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1.
Nature ; 592(7853): 283-289, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33524990

RESUMO

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD-foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD-foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD 'down', one-RBD 'up' state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses. Prime-boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2-18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA1-3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).


Assuntos
/imunologia , /prevenção & controle , Modelos Animais de Doenças , /imunologia , Envelhecimento/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Antígenos Virais/química , Antígenos Virais/genética , Antígenos Virais/imunologia , /terapia , /administração & dosagem , /genética , Linhagem Celular , Ensaios Clínicos como Assunto , Feminino , Humanos , Imunização Passiva , Internacionalidade , Macaca mulatta/imunologia , Macaca mulatta/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Multimerização Proteica , RNA Viral/análise , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , /genética , Solubilidade , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia , Vacinação , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/química , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia
3.
J Clin Invest ; 131(6)2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33492309

RESUMO

The immunopathology of coronavirus disease 2019 (COVID-19) remains enigmatic, causing immunodysregulation and T cell lymphopenia. Monocytic myeloid-derived suppressor cells (M-MDSCs) are T cell suppressors that expand in inflammatory conditions, but their role in acute respiratory infections remains unclear. We studied the blood and airways of patients with COVID-19 across disease severities at multiple time points. M-MDSC frequencies were elevated in blood but not in nasopharyngeal or endotracheal aspirates of patients with COVID-19 compared with healthy controls. M-MDSCs isolated from patients with COVID-19 suppressed T cell proliferation and IFN-γ production partly via an arginase 1-dependent (Arg-1-dependent) mechanism. Furthermore, patients showed increased Arg-1 and IL-6 plasma levels. Patients with COVID-19 had fewer T cells and downregulated expression of the CD3ζ chain. Ordinal regression showed that early M-MDSC frequency predicted subsequent disease severity. In conclusion, M-MDSCs expanded in the blood of patients with COVID-19, suppressed T cells, and were strongly associated with disease severity, indicating a role for M-MDSCs in the dysregulated COVID-19 immune response.


Assuntos
/imunologia , Células Supressoras Mieloides/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Arginase/sangue , /patologia , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Influenza Humana/sangue , Influenza Humana/imunologia , Influenza Humana/patologia , Interferon gama/sangue , Interleucina-6/sangue , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/patologia , Pandemias , Sistema Respiratório/imunologia , Sistema Respiratório/patologia , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/patologia , Adulto Jovem
4.
J Virol ; 95(6)2021 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-33408176

RESUMO

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract (LRT) infections, with increased severity in high-risk human populations, such as infants, the immunocompromised, and the elderly. Although the virus was identified more than 60 years ago, there is still no licensed vaccine available. Over the years, several vaccine delivery strategies have been evaluated. In this study, we developed two recombinant vesicular stomatitis virus (rVSV) vector-based vaccine candidates expressing the RSV-G (attachment) protein (rVSV-G) or F (fusion) protein (rVSV-F). All vectors were evaluated in the cotton rat animal model for their in vivo immunogenicity and protective efficacy against an RSV-A2 virus challenge. Intranasal (i.n.) delivery of rVSV-G and rVSV-F together completely protected the lower respiratory tract (lungs) at doses as low as 103 PFU. In contrast, doses greater than 106 PFU were required to protect the upper respiratory tract (URT) completely. Reimmunization of RSV-immune cotton rats was most effective with rVSV-F. In immunized animals, overall antibody responses were sufficient for protection, whereas CD4 and CD8 T cells were not necessary. A prime-boost immunization regimen increased both protection and neutralizing antibody titers. Overall, mucosally delivered rVSV-vector-based RSV vaccine candidates induce protective immunity and therefore represent a promising immunization regimen against RSV infection.IMPORTANCE Even after decades of intensive research efforts, a safe and efficacious RSV vaccine remains elusive. Expression of heterologous antigens from rVSV vectors has demonstrated several practical and safety advantages over other virus vector systems and live attenuated vaccines. In this study, we developed safe and efficacious vaccine candidates by expressing the two major immunogenic RSV surface proteins in rVSV vectors and delivering them mucosally in a prime-boost regimen. The main immune parameter responsible for protection was the antibody response. These vaccine candidates induced complete protection of both the upper and lower respiratory tracts.


Assuntos
Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vírus Sincicial Respiratório Humano/imunologia , Vesiculovirus/genética , Proteínas do Envelope Viral/imunologia , Proteínas Virais de Fusão/imunologia , Administração através da Mucosa , Animais , Modelos Animais de Doenças , Vetores Genéticos , Imunidade Celular , Imunidade Humoral , Imunização , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Infecções por Vírus Respiratório Sincicial/imunologia , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/genética , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Sigmodontinae , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Vesiculovirus/metabolismo , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/metabolismo , Proteínas Virais de Fusão/genética , Proteínas Virais de Fusão/metabolismo
5.
Cell Death Dis ; 12(1): 53, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33414457

RESUMO

Interleukin-38 has recently been shown to have anti-inflammatory properties in lung inflammatory diseases. However, the effects of IL-38 in viral pneumonia remains unknown. In the present study, we demonstrate that circulating IL-38 concentrations together with IL-36α increased significantly in influenza and COVID-19 patients, and the level of IL-38 and IL-36α correlated negatively and positively with disease severity and inflammation, respectively. In the co-cultured human respiratory epithelial cells with macrophages to mimic lung microenvironment in vitro, IL-38 was able to alleviate inflammatory responses by inhibiting poly(I:C)-induced overproduction of pro-inflammatory cytokines and chemokines through intracellular STAT1, STAT3, p38 MAPK, ERK1/2, MEK, and NF-κB signaling pathways. Intriguingly, transcriptomic profiling revealed that IL-38 targeted genes were associated with the host innate immune response to virus. We also found that IL-38 counteracts the biological processes induced by IL-36α in the co-culture. Furthermore, the administration of recombinant IL-38 could mitigate poly I:C-induced lung injury, with reduced early accumulation of neutrophils and macrophages in bronchoalveolar lavage fluid, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier. Taken together, our study indicates that IL-38 plays a crucial role in protection from exaggerated pulmonary inflammation during poly(I:C)-induced pneumonia, thereby providing the basis of a novel therapeutic target for respiratory viral infections.


Assuntos
/metabolismo , Imunidade Inata/efeitos dos fármacos , Influenza Humana/metabolismo , Interleucinas/farmacologia , Pneumonia/prevenção & controle , Poli I-C/toxicidade , Sistema Respiratório/imunologia , Animais , /virologia , Citocinas/metabolismo , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Vírus da Influenza A/isolamento & purificação , Influenza Humana/imunologia , Influenza Humana/virologia , Interleucina-1/sangue , Interleucinas/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/patologia , Sistema Respiratório/metabolismo , Sistema Respiratório/patologia , /isolamento & purificação
6.
Cell Host Microbe ; 29(2): 236-249.e6, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33357418

RESUMO

To develop a vaccine candidate against coronavirus disease 2019 (COVID-19), we generated a lentiviral vector (LV) eliciting neutralizing antibodies against the Spike glycoprotein of SARS-CoV-2. Systemic vaccination by this vector in mice, in which the expression of the SARS-CoV-2 receptor hACE2 has been induced by transduction of respiratory tract cells by an adenoviral vector, confers only partial protection despite high levels of serum neutralizing activity. However, eliciting an immune response in the respiratory tract through an intranasal boost results in a >3 log10 decrease in the lung viral loads and reduces local inflammation. Moreover, both integrative and non-integrative LV platforms display strong vaccine efficacy and inhibit lung deleterious injury in golden hamsters, which are naturally permissive to SARS-CoV-2 replication and closely mirror human COVID-19 physiopathology. Our results provide evidence of marked prophylactic effects of LV-based vaccination against SARS-CoV-2 and designate intranasal immunization as a powerful approach against COVID-19.


Assuntos
Administração Intranasal/métodos , /imunologia , /imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Cricetinae , Feminino , Vetores Genéticos , Imunidade nas Mucosas , Imunização Secundária , Imunoglobulina A/imunologia , Lentivirus/genética , Lentivirus/imunologia , Masculino , Camundongos , Modelos Animais , Sistema Respiratório/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Carga Viral
7.
Am J Physiol Lung Cell Mol Physiol ; 319(4): L603-L619, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783615

RESUMO

Respiratory cilia are the driving force of the mucociliary escalator, working in conjunction with secreted airway mucus to clear inhaled debris and pathogens from the conducting airways. Respiratory cilia are also one of the first contact points between host and inhaled pathogens. Impaired ciliary function is a common pathological feature in patients with chronic airway diseases, increasing susceptibility to respiratory infections. Common respiratory pathogens, including viruses, bacteria, and fungi, have been shown to target cilia and/or ciliated airway epithelial cells, resulting in a disruption of mucociliary clearance that may facilitate host infection. Despite being an integral component of airway innate immunity, the role of respiratory cilia and their clinical significance during airway infections are still poorly understood. This review examines the expression, structure, and function of respiratory cilia during pathogenic infection of the airways. This review also discusses specific known points of interaction of bacteria, fungi, and viruses with respiratory cilia function. The emerging biological functions of motile cilia relating to intracellular signaling and their potential immunoregulatory roles during infection will also be discussed.


Assuntos
Bactérias/imunologia , Cílios/metabolismo , Fungos/imunologia , Depuração Mucociliar/fisiologia , Vírus/imunologia , Células Epiteliais/metabolismo , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/imunologia , Muco/metabolismo , Sistema Respiratório/imunologia
8.
Med Hypotheses ; 143: 110153, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32763662

RESUMO

Reports from various countries suggest that tobacco smoking might protect from SARS-CoV-2 infection, since the prevalence of smoking in COVID-19 hospitalized patients is lower than in the respective general population. Apart from nicotine or other chemicals contained in tobacco smoke, we propose that a single-stranded RNA virus that infects tobacco leaves, tobacco mosaic virus (TMV), might be implicated in this effect. TMV, though non-pathogenic, is found in smokers' airways, and stimulates adaptive and innate immunity, with release of specific antibodies and interferons. The latter may have preventive and/or therapeutic effects against COVID-19. If confirmed by epidemiological and interventional studies, this might lead to the use of TMV as an immunological adjuvant against SARS-CoV-2 infection and COVID-19 disease.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Modelos Imunológicos , Pandemias , Pneumonia Viral/imunologia , Fumantes , Vírus do Mosaico do Tabaco/imunologia , Produtos do Tabaco/virologia , Fumar Tabaco , Animais , Anticorpos Antivirais/biossíntese , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Resistência à Doença , Humanos , Interferons/biossíntese , Camundongos , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Vírus do Mosaico do Tabaco/isolamento & purificação , Fumar Tabaco/epidemiologia , Receptores Toll-Like/imunologia
10.
J Med Microbiol ; 69(8): 1124-1131, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32597749

RESUMO

Introduction. Acute otitis media (AOM) is the most common bacterial infection in early childhood, but the underlying mechanisms making some children more susceptible are poorly understood.Aim. To examine the associations between bacterial airway colonization in early life and the risk of AOM and tympanostomy tube insertion (TTI), and whether such associations are modulated by an insufficient local immune mediator response to bacterial colonization.Methodology. Bacterial cultures from hypopharyngeal samples were obtained at 1 week, 1 month and 3 months of age in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) cohort comprising 700 children. Twenty immune mediators were quantified from airway mucosal lining fluid sampled at 1 month. AOM symptoms were registered in a daily diary until 3 years. Information on TTI in the first 3 years was obtained from national registers.Results. Children colonized with Streptococcus pneumoniae at 1 month of age had increased incidence of AOM [aIRR 2.43 (1.14-5.21)] and children colonized with Moraxella catarrhalis at 1 month or Haemophilus influenzae at 3 months had an increased risk of TTI [aHR 1.45 (1.00-2.10) and 1.73 (1.10-2.71)]. There were no associations between the local immune mediator response to colonization and risk of AOM or TTI.Conclusion. Pathogenic bacterial airway colonization in early life was found to be associated with an increased risk of otitis media, albeit not consistently. These associations were independent of the local immune response to colonization.


Assuntos
Otite Média/epidemiologia , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Análise de Variância , Distribuição de Qui-Quadrado , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Modelos Lineares , Otite Média/imunologia , Otite Média/microbiologia , Distribuição de Poisson , Análise de Componente Principal , Modelos de Riscos Proporcionais , Fatores de Risco , Estatísticas não Paramétricas
11.
Nat Biotechnol ; 38(8): 970-979, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32591762

RESUMO

To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls. We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells. Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand-receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF. The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure. Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Sistema Respiratório/patologia , Análise de Célula Única , Transcriptoma , Adulto , Idoso , Líquido da Lavagem Broncoalveolar/virologia , Comunicação Celular , Diferenciação Celular , Infecções por Coronavirus/virologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Feminino , Humanos , Sistema Imunitário/patologia , Inflamação/imunologia , Inflamação/patologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Nasofaringe/virologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/virologia , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Índice de Gravidade de Doença
12.
Immunity ; 52(6): 905-909, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32497522

RESUMO

Respiratory viruses affect us throughout our lives, from infancy to old age, causing illnesses ranging from a common cold to severe pneumonia. They belong to several virus families, and although many features of infection with these diverse viruses are shared, some have unique characteristics. Here we explain what happens when we are infected by respiratory viruses, including SARS-CoV-2, which causes COVID-19.


Assuntos
Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Sistema Respiratório/fisiopatologia , Imunidade Adaptativa , Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Infecções por Coronavirus/virologia , Humanos , Imunidade Inata , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Pneumonia Viral/virologia , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , Fenômenos Fisiológicos Virais , Vírus/classificação
13.
Lancet Respir Med ; 8(7): 687-695, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386571

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing a respiratory disease (coronavirus disease 2019, COVID-19) of varying severity in Wuhan, China, and subsequently leading to a pandemic. The transmissibility and pathogenesis of SARS-CoV-2 remain poorly understood. We evaluate its tissue and cellular tropism in human respiratory tract, conjunctiva, and innate immune responses in comparison with other coronavirus and influenza virus to provide insights into COVID-19 pathogenesis. METHODS: We isolated SARS-CoV-2 from a patient with confirmed COVID-19, and compared virus tropism and replication competence with SARS-CoV, Middle East respiratory syndrome-associated coronavirus (MERS-CoV), and 2009 pandemic influenza H1N1 (H1N1pdm) in ex-vivo cultures of human bronchus (n=5) and lung (n=4). We assessed extrapulmonary infection using ex-vivo cultures of human conjunctiva (n=3) and in-vitro cultures of human colorectal adenocarcinoma cell lines. Innate immune responses and angiotensin-converting enzyme 2 expression were investigated in human alveolar epithelial cells and macrophages. In-vitro studies included the highly pathogenic avian influenza H5N1 virus (H5N1) and mock-infected cells as controls. FINDINGS: SARS-CoV-2 infected ciliated, mucus-secreting, and club cells of bronchial epithelium, type 1 pneumocytes in the lung, and the conjunctival mucosa. In the bronchus, SARS-CoV-2 replication competence was similar to MERS-CoV, and higher than SARS-CoV, but lower than H1N1pdm. In the lung, SARS-CoV-2 replication was similar to SARS-CoV and H1N1pdm, but was lower than MERS-CoV. In conjunctiva, SARS-CoV-2 replication was greater than SARS-CoV. SARS-CoV-2 was a less potent inducer of proinflammatory cytokines than H5N1, H1N1pdm, or MERS-CoV. INTERPRETATION: The conjunctival epithelium and conducting airways appear to be potential portals of infection for SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated similarly in the alveolar epithelium; SARS-CoV-2 replicated more extensively in the bronchus than SARS-CoV. These findings provide important insights into the transmissibility and pathogenesis of SARS-CoV-2 infection and differences with other respiratory pathogens. FUNDING: US National Institute of Allergy and Infectious Diseases, University Grants Committee of Hong Kong Special Administrative Region, China; Health and Medical Research Fund, Food and Health Bureau, Government of Hong Kong Special Administrative Region, China.


Assuntos
Betacoronavirus/imunologia , Túnica Conjuntiva/virologia , Infecções por Coronavirus/imunologia , Imunidade Inata/imunologia , Pneumonia Viral/imunologia , Sistema Respiratório/virologia , Tropismo Viral/fisiologia , Replicação Viral/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus/fisiologia , Túnica Conjuntiva/imunologia , Túnica Conjuntiva/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/fisiopatologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/fisiopatologia , Mucosa Respiratória/virologia , Sistema Respiratório/imunologia , Sistema Respiratório/fisiopatologia
14.
Cell Host Microbe ; 27(6): 883-890.e2, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32407669

RESUMO

The outbreaks of 2019 novel coronavirus disease (COVID-19) caused by SARS-CoV-2 infection have posed a severe threat to global public health. It is unclear how the human immune system responds to this infection. Here, we used metatranscriptomic sequencing to profile immune signatures in the bronchoalveolar lavage fluid of eight COVID-19 cases. The expression of proinflammatory genes, especially chemokines, was markedly elevated in COVID-19 cases compared to community-acquired pneumonia patients and healthy controls, suggesting that SARS-CoV-2 infection causes hypercytokinemia. Compared to SARS-CoV, which is thought to induce inadequate interferon (IFN) responses, SARS-CoV-2 robustly triggered expression of numerous IFN-stimulated genes (ISGs). These ISGs exhibit immunopathogenic potential, with overrepresentation of genes involved in inflammation. The transcriptome data was also used to estimate immune cell populations, revealing increases in activated dendritic cells and neutrophils. Collectively, these host responses to SARS-CoV-2 infection could further our understanding of disease pathogenesis and point toward antiviral strategies.


Assuntos
Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata , Pneumonia Viral/imunologia , Sistema Respiratório/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina , Citocinas/análise , Interações Hospedeiro-Patógeno , Humanos , Interferons/metabolismo , Pandemias , Pneumonia Viral/patologia , Sistema Respiratório/patologia
15.
Diabetes Metab Syndr ; 14(4): 489-496, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32388326

RESUMO

BACKGROUND AND AIMS: COVID-19 is a public world crisis, however, it is a self-limited infection. In COVID-19, the strength of immune and respiratory systems is a critical element. Thus, this review was conducted to demonstrate the short and long term effects of increasing the aerobic capacity on increasing the function and strength of immune and respiratory systems, particularly those essential for overcoming COVID-19 infections and associated disorders. METHODS: This review was carried out by searching in Web of Science, Scopus, EBSCO, Medline databases. The search was conducted over clinical trials and literature and systematic reviews on the effects of increasing the aerobic capacity on the function and strength of specific immune and respiratory elements essential for overcoming COVID-19 infections. RESULTS: This review found that increasing the aerobic capacity could produce short-term safe improvements in the function of immune and respiratory systems, particularly those specific for COVID-19 infections. This could be mainly produced through three mechanisms. Firstly, it could improve immunity by increasing the level and function of immune cells and immunoglobulins, regulating CRP levels, and decreasing anxiety and depression. Secondly, it could improve respiratory system functions by acting as an antibiotic, antioxidant, and antimycotic, restoring normal lung tissue elasticity and strength. Lastly, it could act as a protective barrier to decrease COVID-19 risk factors, which helps to decrease the incidence and progression of COVID-19. CONCLUSION: This review summarizes that increasing the aerobic capacity is recommended because it has potential of improving immune and respiratory functions which would help counter COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Exercício Físico , Imunidade Celular/imunologia , Controle de Infecções/métodos , Oxigênio/metabolismo , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Pneumonia Viral/prevenção & controle , Sistema Respiratório/imunologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Humanos , Pneumonia Viral/transmissão , Pneumonia Viral/virologia
16.
Am J Respir Crit Care Med ; 202(5): 672-680, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320637

RESUMO

Rationale: Phthalates are a group of chemicals used in common commercial products. Epidemiological studies suggest that phthalate exposure is associated with development or worsening of allergic diseases such as asthma. However, effects of dibutyl phthalate (DBP) or other phthalates found in high concentrations in indoor air have never been examined in allergic individuals in a controlled exposure setting.Objectives: To investigate the airway effects in humans caused by inhalation of a known concentration of a single phthalate, DBP.Methods: In a randomized crossover study, 16 allergen-sensitized participants were exposed to control air or DBP for 3 hours in an environmental chamber followed immediately by an allergen inhalation challenge. Bronchoalveolar wash and lavage were obtained 24 hours after exposure. Lung function, early allergic response, airway responsiveness, inflammation, immune mediators, and immune cell phenotypes were assessed after DBP exposure.Measurements and Main Results: DBP exposure increased the early allergic response (21.4% decline in FEV1 area under the curve, P = 0.03). Airway responsiveness was increased by 48.1% after DBP exposure in participants without baseline hyperresponsiveness (P = 0.01). DBP increased the recruitment of BAL total macrophages by 4.6% (P = 0.07), whereas the M2 macrophage phenotype increased by 46.9% (P = 0.04). Airway immune mediator levels were modestly affected by DBP.Conclusions: DBP exposure augmented allergen-induced lung function decline, particularly in those without baseline hyperresponsiveness, and exhibited immunomodulatory effects in the airways of allergic individuals. This is the first controlled human exposure study providing biological evidence for phthalate-induced effects in the airways.Clinical trial registered with www.clinicaltrials.gov (NCT02688478).


Assuntos
Poluentes Atmosféricos/efeitos adversos , Dibutilftalato/uso terapêutico , Fluxo Expiratório Forçado/fisiologia , Hipersensibilidade Respiratória/tratamento farmacológico , Sistema Respiratório/imunologia , Adulto , Estudos Cross-Over , Feminino , Fluxo Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Plastificantes/uso terapêutico , Testes de Função Respiratória , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/fisiopatologia , Adulto Jovem
18.
Int J Mol Sci ; 21(5)2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32155894

RESUMO

Eosinophils infiltration and releasing TGF-ß1 in the airways has been implicated in the pathogenesis of asthma, especially during acute episodes provoked by an allergen. TGF-ß1 is a major mediator involved in pro-inflammatory responses and fibrotic tissue remodeling in asthma. We aimed to evaluate the effect of in vivo allergen-activated eosinophils on the expression of COL1A1 and FN in ASM cells in asthma. A total of 12 allergic asthma patients and 11 healthy subjects were examined. All study subjects underwent bronchial challenge with D. pteronyssinus allergen. Eosinophils from peripheral blood were isolated before and 24 h after the bronchial allergen challenge using high-density centrifugation and magnetic separation. Individual co-cultures of blood eosinophils and immortalized human ASM cells were prepared. The TGF-ß1 concentration in culture supernatants was analyzed using ELISA. Gene expression was analyzed using qRT-PCR. Eosinophils integrins were suppressed with linear RGDS peptide before co-culture with ASM cells. Results: The expression of TGF-ß1 in asthmatic eosinophils significantly increased over non-activated asthmatic eosinophils after allergen challenge, p < 0.001. The TGF-ß1 concentration in culture supernatants was significantly higher in samples with allergen-activated asthmatic eosinophils compared to baseline, p < 0.05. The effect of allergen-activated asthmatic eosinophils on the expression of TGF-ß1, COL1A1, and FN in ASM cells was more significant compared to non-activated eosinophils, p < 0.05, however, no difference was found on WNT-5A expression. The incubation of allergen-activated asthmatic eosinophils with RGDS peptide was more effective compared to non-activated eosinophils as the gene expression in ASM cells was downregulated equally to the same level as healthy eosinophils.


Assuntos
Asma/patologia , Testes de Provocação Brônquica/efeitos adversos , Colágeno Tipo I/metabolismo , Eosinófilos/imunologia , Fibronectinas/metabolismo , Miócitos de Músculo Liso/imunologia , Sistema Respiratório/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Adulto , Asma/induzido quimicamente , Asma/imunologia , Asma/metabolismo , Estudos de Casos e Controles , Colágeno Tipo I/genética , Eosinófilos/efeitos dos fármacos , Feminino , Fibronectinas/genética , Regulação da Expressão Gênica , Humanos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética , Adulto Jovem
19.
PLoS One ; 15(3): e0230010, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191737

RESUMO

Peach tree (PT) pollen sensitization is highly prevalent in subjects living in areas where this tree is widely cultivated. None of the allergens responsible for these sensitizations have been identified so far. Our aim was to identify the most relevant PT pollen allergens and analyze their capacity for inducing respiratory symptoms. We studied sixty-two individuals sensitized to PT pollen who developed symptoms after its exposure. The IgE binding profile on peach pollen extract by means of immunoblotting using sera from these subjects was analyzed. Protein extract was fractionated by anion-exchange chromatography and HPLC, fractions run in SDS-PAGE and proteins were identified from IgE-binding bands by mass spectrometry. Several allergenic proteins in the PT pollen extract were recognized by patients' IgE: a glucan endo-1,3-beta-glucosidase-like, a polygalacturonase, an UTP-glucose-1-phosphate uridylyltransferase and a PR-1a protein. This PR-1a protein is a novel allergen frequently recognized with a molecular mass of 18 kDa, named as Pru p 9 following the WHO-IUIS nomenclature. Skin Prick Test (SPT) performed with this allergen was positive in 41% of the PT pollen-sensitized clinical cases. Most of them had rhinitis or rhinoconjunctivitis, but a significant percentage experienced asthma with seasonal symptoms during the period of PT flowering. Nasal Provocation test (NPT) with Pru p 9 was positive in all cases with positive SPT to this new allergen eliciting nasal symptoms similar to those challenged with PT pollen. We demonstrate that PT pollen can induce sensitization and allergy in an exposed population, being Pru p 9 a relevant allergen responsible of respiratory symptoms. Considering the extensive peach worldwide production with a large number of people involved, our results add a great value for the diagnosis and management of subjects allergic to this pollen.


Assuntos
Alérgenos/imunologia , Pólen/imunologia , Prunus persica/imunologia , Sistema Respiratório/imunologia , Adulto , Sequência de Aminoácidos , Feminino , Humanos , Masculino
20.
Immunity ; 52(2): 241-255, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32075727

RESUMO

Asthma is a common chronic respiratory disease affecting more than 300 million people worldwide. Clinical features of asthma and its immunological and molecular etiology vary significantly among patients. An understanding of the complexities of asthma has evolved to the point where precision medicine approaches, including microbiome analysis, are being increasingly recognized as an important part of disease management. Lung and gut microbiota play several important roles in the development, regulation, and maintenance of healthy immune responses. Dysbiosis and subsequent dysregulation of microbiota-related immunological processes affect the onset of the disease, its clinical characteristics, and responses to treatment. Bacteria and viruses are the most extensively studied microorganisms relating to asthma pathogenesis, but other microbes, including fungi and even archaea, can potently influence airway inflammation. This review focuses on recently discovered connections between lung and gut microbiota, including bacteria, fungi, viruses, and archaea, and their influence on asthma.


Assuntos
Asma/imunologia , Asma/microbiologia , Trato Gastrointestinal , Pulmão , Microbiota/imunologia , Animais , Asma/patologia , Asma/fisiopatologia , Disbiose/imunologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/parasitologia , Trato Gastrointestinal/virologia , Humanos , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/parasitologia , Pulmão/virologia , Sistema Respiratório/imunologia , Sistema Respiratório/microbiologia , Sistema Respiratório/parasitologia , Sistema Respiratório/virologia
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