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1.
Adv Sci (Weinh) ; 8(18): 2100316, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34580619

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented global health crisis, resulting in a critical need for effective vaccines that generate protective antibodies. Protein subunit vaccines represent a promising approach but often lack the immunogenicity required for strong immune stimulation. To overcome this challenge, it is first demonstrated that advanced biomaterials can be leveraged to boost the effectiveness of SARS-CoV-2 protein subunit vaccines. Additionally, it is reported that oxygen is a powerful immunological co-adjuvant and has an ability to further potentiate vaccine potency. In preclinical studies, mice immunized with an oxygen-generating coronavirus disease 2019 (COVID-19) cryogel-based vaccine (O2-CryogelVAX) exhibit a robust Th1 and Th2 immune response, leading to a sustained production of highly effective neutralizing antibodies against the virus. Even with a single immunization, O2-CryogelVAX achieves high antibody titers within 21 days, and both binding and neutralizing antibody levels are further increased after a second dose. Engineering a potent vaccine system that generates sufficient neutralizing antibodies after one dose is a preferred strategy amid vaccine shortage. The data suggest that this platform is a promising technology to reinforce vaccine-driven immunostimulation and is applicable to current and emerging infectious diseases.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/imunologia , COVID-19/prevenção & controle , Criogéis/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Oxigênio/administração & dosagem , Oxigênio/imunologia , Animais , Materiais Biocompatíveis , Feminino , Imunidade/imunologia , Camundongos , Modelos Animais , SARS-CoV-2
2.
PLoS One ; 16(8): e0255608, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34352002

RESUMO

BACKGROUND: The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study's focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection. METHODS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas. RESULTS: Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1-2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3-0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3-0.7), PM = 0.0005, PMC = 0.005]. CONCLUSIONS: The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection.


Assuntos
COVID-19/imunologia , Células Matadoras Naturais/imunologia , Receptores KIR/imunologia , Adulto , Idoso , COVID-19/metabolismo , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genes MHC Classe I/imunologia , Predisposição Genética para Doença , Antígenos HLA-C/genética , Haplótipos/genética , Humanos , Imunidade/imunologia , Imunogenética/métodos , Células Matadoras Naturais/metabolismo , Ligantes , Masculino , Pessoa de Meia-Idade , Receptores KIR/genética , Receptores KIR/metabolismo , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença
3.
Cell Death Dis ; 12(8): 788, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385425

RESUMO

In the last months, many studies have clearly described several mechanisms of SARS-CoV-2 infection at cell and tissue level, but the mechanisms of interaction between host and SARS-CoV-2, determining the grade of COVID-19 severity, are still unknown. We provide a network analysis on protein-protein interactions (PPI) between viral and host proteins to better identify host biological responses, induced by both whole proteome of SARS-CoV-2 and specific viral proteins. A host-virus interactome was inferred, applying an explorative algorithm (Random Walk with Restart, RWR) triggered by 28 proteins of SARS-CoV-2. The analysis of PPI allowed to estimate the distribution of SARS-CoV-2 proteins in the host cell. Interactome built around one single viral protein allowed to define a different response, underlining as ORF8 and ORF3a modulated cardiovascular diseases and pro-inflammatory pathways, respectively. Finally, the network-based approach highlighted a possible direct action of ORF3a and NS7b to enhancing Bradykinin Storm. This network-based representation of SARS-CoV-2 infection could be a framework for pathogenic evaluation of specific clinical outcomes. We identified possible host responses induced by specific proteins of SARS-CoV-2, underlining the important role of specific viral accessory proteins in pathogenic phenotypes of severe COVID-19 patients.


Assuntos
COVID-19/metabolismo , COVID-19/virologia , SARS-CoV-2/metabolismo , Interações entre Hospedeiro e Microrganismos , Imunidade/imunologia , Mapas de Interação de Proteínas/fisiologia , Proteoma , Proteômica/métodos , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Proteínas Virais/metabolismo , Proteínas Virais Reguladoras e Acessórias/metabolismo
4.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445801

RESUMO

The cytoplasmic retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) initiate interferon (IFN) production and antiviral gene expression in response to RNA virus infection. Consequently, RLR signalling is tightly regulated by both host and viral factors. Tripartite motif protein 25 (TRIM25) is an E3 ligase that ubiquitinates multiple substrates within the RLR signalling cascade, playing both ubiquitination-dependent and -independent roles in RIG-I-mediated IFN induction. However, additional regulatory roles are emerging. Here, we show a novel interaction between TRIM25 and another protein in the RLR pathway that is essential for type I IFN induction, DEAD-box helicase 3X (DDX3X). In vitro assays and knockdown studies reveal that TRIM25 ubiquitinates DDX3X at lysine 55 (K55) and that TRIM25 and DDX3X cooperatively enhance IFNB1 induction following RIG-I activation, but the latter is independent of TRIM25's catalytic activity. Furthermore, we found that the influenza A virus non-structural protein 1 (NS1) disrupts the TRIM25:DDX3X interaction, abrogating both TRIM25-mediated ubiquitination of DDX3X and cooperative activation of the IFNB1 promoter. Thus, our results reveal a new interplay between two RLR-host proteins that cooperatively enhance IFN-ß production. We also uncover a new and further mechanism by which influenza A virus NS1 suppresses host antiviral defence.


Assuntos
Antivirais/imunologia , Proteína DEAD-box 58/imunologia , RNA Helicases DEAD-box/imunologia , Imunidade/imunologia , Receptores Imunológicos/imunologia , Fatores de Transcrição/imunologia , Proteínas com Motivo Tripartido/imunologia , Ubiquitina-Proteína Ligases/imunologia , Linhagem Celular , Regulação da Expressão Gênica/imunologia , Células HEK293 , Humanos , Vírus da Influenza A/imunologia , Interferons/imunologia , Regiões Promotoras Genéticas/imunologia , Ligação Proteica/imunologia , Transdução de Sinais/imunologia , Ubiquitinação/imunologia
5.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445774

RESUMO

Polyethyleneimine (PEI) induced immune responses were investigated in human bronchial epithelial (hBE) cells and mice. PEI rapidly induced ATP release from hBE cells and pretreatment with glutathione (GSH) blocked the response. PEI activated two conductive pathways, VDAC-1 and pannexin 1, which completely accounted for ATP efflux across the plasma membrane. Moreover, PEI increased intracellular Ca2+ concentration ([Ca2+]i), which was reduced by the pannexin 1 inhibitor, 10Panx (50 µM), the VDAC-1 inhibitor, DIDS (100 µM), and was nearly abolished by pretreatment with GSH (5 mM). The increase in [Ca2+]i involved Ca2+ uptake through two pathways, one blocked by oxidized ATP (oATP, 300 µM) and another that was blocked by the TRPV-1 antagonist A784168 (100 nM). PEI stimulation also increased IL-33 mRNA expression and protein secretion. In vivo experiments showed that acute (4.5 h) PEI exposure stimulated secretion of Th2 cytokines (IL-5 and IL-13) into bronchoalveolar lavage (BAL) fluid. Conjugation of PEI with ovalbumin also induced eosinophil recruitment and secretion of IL-5 and IL-13 into BAL fluid, which was inhibited in IL-33 receptor (ST2) deficient mice. In conclusion, PEI-induced oxidative stress stimulated type 2 immune responses by activating ATP-dependent Ca2+ uptake leading to IL-33 secretion, similar to allergens derived from Alternaria.


Assuntos
Trifosfato de Adenosina/imunologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Imunidade/efeitos dos fármacos , Nanopartículas/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Polietilenoimina/farmacologia , Alérgenos/imunologia , Animais , Cálcio/imunologia , Células Cultivadas , Citocinas/imunologia , Feminino , Humanos , Imunidade/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/imunologia , RNA Mensageiro/imunologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/imunologia
6.
Cell Rep ; 36(6): 109504, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34352226

RESUMO

Early responses to vaccination are important for shaping both humoral and cellular protective immunity. Dissecting innate vaccine signatures may predict immunogenicity to help optimize the efficacy of mRNA and other vaccine strategies. Here, we characterize the cytokine and chemokine responses to the 1st and 2nd dose of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine in antigen-naive and in previously coronavirus disease 2019 (COVID-19)-infected individuals (NCT04743388). Transient increases in interleukin-15 (IL-15) and interferon gamma (IFN-γ) levels early after boost correlate with Spike antibody levels, supporting their use as biomarkers of effective humoral immunity development in response to vaccination. We identify a systemic signature including increases in IL-15, IFN-γ, and IP-10/CXCL10 after the 1st vaccination, which were enriched by tumor necrosis factor alpha (TNF-α) and IL-6 after the 2nd vaccination. In previously COVID-19-infected individuals, a single vaccination results in both strong cytokine induction and antibody titers similar to the ones observed upon booster vaccination in antigen-naive individuals, a result with potential implication for future public health recommendations.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , Quimiocina CXCL10/imunologia , Interferon gama/imunologia , Interleucina-15/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , COVID-19/metabolismo , Vacinas contra COVID-19/administração & dosagem , Feminino , Humanos , Imunidade/imunologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/imunologia
7.
Int Immunopharmacol ; 99: 108050, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34426120

RESUMO

The COVID-19 pandemic challenges have been only partially addressed so far. The pathogenicity of SARS-CoV-2 is considered the combination of severe and high infectivity. Herdimmunity is attained when a critical proportion of the population is immune, providing the virus with fewer chances to spread locally. To overcome the rising tide of the COVID-19 pandemic, efficacious and safe vaccines providing defensive and long-lasting immunity responses are urgently needed.Vaccines that induce virus-neutralizing antibodies with great affinity can optimally fight against infection. Worldwide, over 120 novel vaccine candidates, including live-attenuated, inactivated, viral-vectored nonreplicating and replicating, peptide- and protein-based, and nucleic acid-based approaches are in the process of preclinical and clinical trials (phase 1-4). In addition to comprehensive safety assessments and immune responses, precise clinical management is also important for trials of vaccines. The recent emergence of different variants of SARS-CoV-2 is becoming a new threat for the world and a challenge for scientists to introduce the most influential vaccine against COVID-19. The possibility of natural and vaccine-induced immunity in variants finds it necessary to establish next-generation vaccines, which generate general neutralization against existing and future variants. Here, we summarize the cellular and humoral responses of SARS-CoV-2, current progress in vaccination development, the antibody titer response of available phase 4 vaccinations in vaccinated populations of different countries worldwide, and the success and challenges ahead of vaccine development.


Assuntos
Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Pandemias/prevenção & controle , Teste Sorológico para COVID-19 , Humanos , Imunidade/imunologia , SARS-CoV-2 , Vacinação
8.
Int J Mol Sci ; 22(14)2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34299373

RESUMO

Melanoma is the deadliest type of skin cancer, due to its invasiveness and limited treatment efficacy. The main therapy for primary melanoma and solitary organ metastases is wide excision. Adjuvant therapy, such as chemotherapy and targeted therapies are mainly used for disseminated disease. Radiotherapy (RT) is a powerful treatment option used in more than 50% of cancer patients, however, conventional RT alone is unable to eradicate melanoma. Its general radioresistance is attributed to overexpression of repair genes in combination with cascades of biochemical repair mechanisms. A novel sophisticated technique based on synchrotron-generated, spatially fractionated RT, called Microbeam Radiation Therapy (MRT), has been shown to overcome these treatment limitations by allowing increased dose delivery. With MRT, a collimator subdivides the homogeneous radiation field into an array of co-planar, high-dose microbeams that are tens of micrometres wide and spaced a few hundred micrometres apart. Different preclinical models demonstrated that MRT has the potential to completely ablate tumours, or significantly improve tumour control while dramatically reducing normal tissue toxicity. Here, we discuss the role of conventional RT-induced immunity and the potential for MRT to enhance local and systemic anti-tumour immune responses. Comparative gene expression analysis from preclinical tumour models indicated a specific gene signature for an 'MRT-induced immune effect'. This focused review highlights the potential of MRT to overcome the inherent radioresistance of melanoma which could be further enhanced for future clinical use with combined treatment strategies, in particular, immunotherapy.


Assuntos
Melanoma/radioterapia , Animais , Terapia Combinada/métodos , Humanos , Imunidade/imunologia , Imunoterapia/métodos , Melanoma/imunologia , Melanoma/terapia , Radioterapia/métodos , Síncrotrons
9.
Genome Med ; 13(1): 118, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-34281603

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has been associated with neurological and neuropsychiatric illness in many individuals. We sought to further our understanding of the relationship between brain tropism, neuro-inflammation, and host immune response in acute COVID-19 cases. METHODS: Three brain regions (dorsolateral prefrontal cortex, medulla oblongata, and choroid plexus) from 5 patients with severe COVID-19 and 4 controls were examined. The presence of the virus was assessed by western blot against viral spike protein, as well as viral transcriptome analysis covering > 99% of SARS-CoV-2 genome and all potential serotypes. Droplet-based single-nucleus RNA sequencing (snRNA-seq) was performed in the same samples to examine the impact of COVID-19 on transcription in individual cells of the brain. RESULTS: Quantification of viral spike S1 protein and viral transcripts did not detect SARS-CoV-2 in the postmortem brain tissue. However, analysis of 68,557 single-nucleus transcriptomes from three distinct regions of the brain identified an increased proportion of stromal cells, monocytes, and macrophages in the choroid plexus of COVID-19 patients. Furthermore, differential gene expression, pseudo-temporal trajectory, and gene regulatory network analyses revealed transcriptional changes in the cortical microglia associated with a range of biological processes, including cellular activation, mobility, and phagocytosis. CONCLUSIONS: Despite the absence of detectable SARS-CoV-2 in the brain at the time of death, the findings suggest significant and persistent neuroinflammation in patients with acute COVID-19.


Assuntos
Encéfalo/metabolismo , COVID-19/imunologia , Perfilação da Expressão Gênica/métodos , Imunidade/genética , Imunidade/imunologia , Transcriptoma , Plexo Corióideo/metabolismo , Expressão Gênica , Redes Reguladoras de Genes , Humanos , Inflamação , Microglia , Córtex Pré-Frontal/metabolismo , SARS-CoV-2/genética
10.
J Exp Clin Cancer Res ; 40(1): 240, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301276

RESUMO

BACKGROUND: The yearly Think Tank Meeting of the Italian Network for Tumor Biotherapy (NIBIT) Foundation, brings together in Siena, Tuscany (Italy), experts in immuno-oncology to review the learnings from current immunotherapy treatments, and to propose new pre-clinical and clinical investigations in selected research areas. MAIN: While immunotherapies in non-small cell lung cancer and melanoma led to practice changing therapies, the same therapies had only modest benefit for patients with other malignancies, such as mesothelioma and glioblastoma. One way to improve on current immunotherapies is to alter the sequence of each combination agent. Matching the immunotherapy to the host's immune response may thus improve the activity of the current treatments. A second approach is to combine current immunotherapies with novel agents targeting complementary mechanisms. Identifying the appropriate novel agents may require different approaches than the traditional laboratory-based discovery work. For example, artificial intelligence-based research may help focusing the search for innovative and most promising combination partners. CONCLUSION: Novel immunotherapies are needed in cancer patients with resistance to or relapse after current immunotherapeutic drugs. Such new treatments may include targeted agents or monoclonal antibodies to overcome the immune-suppressive tumor microenvironment. The mode of combining the novel treatments, including vaccines, needs to be matched to the patient's immune status for achieving the maximum benefit. In this scenario, specific attention should be also paid nowadays to the immune intersection between COVID-19 and cancer.


Assuntos
Neoplasias/imunologia , Neoplasias/terapia , Anticorpos Monoclonais/imunologia , COVID-19/imunologia , Humanos , Imunidade/imunologia , Imunoterapia/métodos , Itália , Oncologia/métodos
11.
Life Sci Alliance ; 4(9)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34321327

RESUMO

The use of high-dose of intravenous immunoglobulins (IVIGs) as immunomodulators for the treatment of COVID-19-affected individuals has shown promising results. IVIG reduced inflammation in these patients, who progressively restored respiratory function. However, little is known about how they may modulate immune responses in COVID-19 individuals. Here, we have analyzed the levels of 41 inflammatory biomarkers in plasma samples obtained at day 0 (pretreatment initiation), 3, 7, and 14 from five hospitalized COVID-19 patients treated with a 5-d course of 400 mg/kg/d of IVIG. The plasmatic levels of several cytokines (Tumor Necrosis Factor, IL-10, IL-5, and IL-7), chemokines (macrophage inflammatory protein-1α), growth/tissue repairing factors (hepatic growth factor), complement activation (C5a), and intestinal damage such as Fatty acid-binding protein 2 and LPS-binding protein showed a progressive decreasing trend during the next 2 wk after treatment initiation. This trend was not observed in IVIG-untreated COVID-19 patients. Thus, the administration of high-dose IVIG to hospitalized COVID-19 patients may improve their clinical evolution by modulating their hyperinflammatory and immunosuppressive status.


Assuntos
COVID-19/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Administração Intravenosa , Adulto , Idoso , Biomarcadores/sangue , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Quimiocinas/sangue , Citocinas/sangue , Feminino , Humanos , Imunidade/imunologia , Imunoglobulinas/imunologia , Imunoglobulinas/uso terapêutico , Imunoglobulinas Intravenosas/imunologia , Inflamação/sangue , Inflamação/terapia , Inflamação/virologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação
12.
Med Oncol ; 38(9): 101, 2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34302557

RESUMO

The COVID-19 pandemic has engulfed the entire world and has claimed more than 3 million lives worldwide. This viral disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and mainly characterized by fever, dry cough, fatigue, anosmia, anorexia, and dyspnea. The severity of the disease increases with age and presence of comorbidities, including cancer. Multiple clinical studies have shown that the cancer patients are highly susceptible to the severe form of the viral disease. In this review article, we have summarized the available scientific literature regarding the molecular links between COVID-19 and cancer, which make the cancer patients highly susceptible to COVID-19. Few studies have shown that the angiotensin-converting enzyme 2 (ACE2) receptor, transmembrane protease serine 2 (TMPRSS2), and the immune response and inflammation establish the interconnection between the two diseases. Additionally, we have also discussed whether SARS-CoV-2 can contribute to cancer development in COVID-19 patients. A recent study has suggested that SARS-CoV-2 may create a microenvironment that may support cancer cell proliferation and induce the activation of dormant cancer cells (DCCs). In another study, the blood sera of COVID-19 patients were found to activate epithelial-to-mesenchymal transition (EMT) in cancer cells. Overall, this review article will surely help the scientific community to understand why the cancer patients are so much prone to COVID-19 and will also motivate the researchers to find new therapeutic strategies that may save the lives of many COVID-19-infected cancer patients.


Assuntos
COVID-19/imunologia , Neoplasias/imunologia , Animais , Transição Epitelial-Mesenquimal/imunologia , Humanos , Imunidade/imunologia , Inflamação/imunologia
13.
Rev Med Virol ; 31(4): e2199, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34260778

RESUMO

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Patients can be asymptomatic or present respiratory and gastrointestinal symptoms, and even multiple-organ failure which can lead to death. The balance between an effective antiviral response and dysregulated immune response is the key factor determining the severity of COVID-19 progression. A systematic review was performed using the NCBI-PubMed database to find the articles related to COVID-19 immunity and inflammatory response published from 1 December 2019 to 15 April 2020. Haematological, immunological and biochemical parameters were extracted and correlated with disease severity, age and presence of comorbidities. Twelve articles were analysed comprising a total of 1042 hospitalized patients infected with SARS-CoV-2 and 95 different parameters. Total lymphocyte count and levels of CD3+ and CD4+ T cells were decreased in severe and critical cases. Neutrophilia was found in patients who progressed to acute respiratory distress syndrome (ARDS). Interleukin-six (IL-6) was high in mild and severe patients regardless of comorbidities. Erythrocyte sedimentation rate (ESR) and count and C-reactive protein (CRP) levels were increased regardless of disease severity or presence of comorbidities. High levels of D-dimer and lactate dehydrogenase were present in diabetic patients and patients who developed ARDS. Procalcitonin levels were elevated to varying degrees in severe and critical patients. We conclude that the total lymphocyte count, CD3+ and CD4+ T cells are low, especially in severe and critical COVID-19 patients; ESR, CRP and IL-6 were elevated, independent of the severity of disease. Understanding the inflammatory response of COVID-19 patients is essential for the development of better therapeutic and management strategies.


Assuntos
COVID-19/imunologia , Imunidade/imunologia , Inflamação/imunologia , Biomarcadores/sangue , COVID-19/sangue , COVID-19/complicações , Humanos , Inflamação/etiologia
14.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201771

RESUMO

GM2 gangliosidosis disorders are a group of neurodegenerative diseases that result from a functional deficiency of the enzyme ß-hexosaminidase A (HexA). HexA consists of an α- and ß-subunit; a deficiency in either subunit results in Tay-Sachs Disease (TSD) or Sandhoff Disease (SD), respectively. Viral vector gene transfer is viewed as a potential method of treating these diseases. A recently constructed isoenzyme to HexA, called HexM, has the ability to effectively catabolize GM2 gangliosides in vivo. Previous gene transfer studies have revealed that the scAAV9-HEXM treatment can improve survival in the murine SD model. However, it is speculated that this treatment could elicit an immune response to the carrier capsid and "non-self"-expressed transgene. This study was designed to assess the immunocompetence of TSD and SD mice, and test the immune response to the scAAV9-HEXM gene transfer. HexM vector-treated mice developed a significant anti-HexM T cell response and antibody response. This study confirms that TSD and SD mouse models are immunocompetent, and that gene transfer expression can create an immune response in these mice. These mouse models could be utilized for investigating methods of mitigating immune responses to gene transfer-expressed "non-self" proteins, and potentially improve treatment efficacy.


Assuntos
Dependovirus/genética , Gangliosídeo G(M2)/metabolismo , Vetores Genéticos/administração & dosagem , Imunidade/imunologia , Doença de Sandhoff/imunologia , Doença de Tay-Sachs/imunologia , Cadeia alfa da beta-Hexosaminidase/genética , Animais , Modelos Animais de Doenças , Feminino , Terapia Genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doença de Sandhoff/genética , Doença de Sandhoff/terapia , Doença de Tay-Sachs/genética , Doença de Tay-Sachs/terapia
15.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198897

RESUMO

The introduction of metallic nanoparticles (mNPs) into the diet is a matter of concern for human health. In particular, their effect on the gastrointestinal tract may potentially lead to the increased passage of gluten peptides and the activation of the immune response. In consequence, dietary mNPs could play a role in the increasing worldwide celiac disease (CeD) incidence. We evaluated the potential synergistic effects that peptic-tryptic-digested gliadin (PT) and the most-used food mNPs may induce on the intestinal mucosa. PT interaction with mNPs and their consequent aggregation was detected by transmission electron microscopy (TEM) analyses and UV-Vis spectra. In vitro experiments on Caco-2 cells proved the synergistic cytotoxic effect of PT and mNPs, as well as alterations in the monolayer integrity and tight junction proteins. Exposure of duodenal biopsies to gliadin plus mNPs triggered cytokine production, but only in CeD biopsies. These results suggest that mNPs used in the food sector may alter intestinal homeostasis, thus representing an additional environmental risk factor for the development of CeD.


Assuntos
Doença Celíaca/dietoterapia , Dieta , Glutens/metabolismo , Nanopartículas/uso terapêutico , Biópsia , Células CACO-2 , Doença Celíaca/imunologia , Doença Celíaca/metabolismo , Doença Celíaca/patologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/metabolismo , Homeostase/imunologia , Humanos , Imunidade/efeitos dos fármacos , Imunidade/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Nanopartículas/metabolismo , Triticum/efeitos adversos
16.
Cell Mol Life Sci ; 78(16): 5953-5976, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34223911

RESUMO

SARS-CoV-2 is the virus causing the major pandemic facing the world today. Although, SARS-CoV-2 primarily causes lung infection, a variety of symptoms have proven a systemic impact on the body. SARS-CoV-2 has spread in the community quickly infecting humans from all age, ethnicities and gender. However, fatal outcomes have been linked to specific host factors and co-morbidities such as age, hypertension, immuno-deficiencies, chronic lung diseases or metabolic disorders. A major shift in the microbiome of patients suffering of the coronavirus disease 2019 (COVID-19) have also been observed and is linked to a worst outcome of the disease. As many co-morbidities are already known to be associated with a dysbiosis of the microbiome such as hypertension, diabetes and metabolic disorders. Host factors and microbiome changes are believed to be involved as a network in the acquisition of the infection and the development of the diseases. We will review in detail in this manuscript, the immune response toward SARS-CoV-2 infection as well as the host factors involved in the facilitation and worsening of the infection. We will also address the impact of COVID-19 on the host's microbiome and secondary infection which also worsen the disease.


Assuntos
COVID-19/imunologia , COVID-19/virologia , Pulmão/imunologia , Pulmão/virologia , SARS-CoV-2/imunologia , Replicação Viral/imunologia , Animais , Disbiose/imunologia , Disbiose/virologia , Humanos , Imunidade/imunologia , Microbiota/imunologia , Pandemias
17.
Nat Rev Immunol ; 21(8): 475-484, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34211186

RESUMO

Most COVID-19 vaccines are designed to elicit immune responses, ideally neutralizing antibodies (NAbs), against the SARS-CoV-2 spike protein. Several vaccines, including mRNA, adenoviral-vectored, protein subunit and whole-cell inactivated virus vaccines, have now reported efficacy in phase III trials and have received emergency approval in many countries. The two mRNA vaccines approved to date show efficacy even after only one dose, when non-NAbs and moderate T helper 1 cell responses are detectable, but almost no NAbs. After a single dose, the adenovirus vaccines elicit polyfunctional antibodies that are capable of mediating virus neutralization and of driving other antibody-dependent effector functions, as well as potent T cell responses. These data suggest that protection may require low levels of NAbs and might involve other immune effector mechanisms including non-NAbs, T cells and innate immune mechanisms. Identifying the mechanisms of protection as well as correlates of protection is crucially important to inform further vaccine development and guide the use of licensed COVID-19 vaccines worldwide.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/prevenção & controle , COVID-19/virologia , Vacinas contra COVID-19/administração & dosagem , Humanos , Imunidade/efeitos dos fármacos , Imunidade/imunologia , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
18.
Anticancer Res ; 41(7): 3419-3427, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230137

RESUMO

BACKGROUND/AIM: Liver metastases are among the principal mortality causes in cancer patients. Dendritic cell immunotherapies have shown promising results in some tumors by mediating immunological mechanisms that could be involved in liver metastases during primary tumor growth. The present study aimed to evaluate the impact of prophylactic dendritic cell vaccination on the liver of mice with 4T1 mouse breast carcinoma. MATERIALS AND METHODS: Adult female Balb/c mice were submitted or not to vaccination with dendritic cells before the induction of 4T1 tumor lineage. Liver tissues from mice were analyzed by flow cytometry (markers CD3, CD4, CD8, CD25, IL-10, IL-12, IL-17, TNF-α, IFN-γ, T-bet, GATA3, RORγt, and FoxP3) and hematoxylin-eosin. The dendritic cell vaccine was differentiated and matured ex vivo from the bone marrow. RESULTS: Prophylactic vaccination reduced areas of liver metastases (p=0.0049), induced an increase in the percentage of total T and cytotoxic T lymphocytes (p<0.0001), as well as FoxP3+ (p<0.0001). It also increased the levels of cytokines IL-10 and IL-17 in helper T lymphocytes (p<0.0001). CONCLUSION: The prophylactic dendritic cell vaccine changed the cell phenotype in the immune response of liver, and it was able to reduce metastases. Cytotoxic T cells and regulatory T lymphocytes were more present, likewise, the production of IL-10 and IL-7 simultaneously, demonstrating that the vaccine can induce a state of control of pro-inflammatory responses, which can provide a less favorable environment for metastatic tumor growth.


Assuntos
Neoplasias da Mama/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Neoplasias Hepáticas/imunologia , Fígado/imunologia , Animais , Biomarcadores Tumorais/imunologia , Medula Óssea/imunologia , Neoplasias da Mama/patologia , Modelos Animais de Doenças , Feminino , Imunidade/imunologia , Imunoterapia/métodos , Fígado/patologia , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Vacinação/métodos
19.
Front Immunol ; 12: 639570, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194425

RESUMO

Bacteriophages are able to affect the human immune system. Phage-specific antibodies are considered as major factors shaping phage pharmacokinetics and bioavailability. So far, general knowledge of phage antigenicity nevertheless remains extremely limited. Here we present comparative studies of immunogenicity in two therapeutic bacteriophages, A3R and 676Z, active against Staphylococcus aureus, routinely applied in patients at the Phage Therapy Unit, Poland. Comparison of the overall ability of whole phages to induce specific antibodies in a murine model revealed typical kinetics of IgM and IgG induction by these two phages. In further studies we identified the location of four phage proteins in the virions, with the focus on the external capsid head (Mcp) or tail sheath (TmpH) or an unidentified precise location (ORF059 and ORF096), and we confirmed their role as structural proteins of these viruses. Next, we compared the immune response elicited by these proteins after phage administration in mice. Similar to that in T4 phage, Mcp was the major element of the capsid that induced specific antibodies. Studies of protein-specific sera revealed that antibodies specific to ORF096 were able to neutralize antibacterial activity of the phages. In humans (population level), none of the studied proteins plays a particular role in the induction of specific antibodies; thus none potentially affects in a particular way the effectiveness of A3R and 676Z. Also in patients subjected to phage therapy, we did not observe increased specific immune responses to the investigated proteins.


Assuntos
Imunidade/imunologia , Mamíferos/imunologia , Fagos de Staphylococcus/imunologia , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Anticorpos/imunologia , Formação de Anticorpos/imunologia , Capsídeo/imunologia , Proteínas do Capsídeo/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Cinética , Masculino , Mamíferos/microbiologia , Mamíferos/virologia , Camundongos , Camundongos Endogâmicos C57BL , Terapia por Fagos/métodos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/virologia , Staphylococcus aureus/imunologia , Staphylococcus aureus/virologia , Vírion/imunologia
20.
Nat Med ; 27(9): 1544-1552, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34253928

RESUMO

Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 ( NCT03500991 ), an ongoing phase 1 clinical trial at Seattle Children's evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients.


Assuntos
Glioblastoma/terapia , Imunoterapia Adotiva/efeitos adversos , Receptor ErbB-2/genética , Receptores de Antígenos Quiméricos/genética , Antígenos CD19/imunologia , Quimiocina CCL2/genética , Quimiocina CXCL10/genética , Feminino , Glioblastoma/líquido cefalorraquidiano , Glioblastoma/genética , Glioblastoma/imunologia , Humanos , Imunidade/genética , Imunidade/imunologia , Estimativa de Kaplan-Meier , Masculino , Recidiva Local de Neoplasia/líquido cefalorraquidiano , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/terapia , Receptor ErbB-2/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
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