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In this study, we use machine learning algorithms with QM-derived COSMO-RS descriptors, along with Morgan fingerprints, to predict the absolute solubility of drug-like compounds. The QM-derived descriptors account for the molecular properties of the solute, i.e., the solute-solute interactions in an artificial-liquid-state (super-cooled liquid), and the solute-solvent interactions in solution. We employ two main approaches to predict solubility: (i) a hypothetical pathway that involves melting the solute at room temperature T = T¯ ([Formula: see text]) and mixing the artificially liquid solute into the solvent ([Formula: see text]). In this approach [Formula: see text] is predicted using machine learning models, and the [Formula: see text] is obtained from COSMO-RS calculations; (ii) direct solubility prediction using machine learning algorithms. The models were trained on a large number of Bayer in-house compounds for which water solubility data is available at physiological pH of 6.5 and ambient temperature. We also evaluated our models using external datasets from a solubility challenge. Our models present great improvements compared to the absolute solubility prediction with the QSAR model for the artificial liquid state as implemented in the COSMOtherm software, for both in-house and external datasets. We are furthermore able to demonstrate the superiority of QM-derived descriptors compared to cheminformatics descriptors. We finally present low-cost alternative models using fragment-based COSMOquick calculations with only marginal reduction in the quality of predicted solubility.
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Modelos Químicos , Água , Solubilidade , Água/química , Aprendizado de Máquina , Solventes/químicaRESUMO
The replication and pathogenicity of influenza A viruses (IAVs) critically depend on their ability to tolerate the antiviral interferon (IFN) response. To determine a potential role for the IAV hemagglutinin (HA) in viral sensitivity to IFN, we studied the restriction of IAV infection in IFN-ß-treated human epithelial cells by using 2:6 recombinant IAVs that shared six gene segments of A/Puerto Rico/8/1934 virus (PR8) and contained HAs and neuraminidases of representative avian, human, and zoonotic H5N1 and H7N9 viruses. In A549 and Calu-3 cells, viruses displaying a higher pH optimum of HA-mediated membrane fusion, H5N1-PR8 and H7N9-PR8, were less sensitive to the IFN-induced antiviral state than their counterparts with HAs from duck and human viruses, which fused at a lower pH. The association between a high pH optimum of fusion and reduced IFN sensitivity was confirmed by using HA point mutants of A/Hong Kong/1/1968-PR8 that differed solely by their fusion properties. Furthermore, similar effects of the viral fusion pH on IFN sensitivity were observed in experiments with (i) primary human type II alveolar epithelial cells and differentiated cultures of human airway epithelial cells, (ii) nonrecombinant zoonotic and pandemic IAVs, and (iii) preparations of IFN-α and IFN-λ1. A higher pH of membrane fusion and reduced sensitivity to IFN correlated with lower restriction of the viruses in MDCK cells stably expressing the IFN-inducible transmembrane proteins IFITM2 and IFITM3, which are known to inhibit viral fusion. Our results reveal that the pH optimum of HA-driven membrane fusion of IAVs is a determinant of their sensitivity to IFN and IFITM proteins.IMPORTANCE The IFN system constitutes an important innate defense against viral infection. Substantial information is available on how IAVs avoid detection by sensors of the IFN system and disable IFN signaling pathways. Much less is known about the ability of IAVs to tolerate the antiviral activity of IFN-induced cellular proteins. The IFN-induced proteins of the IFITM family block IAV entry into target cells and can restrict viral spread and pathogenicity. Here we show for the first time that the sensitivity of IAVs to the IFN-induced antiviral state and IFITM2 and IFITM3 proteins depends on the pH value at which the viral HA undergoes a conformational transition and mediates membrane fusion. Our data imply that the high pH optimum of membrane fusion typical of zoonotic IAVs of gallinaceous poultry, such as H5N1 and H7N9, may contribute to their enhanced virulence in humans.
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Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Interações Hospedeiro-Patógeno , Virus da Influenza A Subtipo H5N1/fisiologia , Subtipo H7N9 do Vírus da Influenza A/fisiologia , Interferons/imunologia , Fusão de Membrana , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Células A549 , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Linhagem Celular , Cães , Patos , Células Epiteliais/efeitos dos fármacos , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Concentração de Íons de Hidrogênio , Virus da Influenza A Subtipo H5N1/química , Virus da Influenza A Subtipo H5N1/genética , Subtipo H7N9 do Vírus da Influenza A/química , Subtipo H7N9 do Vírus da Influenza A/genética , Interferon beta/imunologia , Células Madin Darby de Rim Canino , Proteínas de Membrana/genética , Proteínas de Ligação a RNA/genética , Internalização do Vírus , Replicação ViralRESUMO
Major differences in the transcriptional program underlying the phenotypic switch between exponential and post-exponential growth of Legionella pneumophila were formerly described characterizing important alterations in infection capacity. Additionally, a third state is known where the bacteria transform in a viable but nonculturable state under stress, such as starvation. We here describe phase-related proteomic changes in exponential phase (E), postexponential phase (PE) bacteria, and unculturable microcosms (UNC) containing viable but nonculturable state cells, and identify phase-specific proteins. We present data on different bacterial subproteomes of E and PE, such as soluble whole cell proteins, outer membrane-associated proteins, and extracellular proteins. In total, 1368 different proteins were identified, 922 were quantified and 397 showed differential abundance in E/PE. The quantified subproteomes of soluble whole cell proteins, outer membrane-associated proteins, and extracellular proteins; 841, 55, and 77 proteins, respectively, were visualized in Voronoi treemaps. 95 proteins were quantified exclusively in E, such as cell division proteins MreC, FtsN, FtsA, and ZipA; 33 exclusively in PE, such as motility-related proteins of flagellum biogenesis FlgE, FlgK, and FliA; and 9 exclusively in unculturable microcosms soluble whole cell proteins, such as hypothetical, as well as transport/binding-, and metabolism-related proteins. A high frequency of differentially abundant or phase-exclusive proteins was observed among the 91 quantified effectors of the major virulence-associated protein secretion system Dot/Icm (> 60%). 24 were E-exclusive, such as LepA/B, YlfA, MavG, Lpg2271, and 13 were PE-exclusive, such as RalF, VipD, Lem10. The growth phase-related specific abundance of a subset of Dot/Icm virulence effectors was confirmed by means of Western blotting. We therefore conclude that many effectors are predominantly abundant at either E or PE which suggests their phase specific function. The distinct temporal or spatial presence of such proteins might have important implications for functional assignments in the future or for use as life-stage specific markers for pathogen analysis.
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Proteínas de Bactérias/metabolismo , Legionella pneumophila/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Western Blotting , Cromatografia Líquida , Humanos , Legionella pneumophila/crescimento & desenvolvimento , Legionella pneumophila/patogenicidade , Doença dos Legionários/microbiologia , Estágios do Ciclo de Vida , Espectrometria de Massas em Tandem , VirulênciaRESUMO
Tick-borne encephalitis (TBE) is a serious neurological disease caused by TBE virus (TBEV). Because antiviral treatment options are not available, vaccination is the key prophylactic measure against TBEV infections. Despite the availability of effective vaccines, cases of vaccination breakthrough infections have been reported. The multienzymatic non-structural protein 3 (NS3) of orthoflaviviruses plays an important role in polyprotein processing and virus replication. In the present study, we evaluated NS3 of TBEV as a potential vaccine target for the induction of protective immunity. To this end, a recombinant modified vaccinia virus Ankara that drives the expression of the TBEV NS3 gene (MVA-NS3) was constructed. MVA-NS3 was used to immunize C57BL/6 mice. It induced NS3-specific immune responses, in particular T cell responses, especially against the helicase domain of NS3. However, MVA-NS3-immunized mice were not protected from subsequent challenge infection with a lethal dose of the TBEV strain Neudoerfl, indicating that in contrast to immunity to prME and NS1, NS3-specific immunity is not an independent correlate of protection against TBEV in this mouse model.
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Rift Valley fever (RVF) is a mosquito-borne zoonotic disease caused by RVF virus (RVFV). RVFV infections in humans are usually asymptomatic or associated with mild febrile illness, although more severe cases of haemorrhagic disease and encephalitis with high mortality also occur. Currently, there are no licensed human vaccines available. The safety and efficacy of a genetically engineered four-segmented RVFV variant (hRVFV-4s) as a potential live-attenuated human vaccine has been tested successfully in mice, ruminants, and marmosets though the correlates of protection of this vaccine are still largely unknown. In the present study, we have assessed hRVFV-4s-induced humoral and cellular immunity in a mouse model of RVFV infection. Our results confirm that a single dose of hRVFV-4s is highly efficient in protecting naïve mice from developing severe disease following intraperitoneal challenge with a highly virulent RVFV strain and data show that virus neutralizing (VN) serum antibody titres in a prime-boost regimen are significantly higher compared to the single dose. Subsequently, VN antibodies from prime-boost-vaccinated recipients were shown to be protective when transferred to naïve mice. In addition, hRVFV-4s vaccination induced a significant virus-specific T cell response as shown by IFN-γ ELISpot assay, though these T cells did not provide significant protection upon passive transfer to naïve recipient mice. Collectively, this study highlights hRVFV-4s-induced VN antibodies as a major correlate of protection against lethal RVFV infection.
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Anticorpos Neutralizantes , Anticorpos Antivirais , Febre do Vale de Rift , Vírus da Febre do Vale do Rift , Vacinas Atenuadas , Vacinas Virais , Animais , Vírus da Febre do Vale do Rift/imunologia , Vírus da Febre do Vale do Rift/genética , Febre do Vale de Rift/prevenção & controle , Febre do Vale de Rift/imunologia , Vacinas Virais/imunologia , Vacinas Virais/administração & dosagem , Camundongos , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Feminino , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/administração & dosagem , Modelos Animais de Doenças , Imunidade Celular , Linfócitos T/imunologia , Imunidade Humoral , Camundongos Endogâmicos BALB C , Interferon gama/imunologia , VacinaçãoRESUMO
Magnetic Resonance (MR) thermometry is used for the monitoring of MR-guided microwave ablations (MWA), and for the intraoperative evaluation of ablation regions. Nevertheless, the accuracy of temperature mapping may be compromised by electromagnetic interference emanating from the microwave (MW) generator. This study evaluated different setups for improving magnetic resonance imaging (MRI) during MWA with a modified MW generator. MWA was performed in 15 gel phantoms comparing three setups: The MW generator was placed outside the MR scanner room, either connected to the MW applicator using a penetration panel with a radiofrequency (RF) filter and a 7â¯m coaxial cable (Setup 1), or through a waveguide using a 5â¯m coaxial cable (Setup 2). Setup 3 employed the MW generator within the MR scan room, connected by a 5â¯m coaxial cable. The coaxial cables in setups 2 and 3 were modified with custom shielding to reduce interference. The setups during ablation (active setup) were compared to a reference setup without the presence of the MW system. Thermometry and thermal dose maps (CEM43 model) were compared for the three configurations. Primary endpoints for assessment were signal-to-noise ratio (SNR), temperature precision, Sørensen-Dice-Coefficient (DSC), and RF-noise spectra. Setup 3 showed highly significant electromagnetic interference during ablation with a SNR decrease by -60.4%±13.5% (p<0.001) compared to reference imaging. For setup 1 and setup 2 no significant decrease in SNR was measured with differences of -2.9%±9.8% (p=0.6) and -1.5%±12.8% (p=0.8), respectively. SNR differences were significant between active setups 1 and 3 with -51.2%±16.1% (p<0.001) and between active setups 2 and 3 with -59.0%±15.5% (p<0.001) but not significant between active setups 1 and 2 with 19.0%±13.7% (p=0.09). Furthermore, no significant differences were seen in temperature precision or DSCs between all setups, ranging from 0.33⯰C⯱â¯0.04⯰C (Setup 1) to 0.38⯰C⯱â¯0.06⯰C (Setup 3) (p=0.6) and from 87.0%±1.6% (Setup 3) to 88.1%±1.6% (Setup 2) (p=0.58), respectively. Both setups (1 and 2) with the MW generator outside the MR scanner room were beneficial to reduce electromagnetic interference during MWA. Moreover, provided that a shielded cable is utilized in setups 2 and 3, all configurations displayed negligible differences in temperature precision and DSCs, indicating that the location of the MW generator does not significantly impact the accuracy of thermometry during MWA.
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Introduction: Tick-borne encephalitis virus (TBEV) is one of the most relevant tick-transmitted neurotropic arboviruses in Europe and Asia and the causative agent of tick-borne encephalitis (TBE). Annually more than 10,000 TBE cases are reported despite having vaccines available. In Europe, the vaccines FSME-IMMUN® and Encepur® based on formaldehyde-inactivated whole viruses are licensed. However, demanding vaccination schedules contribute to sub-optimal vaccination uptake and breakthrough infections have been reported repeatedly. Due to its immunogenic properties as well as its role in viral replication and disease pathogenesis, the non-structural protein 1 (NS1) of flaviviruses has become of interest for non-virion based flavivirus vaccine candidates in recent years. Methods: Therefore, immunogenicity and protective efficacy of TBEV NS1 expressed by neuraminidase (NA)-deficient Influenza A virus (IAV) or Modified Vaccinia virus Ankara (MVA) vectors were investigated in this study. Results: With these recombinant viral vectors TBEV NS1-specific antibody and T cell responses were induced. Upon heterologous prime/boost regimens partial protection against lethal TBEV challenge infection was afforded in mice. Discussion: This supports the inclusion of NS1 as a vaccine component in next generation TBEV vaccines.
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Vírus da Encefalite Transmitidos por Carrapatos , Encefalite Transmitida por Carrapatos , Vacinas contra Influenza , Influenza Humana , Orthomyxoviridae , Animais , Camundongos , Humanos , Vaccinia virus , Anticorpos Antivirais , Influenza Humana/prevenção & controle , Imunidade CelularRESUMO
Introduction: Tick-borne encephalitis virus (TBEV) is an important human pathogen that can cause a serious disease involving the central nervous system (tick-borne encephalitis, TBE). Although approved inactivated vaccines are available, the number of TBE cases is rising, and breakthrough infections in fully vaccinated subjects have been reported in recent years. Methods: In the present study, we generated and characterized a recombinant Modified Vaccinia virus Ankara (MVA) for the delivery of the pre-membrane (prM) and envelope (E) proteins of TBEV (MVA-prME). Results: MVA-prME was tested in mice in comparison with a licensed vaccine FSME-IMMUN® and proved to be highly immunogenic and afforded full protection against challenge infection with TBEV. Discussion: Our data indicate that MVA-prME holds promise as an improved next-generation vaccine for the prevention of TBE.
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Vírus da Encefalite Transmitidos por Carrapatos , Vacinas Virais , Humanos , Animais , Camundongos , Vírus da Encefalite Transmitidos por Carrapatos/genética , Anticorpos Neutralizantes , Anticorpos Antivirais , Vaccinia virus/genéticaRESUMO
The MRI hybrid ablation system is an approach to use the MR (magnetic resonance) scanner's radiofrequency amplifier itself as power source for ablation. Hereby, an electrode is connected to the MR internal radiofrequency amplifier. An average RF power is provided through a train of short RF pulses, which is sufficient to thermally destroy tissue. However, ablation with too high power values can cause tissue carbonizations, thus impeding the ablation procedure. Therefore, monitoring of the energy and the power absorbed inside the tissue is necessary. For this purpose, a measurement system was designed to measure the energy applied to the tissue when using the concept of an MRI hybrid ablation system. The system consists of a dual-directional coupler, RF-to-RMS sensors, and a microcontroller. The gradient calculation of the measured energy curve provides information about the absorbed RF power in the tissue. Validation measurements of the system were performed and compared with measurements from the MR-internal power measurement system. The energy monitoring system was also tested in an ablation experiment with ex-vivo animal tissue using the MRI hybrid ablation system. The measurements showed that the applied RF power can be monitored in real-time. It has been shown that the mean RF power absorbed in the patient decreased during an ablation procedure due to an occurring impedance mismatch and tissue changes. In further work, the influence of the monitoring system on the quality of the MR images should be investigated. Clinical relevance- This paper demonstrates an energy monitoring system for an RF ablation system, which can be used inside an MR environment.
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Ablação por Cateter , Amplificadores Eletrônicos , Animais , Arritmias Cardíacas , Ablação por Cateter/métodos , Eletrodos , Imageamento por Ressonância Magnética/métodos , Ondas de RádioRESUMO
Cancer is a disease which requires a significant amount of careful medical attention. For minimally-invasive thermal ablation procedures, the monitoring of heat distribution is one of the biggest challenges. In this work, three approaches for volumetric heat map reconstruction (Delauney triangulation, minimum volume enclosing ellipsoids (MVEE) and splines) are presented based on uniformly distributed 2D MRI phase images rotated around the applicator's main axis. We compare them with our previous temperature interpolation method with respect to accuracy, robustness and adaptability. All approaches are evaluated during MWA treatment on the same data sets consisting of 13 ex vivo bio protein phantoms, including six phantoms with simulated heat sink effects. Regarding accuracy, the DSC similarity results show a strong trend towards the MVEE ([Formula: see text]) and the splines ([Formula: see text]) method compared to the Delauney triangulation ([Formula: see text]) or the temperature interpolation ([Formula: see text]). Robustness is increased for all three approaches and the adaptability shows a significant trend towards the initial interpolation method and the splines. To overcome local inhomogeneities in the acquired data, the use of adaptive simulations should be considered in the future. In addition, the transfer to in vivo animal experiments should be considered to test for clinical applicability.
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Lesões dos Tecidos Moles , Termometria , Algoritmos , Animais , Imageamento por Ressonância Magnética/métodos , Necrose , Imagens de Fantasmas , Termometria/métodosRESUMO
In brain tissue of three harbor seals of the German North Sea coast, high virus loads of highly pathogenic avian influenza virus (HPAIV) H5N8 were detected. Identification of different virus variants indicates high exposure to HPAIV circulating in wild birds, but there is no evidence for H5 specific antibodies in healthy seals. Replication of avian viruses in seals may allow HPAIV to acquire mutations needed to adapt to mammalian hosts as shown by PB2 627K variants detected in these cases.
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Vírus da Influenza A Subtipo H5N8 , Vírus da Influenza A , Influenza Aviária , Phoca , Animais , Vírus da Influenza A Subtipo H5N8/genética , Vírus da Influenza A/genética , Influenza Aviária/epidemiologia , Mar do NorteRESUMO
Irreversible electroporation (IRE) is a non-thermal tumor ablation method where strong electrical fields between at least two electrodes are used and can be seen as an alternative to thermal ablation techniques. The therapy outcome directly dependents on the position of the electrodes. Real-time monitoring of the IRE by magnetic resonance imaging (MRI) would allow to detect unwanted electrode displacement and to apply visualization methods for the ablation area. This requires that the IRE generator does not significantly interfere with the MRI. Currently, there is no IRE generator available designed for MRI-guided IRE.This paper presents an IRE system specifically developed for use in an MRI environment. The system is initially tested with a standard IRE sequence and then the interference between a clinical 3 T MRI device and the IRE system is investigated using a noise measurement and the signal-to-noise ratio (SNR) of images acquired with a gradient echo (GRE) sequence. The results show, that although the SNR of the images decrease by maximal 36 % when the IRE system is switched on, image quality does not visibly degrade. Hence, MRI-guided IRE is feasible with the proposed system.Clinical relevance- This paper demonstrates the possibility of MRI-guided IRE with only minor image degradation when the IRE system is used in parallel with MRI imaging.
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Técnicas de Ablação , Eletroporação , Eletrodos , Imageamento por Ressonância MagnéticaRESUMO
Magnetic Resonance Imaging (MRI) guided Microwave Ablation (MWA) allows for real-time therapy monitoring with MRI-thermometry. The MWA generator emits Radio Frequency (RF) interference, which can limit the accuracy of therapy monitoring. The image quality is enhanced by Floating Cable Traps (FCTs) that are used to attenuate common mode currents on supply lines between a MWA generator, and its ablation applicator. The effect of an FCT on the Signal to Noise Ratio (SNR), and changes in the MRI spectrum are discussed in this paper. The application of FCT can bring significant improvements in both, the MRI spectrum and the SNR.Floating Cable Traps are user-friendly. FCT enable coaxial cables to reduce interferences emitted in MRI guided interventions. It is used to selectively attenuate frequencies in the MRI's range. This can increase the image's Signal to Noise Ratio.
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Micro-Ondas , Termometria , Imageamento por Ressonância Magnética , Impressão Tridimensional , Razão Sinal-RuídoRESUMO
Tick-borne encephalitis virus (TBEV), a member of the family Flaviviridae, is one of the most important tick-transmitted viruses in Europe and Asia. Being a neurotropic virus, TBEV causes infection of the central nervous system, leading to various (permanent) neurological disorders summarized as tick-borne encephalitis (TBE). The incidence of TBE cases has increased due to the expansion of TBEV and its vectors. Since antiviral treatment is lacking, vaccination against TBEV is the most important protective measure. However, vaccination coverage is relatively low and immunogenicity of the currently available vaccines is limited, which may account for the vaccine failures that are observed. Understanding the TBEV-specific correlates of protection is of pivotal importance for developing novel and improved TBEV vaccines. For affording robust protection against infection and development of TBE, vaccines should induce both humoral and cellular immunity. In this review, the adaptive immunity induced upon TBEV infection and vaccination as well as novel approaches to produce improved TBEV vaccines are discussed.
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Currently, infections with SARS-Coronavirus-2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, are responsible for substantial morbidity and mortality worldwide. Older adults subjects > 60 years of age account for > 95% of the over one million fatal cases reported to date. It is unclear why in this age group SARS-CoV-2 infection causes more severe disease than in young adults. We hypothesized that differences in SARS-CoV-2 cross-reactive cellular immunity induced after infection with human coronaviruses (HCoVs), like OC43 and NL63, were at the basis of the differential mortality (and morbidity) observed after SARS-CoV-2 infection, because a small proportion of HCoV-specific T cells cross-react with SARS-CoV-2. Our data demonstrate that pre-existing T cell immunity induced by circulating human alpha- and beta-HCoVs is present in young adult individuals, but virtually absent in older adult subjects. Consequently, the frequency of cross-reactive T cells directed to the novel pandemic SARS-CoV-2 was minimal in most older adults. To the best of our knowledge, this is the first time that the presence of cross-reactive T cells to SARS-CoV-2 is compared in young and older adults. Our findings provide at least a partial explanation for the more severe clinical outcome of SARS-CoV-2 infection observed in the elderly. Moreover, this information could help to design efficacious vaccines for this age group, aiming at the induction of cell-mediated immunity.
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Anticorpos Antivirais/imunologia , Coronavirus Humano NL63/imunologia , Coronavirus Humano OC43/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Adulto , Idoso , COVID-19/imunologia , COVID-19/patologia , Reações Cruzadas/imunologia , Humanos , Imunidade Celular/imunologia , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/imunologia , Adulto JovemRESUMO
INTRODUCTION: Various viruses, including poxviruses, adenoviruses and vesicular stomatitis virus, have been considered as vaccine vectors for the delivery of antigens of interest in the development of vaccines against newly emerging pathogens. AREAS COVERED: Here, we review results that have been obtained with influenza A viruses (IAV) as vaccine vectors. With the advent of reverse genetics technology, IAV-based recombinant vaccine candidates have been constructed that induce protective immunity to a variety of different pathogens of interest, including West Nile virus, Plasmodium falciparum and respiratory syncytial virus. The various cloning strategies to produce effective and attenuated, safe to use IAV-based viral vectors are discussed. EXPERT COMMENTARY: It was concluded that IAV-based vector system has several advantages and holds promise for further development.
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Vetores Genéticos , Vírus da Influenza A/genética , Malária Falciparum/prevenção & controle , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas Sintéticas/imunologia , Febre do Nilo Ocidental/prevenção & controle , Humanos , Plasmodium falciparum/imunologia , Vírus Sinciciais Respiratórios/imunologia , Genética Reversa , Vacinas Atenuadas/imunologia , Vírus do Nilo Ocidental/imunologiaRESUMO
Effective vaccines are the cornerstone of our defenses against acute influenza virus infections that result in â¼500 000 annual deaths worldwide. For decades, an on-going concerted effort has been to develop a universal influenza vaccine to combat the looming threat of potentially pandemic emerging and re-emerging influenza viruses. To address the need for rapid efficacious vaccines that could mitigate the impact of seasonal and future pandemics, multiple platforms are under development and/or investigation. What is clear is that any universal vaccine must provide long-lasting cross-protective immunity that can induce both B and T cell responses. This review will explore some of the universal influenza vaccine platforms in the contexts of their ability to induce long-lasting and cross-protective T cell immunity.
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Anticorpos Antivirais/imunologia , Proteção Cruzada , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Orthomyxoviridae/imunologia , Animais , Ensaios Clínicos como Assunto , Humanos , Camundongos , Infecções por Orthomyxoviridae/imunologia , Linfócitos T/imunologia , VacinaçãoRESUMO
Despite causing pandemics and yearly epidemics that result in significant morbidity and mortality, our arsenal of options to treat influenza A virus (IAV) infections remains limited and is challenged by the virus itself. While vaccination is the preferred intervention strategy against influenza, its efficacy is reduced in the elderly and infants who are most susceptible to severe and/or fatal infections. In addition, antigenic variation of IAV complicates the production of efficacious vaccines. Similarly, effectiveness of currently used antiviral drugs is jeopardized by the development of resistance to these drugs. Like many viruses, IAV is reliant on host factors and signaling-pathways for its replication, which could potentially offer alternative options to treat infections. While host-factors have long been recognized as attractive therapeutic candidates against other viruses, only recently they have been targeted for development as IAV antivirals. Future strategies to combat IAV infections will most likely include approaches that alter host-virus interactions on the one hand or dampen harmful host immune responses on the other, with the use of biological response modifiers (BRMs). In principle, BRMs are biologically active agents including antibodies, small peptides, and/or other (small) molecules that can influence the immune response. BRMs are already being used in the clinic to treat malignancies and autoimmune diseases. Repurposing such agents would allow for accelerated use against severe and potentially fatal IAV infections. In this review, we will address the potential therapeutic use of different BRM classes to modulate the immune response induced after IAV infections.
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Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Imunomodulação/efeitos dos fármacos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/imunologia , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Animais , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fatores Imunológicos/química , Influenza Humana/metabolismo , Influenza Humana/virologia , Resultado do TratamentoRESUMO
Influenza A and B virus infections are a major cause of respiratory disease in humans and are responsible for substantial morbidity and mortality worldwide. Vaccination against influenza mainly aims at the induction of virus neutralizing serum antibodies, which are an important correlate of protection provided that the antibodies match the strains causing the outbreaks antigenically. In addition, virus-specific T cells are known to contribute to protective immunity to influenza virus infections by limiting duration and severity of the disease. As the majority of virus-specific T cells recognize epitopes located in relatively conserved proteins, like the Nucleoprotein and Matrix 1 protein, they display a high degree of cross-reactivity with a wide range of influenza viruses, including newly emerging viruses of alternative subtypes. Advancing our understanding of influenza virus-specific T cell responses and their role in protective immunity against influenza will aid the rational design of novel vaccines that could induce robust, broad and long-lasting immune responses. Here, we discuss the contribution of influenza virus-specific CD4+ and CD8+ T cells to protective immunity against influenza infection and the requirements and strategies for their induction by natural infection or vaccination, especially in children.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Orthomyxoviridae/imunologia , Desenho de Fármacos , Humanos , Imunidade Celular , VacinaçãoRESUMO
The need of external ablation generators complicates the setup of magnetic resonance (MR) guided interventions, e. g. due to inserting devices with ferrite components into the MR room or because of image distortions due to RF interferences. By using the power provided from the MR internal power amplifier, it is possible to avoid external ablation generators. Using imaging sequences with a high duty cycle, a sufficient mean power value can be generated to destroy tissue. In this paper, it has been shown that it is possible to destroy tissue with such an ablation MRI hybrid system. Simulations were done to calculate the specific absorption rate (SAR) generated by an ablation electrode at the Larmor frequency for a 3 T MR device. The SAR values were then compared with ablation experiments performed inside an MR device with protein phantoms.