVID-19 only served as a mediator at Time 1. Conclusion: These results indicate that Chinese people might experience lower COVID-19 related stress as the pandemic progresses. The perceived threat of COVID-19 played a more critical role in stress experienced at Time 1. These findings not only underscore the importance of social support under the context of Chinese society, but also have implications for developing specific interventions targeting different perceptions of COVID-19 to reduce pandemic-related stress during the different waves of this pandemic.

9.
Cell Rep Med ; 3(9): 100743, 2022 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-36084644

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2 was a dominant circulating SARS-CoV-2 variant worldwide. Recent reports hint that BA.2 is similarly potent regarding antibody evasion but may be more transmissible than BA.1. The pathogenicity of BA.2 remains unclear and is of critical public health significance. Here we investigated the virological features and pathogenicity of BA.2 with in vitro and in vivo models. We show that BA.2 is less dependent on transmembrane protease serine 2 (TMPRSS2) for virus entry in comparison with BA.1 in vitro. In K18-hACE2 mice, BA.2 replicates more efficiently than BA.1 in the nasal turbinates and replicates marginally less efficiently in the lungs, leading to decreased body weight loss and improved survival. Our study indicates that BA.2 is similarly attenuated in lungs compared with BA.1 but is potentially more transmissible because of its better replication at the nasal turbinates.


Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Humanos , Ratones , SARS-CoV-2/genética , Serina , Virulencia
10.
Front Immunol ; 13: 861050, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35401572

RESUMEN

It has been reported that multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) including Alpha, Beta, Gamma, and Delta can reduce neutralization by antibodies, resulting in vaccine breakthrough infections. Virus-antiserum neutralization assays are typically performed to monitor potential vaccine breakthrough strains. However, experiment-based methods took several weeks whether newly emerging variants can break through current vaccines or therapeutic antibodies. To address this, we sought to establish a computational model to predict the antigenicity of SARS-CoV-2 variants by sequence alone. In this study, we firstly identified the relationship between the antigenic difference transformed from the amino acid sequence and the antigenic distance from the neutralization titers. Based on this correlation, we obtained a computational model for the receptor-binding domain (RBD) of the spike protein to predict the fold decrease in virus-antiserum neutralization titers with high accuracy (~0.79). Our predicted results were comparable to experimental neutralization titers of variants, including Alpha, Beta, Delta, Gamma, Epsilon, Iota, Kappa, and Lambda, as well as SARS-CoV. Here, we predicted the fold of decrease of Omicron as 17.4-fold less susceptible to neutralization. We visualized all 1,521 SARS-CoV-2 lineages to indicate variants including Mu, B.1.630, B.1.633, B.1.649, and C.1.2, which can induce vaccine breakthrough infections in addition to reported VOCs Beta, Gamma, Delta, and Omicron. Our study offers a quick approach to predict the antigenicity of SARS-CoV-2 variants as soon as they emerge. Furthermore, this approach can facilitate future vaccine updates to cover all major variants. An online version can be accessed at http://jdlab.online.


Asunto(s)
Antígenos Virales , Vacunas contra la COVID-19 , COVID-19 , SARS-CoV-2 , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Antígenos Virales/inmunología , COVID-19/prevención & control , Vacunas contra la COVID-19/inmunología , Humanos , Sueros Inmunes , Pruebas de Neutralización , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética
11.
JCI Insight ; 7(11)2022 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-35446790

RESUMEN

SARS-CoV-2 has been confirmed in over 450 million confirmed cases since 2019. Although several vaccines have been certified by the WHO and people are being vaccinated on a global scale, it has been reported that multiple SARS-CoV-2 variants can escape neutralization by antibodies, resulting in vaccine breakthrough infections. Bacillus Calmette-Guérin (BCG) is known to induce heterologous protection based on trained immune responses. Here, we investigated whether BCG-induced trained immunity protected against SARS-CoV-2 in the K18-hACE2 mouse model. Our data demonstrate that i.v. BCG (BCG-i.v.) vaccination induces robust trained innate immune responses and provides protection against WT SARS-CoV-2, as well as the B.1.617.1 and B.1.617.2 variants. Further studies suggest that myeloid cell differentiation and activation of the glycolysis pathway are associated with BCG-induced training immunity in K18-hACE2 mice. Overall, our study provides the experimental evidence that establishes a causal relationship between BCG-i.v. vaccination and protection against SARS-CoV-2 challenge.


Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Vacuna BCG , COVID-19/prevención & control , Humanos , Melfalán , Ratones , gammaglobulinas
12.
Front Psychiatry ; 13: 828379, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35264988

RESUMEN

Background: COVID-19 outbreak have a long-term negative impact on mental health. Meanwhile, it may also provide opportunities for positive outcomes (e.g., post-traumatic growth). Resilience and social support could serve as psychological resources to protect individuals against the detrimental effects of the COVID-19 crisis and enable people to develop positive changes during challenging times. Objective: By testing the roles of resilience and social support in the relationship between COVID-19 related stress and negative mental health outcomes (depression and anxiety), as well as the relationship between COVID-19 related stress and positive mental health outcomes (post-traumatic growth, PTG), this study aimed to investigate the psychological mechanisms involved in different mental health outcomes induced by COVID-19. Methods: An online survey was conducted 1 year after the peak of the COVID-19 outbreak (from April to August 2021) in China. The survey includes demographic questionnaires and six scales: the Impact of Event Scale-Revised for COVID-19 (IES-RC), the 10-item Connor-Davidson Resilience Scale (CD-RISC-10), the Perceived Social Support Scale (PSSS), the Center for Epidemiological Studies Depression Scale (CES-D), the Generalized Anxiety Disorder scale (GAD-7) and the Posttraumatic Growth Inventory (PTGI). The structural equation model (SEM) was used to evaluate the relations and mechanisms between COVID-19 related stress and resilience, social support in depression, anxiety, and PTG. Results: A total of 771 Chinese subjects completed the questionnaire, including 416 (54%) females. COVID-19 related stress was associated with anxiety (P < 0.001), PTG (P < 0.001), and depression (P < 0.001). Resilience was related to depression (P < 0.001), anxiety (P < 0.001), and PTG (P < 0.001). Social support was associated with depression (P < 0.001), anxiety (P < 0.001), and PTG (P < 0.001). Under SEM analysis, resilience mediated the effects of COVID-19 related stress on depression and post-traumatic growth. Social support mediated the impacts of COVID-19 related stress on post-traumatic growth, depression, and anxiety. The path coefficients of the mediation effects were statistically significant. Conclusions: The current findings suggest that COVID-19 related stress has a double-edged effect on mental health. Depression, anxiety, and PTG coexist in Chinese individuals 1 year after the peak of the pandemic. Resilience and social support serve as important protective factors of mental health, safeguard people from the negative mental health outcomes of the COVID-19, and promote PTG.

13.
Viruses ; 14(2)2022 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-35215983

RESUMEN

Omicron was designated by the WHO as a VOC on 26 November 2021, only 4 days after its sequence was first submitted. However, the impact of Omicron on current antibodies and vaccines remains unknown and evaluations are still a few weeks away. We analysed the mutations in the Omicron variant against epitopes. In our database, 132 epitopes of the 120 antibodies are classified into five groups, namely NTD, RBD-1, RBD-2, RBD-3, and RBD-4. The Omicron mutations impact all epitopes in NTD, RBD-1, RBD-2, and RBD-3, with no antibody epitopes spared by these mutations. Only four out of 120 antibodies may confer full resistance to mutations in the Omicron spike, since all antibodies in these three groups contain one or more epitopes that are affected by these mutations. Of all antibodies under EUA, the neutralisation potential of Etesevimab, Bamlanivimab, Casirivimab, Imdevima, Cilgavimab, Tixagevimab, Sotrovimab, and Regdanvimab might be dampened to varying degrees. Our analysis suggests the impact of Omicron on current therapeutic antibodies by the Omicron spike mutations may also apply to current COVID-19 vaccines.


Asunto(s)
Anticuerpos Monoclonales/análisis , Anticuerpos Antivirales/farmacología , Simulación por Computador , Mutación/inmunología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Anticuerpos Monoclonales/clasificación , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Neutralizantes/farmacología , Bases de Datos Factuales , Epítopos/inmunología , Humanos , Inmunoglobulina G/farmacología , Pruebas de Neutralización , Glicoproteína de la Espiga del Coronavirus/inmunología
14.
Nature ; 603(7902): 693-699, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35062016

RESUMEN

The Omicron (B.1.1.529) variant of SARS-CoV-2 emerged in November 2021 and is rapidly spreading among the human population1. Although recent reports reveal that the Omicron variant robustly escapes vaccine-associated and therapeutic neutralization antibodies2-10, the pathogenicity of the virus remains unknown. Here we show that the replication of Omicron is substantially attenuated in human Calu3 and Caco2 cells. Further mechanistic investigations reveal that Omicron is inefficient in its use of transmembrane serine protease 2 (TMPRSS2) compared with wild-type SARS-CoV-2 (HKU-001a) and previous variants, which may explain its reduced replication in Calu3 and Caco2 cells. The replication of Omicron is markedly attenuated in both the upper and lower respiratory tracts of infected K18-hACE2 mice compared with that of the wild-type strain and Delta (B.1.617.2) variant, resulting in its substantially ameliorated lung pathology. Compared with wild-type SARS-CoV-2 and the Alpha (B.1.1.7), Beta (1.351) and Delta variants, infection by Omicron causes the lowest reduction in body weight and the lowest mortality rate. Overall, our study demonstrates that the replication and pathogenicity of the Omicron variant of SARS-CoV-2 in mice is attenuated compared with the wild-type strain and other variants.


Asunto(s)
COVID-19/patología , COVID-19/virología , SARS-CoV-2/patogenicidad , Replicación Viral , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , COVID-19/inmunología , Células CACO-2 , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo , Serina Endopeptidasas/metabolismo , Virulencia
15.
Front Immunol ; 12: 730116, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34745099

RESUMEN

Klebsiella pneumoniae found in the normal flora of the human oral and intestinal tract mainly causes hospital-acquired infections but can also cause community-acquired infections. To date, most clinical trials of vaccines against K. pneumoniae have ended in failure. Furthermore, no single conserved protein has been identified as an antigen candidate to accelerate vaccine development. In this study, we identified five outer membrane proteins of K. pneumoniae, namely, Kpn_Omp001, Kpn_Omp002, Kpn_Omp003, Kpn_Omp004, and Kpn_Omp005, by using reliable second-generation proteomics and bioinformatics. Mice vaccinated with these five KOMPs elicited significantly higher antigen-specific IgG, IgG1, and IgG2a. However, only Kpn_Omp001, Kpn_Omp002, and Kpn_Omp005 were able to induce a protective immune response with two K. pneumoniae infection models. These protective effects were accompanied by the involvement of different immune responses induced by KOMPs, which included KOMPs-specific IFN-γ-, IL4-, and IL17A-mediated immune responses. These findings indicate that Kpn_Omp001, Kpn_Omp002, and Kpn_Omp005 are three potential Th1, Th2, and Th17 candidate antigens, which could be developed into multivalent and serotype-independent vaccines against K. pneumoniae infection.


Asunto(s)
Proteínas de la Membrana Bacteriana Externa/farmacología , Vacunas Bacterianas/farmacología , Infecciones por Klebsiella/prevención & control , Klebsiella pneumoniae/inmunología , Desarrollo de Vacunas , Animales , Carga Bacteriana , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas de la Membrana Bacteriana Externa/inmunología , Vacunas Bacterianas/genética , Vacunas Bacterianas/inmunología , Modelos Animales de Enfermedad , Células HL-60 , Humanos , Inmunogenicidad Vacunal , Infecciones por Klebsiella/inmunología , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/genética , Ratones Endogámicos BALB C , Fagocitos/inmunología , Fagocitos/microbiología , Fagocitosis , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacología , Linfocitos T/inmunología , Linfocitos T/microbiología , Vacunación , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/farmacología
16.
EBioMedicine ; 73: 103643, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34689086

RESUMEN

BACKGROUND: Wildtype mice are not susceptible to SARS-CoV-2 infection. Emerging SARS-CoV-2 variants, including B.1.1.7, B.1.351, P.1, and P.3, contain mutations in spike that has been suggested to associate with an increased recognition of mouse ACE2, raising the postulation that these SARS-CoV-2 variants may have evolved to expand species tropism to wildtype mouse and potentially other murines. Our study evaluated this possibility with substantial public health importance. METHODS: We investigated the capacity of wildtype (WT) SARS-CoV-2 and SARS-CoV-2 variants in infecting mice (Mus musculus) and rats (Rattus norvegicus) under in vitro and in vivo settings. Susceptibility to infection was evaluated with RT-qPCR, plaque assays, immunohistological stainings, and neutralization assays. FINDINGS: Our results reveal that B.1.1.7 and other N501Y-carrying variants but not WT SARS-CoV-2 can infect wildtype mice. High viral genome copies and high infectious virus particle titres are recovered from the nasal turbinate and lung of B.1.1.7-inocluated mice for 4-to-7 days post infection. In agreement with these observations, robust expression of viral nucleocapsid protein and histopathological changes are detected from the nasal turbinate and lung of B.1.1.7-inocluated mice but not that of the WT SARS-CoV-2-inoculated mice. Similarly, B.1.1.7 readily infects wildtype rats with production of infectious virus particles. INTERPRETATION: Our study provides direct evidence that the SARS-CoV-2 variant, B.1.1.7, as well as other N501Y-carrying variants including B.1.351 and P.3, has gained the capability to expand species tropism to murines and public health measures including stringent murine control should be implemented to facilitate the control of the ongoing pandemic. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.


Asunto(s)
COVID-19/patología , SARS-CoV-2/fisiología , Tropismo Viral , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19/virología , Femenino , Humanos , Pulmón/patología , Pulmón/virología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Pruebas de Neutralización , Proteínas de la Nucleocápside/inmunología , Proteínas de la Nucleocápside/metabolismo , ARN Viral/análisis , ARN Viral/metabolismo , Ratas , Ratas Sprague-Dawley , SARS-CoV-2/inmunología , SARS-CoV-2/aislamiento & purificación , Cornetes Nasales/patología , Cornetes Nasales/virología , Internalización del Virus
17.
Commun Biol ; 4(1): 609, 2021 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-34021234

RESUMEN

Unbidden distressing memories inflict serious damage on mental health. Extant research highlights the importance of associative learning in modulating aversive memory. We report that conscious active suppression eliminates learned fear responses independent of memory triggers and is related to individual difference in thought control ability; in contrast, thought diversion only reduces cue-specific fear response. These results suggest potential avenues for treatment of persistent maladaptive memories by engaging declarative mnemonic control mechanisms.


Asunto(s)
Aprendizaje por Asociación/fisiología , Miedo/fisiología , Inhibición Psicológica , Memoria/fisiología , Adulto , Femenino , Humanos , Masculino , Adulto Joven
18.
Nat Commun ; 12(1): 2537, 2021 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-33953170

RESUMEN

Metastasis accounts for 90% of cancer-related deaths and, currently, there are no effective clinical therapies to block the metastatic cascade. A need to develop novel therapies specifically targeting fundamental metastasis processes remains urgent. Here, we demonstrate that Salmonella YB1, an engineered oxygen-sensitive strain, potently inhibits metastasis of a broad range of cancers. This process requires both IFN-γ and NK cells, as the absence of IFN-γ greatly reduces, whilst depletion of NK cells in vivo completely abolishes, the anti-metastatic ability of Salmonella. Mechanistically, we find that IFN-γ is mainly produced by NK cells during early Salmonella infection, and in turn, IFN-γ promotes the accumulation, activation, and cytotoxicity of NK cells, which kill the metastatic cancer cells thus achieving an anti-metastatic effect. Our findings highlight the significance of a self-regulatory feedback loop of NK cells in inhibiting metastasis, pointing a possible approach to develop anti-metastatic therapies by harnessing the power of NK cells.


Asunto(s)
Interferón gamma/metabolismo , Interferón gamma/farmacología , Células Asesinas Naturales/inmunología , Activación de Linfocitos/efectos de los fármacos , Metástasis de la Neoplasia/inmunología , Infecciones por Salmonella/metabolismo , Salmonella/genética , Animales , Citocinas/metabolismo , Femenino , Inmunidad Innata , Inmunoterapia/métodos , Interferón gamma/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Infecciones por Salmonella/tratamiento farmacológico
19.
Emerg Microbes Infect ; 10(1): 874-884, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33890550

RESUMEN

The Coronavirus Disease 2019 (COVID-19) pandemic is unlikely to abate until sufficient herd immunity is built up by either natural infection or vaccination. We previously identified ten linear immunodominant sites on the SARS-CoV-2 spike protein of which four are located within the RBD. Therefore, we designed two linkerimmunodominant site (LIS) vaccine candidates which are composed of four immunodominant sites within the RBD (RBD-ID) or all the 10 immunodominant sites within the whole spike (S-ID). They were administered by subcutaneous injection and were tested for immunogenicity and in vivo protective efficacy in a hamster model for COVID-19. We showed that the S-ID vaccine induced significantly better neutralizing antibody response than RBD-ID and alum control. As expected, hamsters vaccinated by S-ID had significantly less body weight loss, lung viral load, and histopathological changes of pneumonia. The S-ID has the potential to be an effective vaccine for protection against COVID-19.


Asunto(s)
Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Epítopos Inmunodominantes/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Animales , Cricetinae , Femenino , Células HEK293 , Humanos , Masculino , Mesocricetus , Ratones , Ratones Endogámicos BALB C , Vacunación
20.
Sci Rep ; 10(1): 12913, 2020 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-32737357

RESUMEN

Delay discounting describes the phenomenon whereby the subjective value of a reward declines as the time until its receipt increases. Individuals differ in the subjective value that they assign to future rewards, yet, the components feeding into this appraisal of value remain unclear. We examined whether temporal psychological distance, i.e. the closeness one feels to the past and future, is one such component. English speakers in the USA and Mandarin speakers in China completed a delay discounting task and organized past and future world events on a canvas according to their representation of the event's temporal position relative to themselves. Previous work has identified linguistic and cultural differences in time conception between these populations, thus, we hypothesized that this sample would display the variability necessary to probe whether temporal psychological distance plays a role in reward valuation. We found that English speakers employed horizontal, linear representations of world events, while Mandarin speakers used more two-dimensional, circular representations. Across cultures, individuals who represented the future as more distant discounted future rewards more strongly. Distance representations of past events, however, were associated with discounting behaviors selectively in Mandarin speakers. This suggests that temporal psychological distance plays a fundamental role in farsighted decision-making.


Asunto(s)
Conducta de Elección/fisiología , Cultura , Descuento por Demora/fisiología , Lenguaje , Adolescente , Adulto , China , Toma de Decisiones , Femenino , Humanos , Masculino , Estados Unidos
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