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1.
Nat Commun ; 12(1): 1386, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33654090

RESUMO

The COVID-19 pandemic is a global health crisis that poses a great challenge to the public health system of affected countries. Safe and effective vaccines are needed to overcome this crisis. Here, we develop and assess the protective efficacy and immunogenicity of an inactivated SARS-CoV-2 vaccine in rhesus macaques. Twenty macaques were divided into four groups of five animals each. One group was administered a placebo, while three groups were immunized with three different vaccine candidates of BBV152 at 0 and 14 days. All the macaques were challenged with SARS-CoV-2 fourteen days after the second dose. The protective response was observed with increasing SARS-CoV-2 specific IgG and neutralizing antibody titers from 3rd-week post-immunization. Viral clearance was observed from bronchoalveolar lavage fluid, nasal swab, throat swab and lung tissues at 7 days post-infection in the vaccinated groups. No evidence of pneumonia was observed by histopathological examination in vaccinated groups, unlike the placebo group which exhibited interstitial pneumonia and localization of viral antigen in the alveolar epithelium and macrophages by immunohistochemistry. This vaccine candidate BBV152 has completed Phase I/II (NCT04471519) clinical trials in India and is presently in phase III, data of this study substantiates the immunogenicity and protective efficacy of the vaccine candidates.


Assuntos
/uso terapêutico , /patogenicidade , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Imuno-Histoquímica , Linfócitos/imunologia , Linfócitos/metabolismo , Macaca mulatta , Masculino , Pneumonia/imunologia , Pneumonia/metabolismo
2.
Front Immunol ; 12: 618807, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679760

RESUMO

Type 2 inflammation is found in most forms of asthma, which may co-exist with recurrent viral infections, bacterial colonization, and host cell death. These processes drive the accumulation of intracellular cyclic-di-nucleotides such as cyclic-di-GMP (CDG). Group 2 innate lymphoid cells (ILC2s) are critical drivers of type 2 lung inflammation during fungal allergen exposure in mice; however, it is unclear how CDG regulates lung ILC responses during lung inflammation. Here, we show that intranasal CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed CD127+ST2+ ILC2s and type 2 lung inflammation during Alternaria and IL-33 exposure. Further, CD127-ST2-Thy1.2+ lung ILCs, which showed a transcriptomic signature consistent with ILC1s, were expanded and activated by CDG combined with either Alternaria or IL-33. CDG-mediated suppression of type 2 inflammation occurred independent of IL-18R, IL-12, and STAT6 but required the stimulator of interferon genes (STING) and type 1 IFN signaling. Thus, CDG potently suppresses ILC2-driven lung inflammation and promotes ILC1 responses. These results suggest potential therapeutic modulation of STING to suppress type 2 inflammation and/or increase anti-viral responses during respiratory infections.


Assuntos
Alternaria/imunologia , Alternariose/imunologia , GMP Cíclico/análogos & derivados , Imunidade Inata , Pulmão/imunologia , Proteínas de Membrana/imunologia , Pneumonia/imunologia , Alternariose/genética , Alternariose/patologia , Animais , GMP Cíclico/genética , GMP Cíclico/imunologia , Citocinas/genética , Citocinas/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Pulmão/microbiologia , Pulmão/patologia , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Pneumonia/genética , Pneumonia/microbiologia , Pneumonia/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia
3.
J Immunother Cancer ; 9(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33574054

RESUMO

By the beginning of the global pandemic, SARS-CoV-2 infection has dramatically impacted on oncology daily practice. In the current oncological landscape, where immunotherapy has revolutionized the treatment of several malignancies, distinguishing between COVID-19 and immune-mediated pneumonitis can be hard because of shared clinical, radiological and pathological features. Indeed, their common mechanism of aberrant inflammation could lead to a mutual and amplifying interaction.We describe the case of a 65-year-old patient affected by metastatic squamous head and neck cancer and candidate to an experimental therapy including an anti-PD-L1 agent. COVID-19 ground-glass opacities under resolution were an incidental finding during screening procedures and worsened after starting immunotherapy. The diagnostic work-up was consistent with ICIs-related pneumonia and it is conceivable that lung injury by SARS-CoV-2 has acted as an inflammatory primer for the development of the immune-related adverse event.Patients recovered from COVID-19 starting ICIs could be at greater risk of recall immune-mediated pneumonitis. Nasopharyngeal swab and chest CT scan are recommended before starting immunotherapy. The awareness of the phenomenon could allow an easier interpretation of radiological changes under treatment and a faster diagnostic work-up to resume ICIs. In the presence of clinical benefit, for asymptomatic ICIs-related pneumonia a watchful-waiting approach and immunotherapy prosecution are suggested.


Assuntos
/diagnóstico , Neoplasias Pulmonares/diagnóstico , Pneumonia/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Idoso , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , /imunologia , Diagnóstico Diferencial , Humanos , /efeitos adversos , Imunoterapia/efeitos adversos , Lesão Pulmonar/diagnóstico , Lesão Pulmonar/diagnóstico por imagem , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/virologia , Masculino , Nasofaringe/metabolismo , Nasofaringe/patologia , Metástase Neoplásica , Pandemias , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Pneumonia/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
4.
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
5.
Curr Opin Infect Dis ; 34(2): 169-174, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33394726

RESUMO

PURPOSE OF REVIEW: This review aims to evaluate the evidence and recommendations for the prescription of corticosteroids as adjunctive therapy in patients with severe community-acquired pneumonia. RECENT FINDINGS: Corticosteroids have been prescribed with the objective to attenuate the marked and persistent activation of the immune system. However, some causes of community-acquired pneumonia, namely viral, are associated with unexpected low levels of cytokines and depressed cellular immunity. As a result, several recent randomized controlled trials and large prospective observational studies repeatedly showed that corticosteroids had no impact on survival, and in some types of pneumonia like influenza, its use was associated with potential harmful effects like invasive aspergillosis. Apart from this, adverse effects, namely hyperglycemia, superinfections and increased length-of-stay, were frequent findings in the corticosteroid-treated patients. SUMMARY: According to the current evidence, corticosteroids are recommended in Pneumocystis jiroveci pneumonia in HIV-infected patients and recommendations are against its use in influenza. In all other forms of severe community-acquired pneumonia, with the exclusion of SARS-CoV-2 pneumonia, the strength of the evidence does not support the safe and widespread use of corticosteroids as adjunctive therapy. Further studies are needed to identify subgroups of severe community-acquired pneumonia that can benefit or not from corticosteroids.


Assuntos
Corticosteroides/uso terapêutico , Pneumonia/tratamento farmacológico , Corticosteroides/efeitos adversos , Tomada de Decisão Clínica , Terapia Combinada , Infecções Comunitárias Adquiridas , Humanos , Pneumonia/etiologia , Pneumonia/imunologia , Pneumonia/patologia , Guias de Prática Clínica como Assunto , Segurança
6.
Nat Immunol ; 22(2): 118-127, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33462453

RESUMO

Macrophages have long been considered as particularly plastic cells. However, recent work combining fate mapping, single-cell transcriptomics and epigenetics has undermined the macrophage plasticity dogma. Here, we discuss recent studies that have carefully dissected the response of individual macrophage subsets to pulmonary insults and call for an adjustment of the macrophage plasticity concept. We hypothesize that prolonged tissue residency shuts down much of the plasticity of macrophages and propose that the restricted plasticity of resident macrophages has been favored by evolution to safeguard tissue homeostasis. Recruited monocytes are more plastic and their differentiation into resident macrophages during inflammation can result in a dual imprinting from both the ongoing inflammation and the macrophage niche. This results in inflammation-imprinted resident macrophages, and we speculate that rewired niche circuits could maintain this inflammatory state. We believe that this revisited plasticity model offers opportunities to reset the macrophage pool after a severe inflammatory episode.


Assuntos
Plasticidade Celular , Pulmão/imunologia , Macrófagos Alveolares/imunologia , Pneumonia/imunologia , Animais , Microambiente Celular , Epigênese Genética , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Fenótipo , Pneumonia/genética , Pneumonia/metabolismo , Transdução de Sinais
7.
Cytokine ; 137: 155312, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33128927

RESUMO

BACKGROUND: COVID-19, as a newly-emerged viral infection has now spread all over the world after originating in Wuhan, China. Pneumonia is the hallmark of the disease, with dyspnea in half of the patients and acute respiratory distress syndrome (ARDS) in up to one -third of the cases. Pulmonary edema, neutrophilic infiltration, and inflammatory cytokine release are the pathologic signs of this disease. The anti-inflammatory effect of the photobiomodulation (PBM) has been confirmed in many previous studies. Therefore, this review study was conducted to evaluate the direct effect of PBM on the acute lung inflammation or ARDS and also accelerating the regeneration of the damaged tissues. The indirect effects of PBM on modulation of the immune system, increasing the blood flow and oxygenation in other tissues were also considered. METHODOLOGY: The databases of PubMed, Cochrane library, and Google Scholar were searched to find the relevant studies. Keywords included the PBM and related terms, lung inflammation, and COVID-19 -related signs. Studies were categorized with respect to the target tissue, laser parameters, and their results. RESULTS: Seventeen related papers were included in this review. All of them were in animal models. They showed that the PBM could significantly decrease the pulmonary edema, neutrophil influx, and generation of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), intracellular adhesion molecule (ICAM), reactive oxygen species (ROS), isoform of nitric oxide synthase (iNOS), and macrophage inflammatory protein 2 (MIP-2)). CONCLUSION: Our findings revealed that the PBM could be helpful in reducing the lung inflammation and promoting the regeneration of the damaged tissue. PBM can increase the oxygenation indirectly in order to rehabilitate the affected organs. Thus, the infra-red lasers or light-emitting diodes (LEDs) are recommended in this regard.


Assuntos
/radioterapia , Terapia com Luz de Baixa Intensidade , Pulmão/efeitos da radiação , Pneumonia/radioterapia , /sangue , Citocinas/metabolismo , Humanos , Pulmão/fisiopatologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Pneumonia/imunologia , Pneumonia/fisiopatologia , PubMed , Edema Pulmonar/imunologia , Edema Pulmonar/fisiopatologia , Edema Pulmonar/radioterapia , Espécies Reativas de Oxigênio/metabolismo , /radioterapia
8.
Nat Commun ; 11(1): 5859, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203833

RESUMO

The outbreak of COVID-19 has become a worldwide pandemic. The pathogenesis of this infectious disease and how it differs from other drivers of pneumonia is unclear. Here we analyze urine samples from COVID-19 infection cases, healthy donors and non-COVID-19 pneumonia cases using quantitative proteomics. The molecular changes suggest that immunosuppression and tight junction impairment occur in the early stage of COVID-19 infection. Further subgrouping of COVID-19 patients into moderate and severe types shows that an activated immune response emerges in severely affected patients. We propose a two-stage mechanism of pathogenesis for this unusual viral infection. Our data advance our understanding of the clinical features of COVID-19 infections and provide a resource for future mechanistic and therapeutics studies.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Betacoronavirus/patogenicidade , Biomarcadores/urina , Infecções por Coronavirus/urina , Progressão da Doença , Humanos , Tolerância Imunológica , Pandemias , Pneumonia/imunologia , Pneumonia/patologia , Pneumonia/urina , Pneumonia Viral/urina , Proteoma/análise , Junções Íntimas/patologia
9.
Medicine (Baltimore) ; 99(45): e22390, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157914

RESUMO

Community-acquired pneumonia (CAP) is a worldwide cause of morbidity and mortality. Immunoglobulins (Igs) and B cells quantification studies in CAP are few and show discrepancies. Serum IgA acts as a powerful natural anti-inflammatory factor, but its role in the CAP has not yet been defined. The highly sensitive xMAP Luminex technique allows better immunoglobulins quantification. The aim of this study was to analyze the relation between clinical severity and circulating Igs and B cells in adults with CAP.Igs (M, A, G1, G2, G3, and G4) and B cells were quantified in peripheral blood of 190 Chilean patients ≥18 years old hospitalized for CAP and in 21 adults without respiratory disease, using xMAP Luminex and flow cytometry, respectively. Clinical history was recorded and PSI and CURB-65 scores were calculated for evaluation of clinical severity.The total IgM, IgG2 and total IgG levels were lower in CAP than in asymptomatic adults (P < .05). No significant differences of Igs levels were found between patients classified as severe and mild by PSI and CURB-65 scores. Fatal cases had higher levels of IgA (P < .05). No differences in CD19 B cells frequency was found between CAP and asymptomatic adults (P = .40). In PSI severe cases, CD19 B cells were significantly lower than in mild cases (P = .008). No differences were found in CURB-65 severe and mild groups (P = .11). In fatal cases (11/82) group, CD19 B cells frequency was lower than in 71 survivors (P = .2). No differences in memory B lymphocytes were detected between asymptomatic and CAP adults, severe and mild patients, survivors and fatal cases (P > .05).Serum IgA levels were significantly higher in fatal CAP cases, raising it as a potential biomarker for severe disease considering its relatively universal availability. In PSI severe patients, B cells showed lower levels and could have a role on its physiopathology. Finding new markers rooted in physiopathology could improve the possibility of scoring severe CAP cases. Luminex technology showed promising quantification serum Igs.


Assuntos
Linfócitos B/imunologia , Infecções Comunitárias Adquiridas/imunologia , Imunoglobulinas/sangue , Pneumonia/imunologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Contagem de Células , Chile , Estudos Transversais , Feminino , Citometria de Fluxo , Humanos , Testes Imunológicos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
10.
Medicine (Baltimore) ; 99(41): e22567, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031304

RESUMO

BACKGROUND: We put the meta-analysis into practice to reveal the relationship between the incidence risk of immune-related pneumonitis and the use of programmed cell death-1 (PD-1) and ligand 1 (PD-L1) inhibitors related pneumonitis in cancer patients. METHOD: The meta-analysis was put into practice according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Odds ratio (OR) was evaluated by random effect model. RESULTS: After screening and eligibility assessment, 33 clinical trials involving 19,854 patients were selected and used for the final meta-analysis after selection criteria checked. Compared with chemotherapy, the use of PD-1/PD-L1 inhibitors alone increased the incidence risk of all-grade (OR = 4.29, 95% confidence interval: [2.97, 6.19], P < .00001) and grade 3 to 5 immune-related pneumonitis (OR = 3.53, 95% confidence interval: [2.04, 6.11], P < .00001). Similar trend could also be found when PD-1/PD-L1 inhibitors were prescribed alone or in combination with other anti-tumor therapies. CONCLUSION: Whether PD-1/PD-L1 inhibitors were used alone or combined with other antitumor drugs, the incidence risk of immune-related pneumonitis would be increased.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Pneumonia/induzido quimicamente , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Humanos , Pneumonia/imunologia
11.
Breast Cancer Res ; 22(1): 117, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33126915

RESUMO

Severe coronavirus disease 2019 (COVID-19) causes a hyperactivation of immune cells, resulting in lung inflammation. Recent studies showed that COVID-19 induces the production of factors previously implicated in the reawakening of dormant breast cancer cells such as neutrophil extracellular traps (NETs). The presence of NETs and of a pro-inflammatory microenvironment may therefore promote breast cancer reactivation, increasing the risk of pulmonary metastasis. Further studies will be required to confirm the link between COVID-19 and cancer recurrence. However, an increased awareness on the potential risks for breast cancer patients with COVID-19 may lead to improved treatment strategies to prevent metastatic relapse.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/virologia , Infecções por Coronavirus/imunologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/virologia , Pneumonia Viral/imunologia , Betacoronavirus/imunologia , Neoplasias da Mama/patologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/imunologia , Feminino , Humanos , Pulmão/imunologia , Pulmão/patologia , Recidiva Local de Neoplasia/patologia , Neutrófilos/imunologia , Pandemias , Pneumonia/imunologia , Pneumonia/virologia , Pneumonia Viral/virologia , Microambiente Tumoral/imunologia
12.
Stroke ; 51(10): 3156-3168, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32897811

RESUMO

Understanding the relationship between infection and stroke has taken on new urgency in the era of the coronavirus disease 2019 (COVID-19) pandemic. This association is not a new concept, as several infections have long been recognized to contribute to stroke risk. The association of infection and stroke is also bidirectional. Although infection can lead to stroke, stroke also induces immune suppression which increases risk of infection. Apart from their short-term effects, emerging evidence suggests that poststroke immune changes may also adversely affect long-term cognitive outcomes in patients with stroke, increasing the risk of poststroke neurodegeneration and dementia. Infections at the time of stroke may also increase immune dysregulation after the stroke, further exacerbating the risk of cognitive decline. This review will cover the role of acute infections, including respiratory infections such as COVID-19, as a trigger for stroke; the role of infectious burden, or the cumulative number of infections throughout life, as a contributor to long-term risk of atherosclerotic disease and stroke; immune dysregulation after stroke and its effect on the risk of stroke-associated infection; and the impact of infection at the time of a stroke on the immune reaction to brain injury and subsequent long-term cognitive and functional outcomes. Finally, we will present a model to conceptualize the many relationships among chronic and acute infections and their short- and long-term neurological consequences. This model will suggest several directions for future research.


Assuntos
Aterosclerose/epidemiologia , Infecções/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/fisiopatologia , Aterosclerose/imunologia , Aterosclerose/fisiopatologia , Bacteriemia/epidemiologia , Bacteriemia/imunologia , Bacteriemia/fisiopatologia , Betacoronavirus , Doença Crônica , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/fisiopatologia , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/fisiopatologia , Endotélio/fisiopatologia , Infecções por HIV/epidemiologia , Infecções por HIV/imunologia , Infecções por HIV/fisiopatologia , Humanos , Hospedeiro Imunocomprometido/imunologia , Infecções/imunologia , Infecções/fisiopatologia , Inflamação/imunologia , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Influenza Humana/fisiopatologia , Pandemias , Ativação Plaquetária , Agregação Plaquetária , Pneumonia/epidemiologia , Pneumonia/imunologia , Pneumonia/fisiopatologia , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Pneumonia Viral/fisiopatologia , Prognóstico , Fatores de Risco , Acidente Vascular Cerebral/imunologia , Trombose/epidemiologia , Trombose/imunologia , Infecção pelo Vírus da Varicela-Zoster/epidemiologia , Infecção pelo Vírus da Varicela-Zoster/imunologia , Infecção pelo Vírus da Varicela-Zoster/fisiopatologia
13.
BMJ Open Respir Res ; 7(1)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32913008

RESUMO

We and others propose vimentin as a possible cellular target for the treatment of COVID-19. This innovative idea is so recent that it requires further attention and debate. The significant role played by vimentin in virus-induced infection however is well established: (1) vimentin has been reported as a co-receptor and/or attachment site for SARS-CoV; (2) vimentin is involved in viral replication in cells; (3) vimentin plays a fundamental role in both the viral infection and the consequent explosive immune-inflammatory response and (4) a lower vimentin expression is associated with the inhibition of epithelial to mesenchymal transition and fibrosis. Moreover, the absence of vimentin in mice makes them resistant to lung injury. Since vimentin has a twofold role in the disease, not only being involved in the viral infection but also in the associated life-threatening lung inflammation, the use of vimentin-targeted drugs may offer a synergistic advantage as compared with other treatments not targeting vimentin. Consequently, we speculate here that drugs which decrease the expression of vimentin can be used for the treatment of patients with COVID-19 and advise that several Food and Drug Administration-approved drugs be immediately tested in clinical trials against SARS-CoV-2, thus broadening therapeutic options for this type of viral infection.


Assuntos
Antivirais/farmacologia , Betacoronavirus/fisiologia , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Vimentina/fisiologia , Internalização do Vírus/efeitos dos fármacos , Animais , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Regulação para Baixo , Descoberta de Drogas/métodos , Humanos , Camundongos , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Pneumonia/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Receptores Virais , Replicação Viral/fisiologia
15.
Mult Scler Relat Disord ; 45: 102442, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32777745

RESUMO

BACKGROUND: Recently SARS-CoV-2 has spread worldwide causing a pandemic. Little is known about disease severity in immunocompromised hosts and people receiving disease modifying therapies (DMTs). In the last decades DMTs have been widely employed, and ocrelizumab represents one of the newest therapies for the relapsing remitting and progressive forms of multiple sclerosis (MS). OBJECTIVES: to describe SARS-CoV-2 related pneumonia in two MS patients under ocrelizumab treatment. METHODS: Case series. RESULTS: Patients showed a mild clinical course of SARS-CoV-2 related pneumonia without complications or sequelae. CONCLUSION: Ocrelizumab treatment is not necessarily associated to increased severity in MS patients with SARS-CoV-2 infection.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Coronavirus/complicações , Hospedeiro Imunocomprometido , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Pneumonia Viral/complicações , Adulto , Betacoronavirus , Infecções por Coronavirus/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia/imunologia , Pneumonia/virologia , Pneumonia Viral/imunologia
16.
J Stroke Cerebrovasc Dis ; 29(9): 104942, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807413

RESUMO

BACKGROUND AND OBJECTIVES: Studies implicate the lung in moderating systemic immune activation via effects on circulating leukocytes. In this study, we investigated whether targeted expression of the antioxidant extracellular superoxide dismutase (SOD3) within the lung would influence post-ischemic peripheral neutrophil activation and CNS reperfusion injury. METHODS: Adult, male mice expressing human SOD3 within type II pneumocytes were subjected to 15 min of transient global cerebral ischemia. Three days post-reperfusion, lung and brain tissue was collected and analyzed by immunohistochemistry for inflammation and injury markers. In vitro motility and neurotoxicity assays were conducted to ascertain the direct effects of hSOD3 on PMN activation. Results were compared against C57BL/6 age and sex-matched controls. RESULTS: Relative to wild-type controls, hSOD3 heterozygous mice exhibited a reduction in lung inflammation, blood-brain barrier damage, and post-ischemic neuronal injury within the hippocampus and cortex. PMNs harvested from hSOD3 mice were also resistant to LPS priming, slower-moving, and less toxic to primary neuronal cultures. CONCLUSIONS: Constitutive, focal expression of hSOD3 is neuroprotective in a model of global cerebral ischemia-reperfusion injury. The underlying mechanism of SOD3-dependent protection is attributable in part to effects on the activation state and toxic potential of circulating neutrophils. These results implicate lung-brain coupling as a determinant of cerebral ischemia-reperfusion injury and highlight post-stroke lung inflammation as a potential therapeutic target in acute ischemic cerebrovascular injuries.


Assuntos
Células Epiteliais Alveolares/enzimologia , Isquemia Encefálica/enzimologia , Encéfalo/metabolismo , Neurônios/metabolismo , Ativação de Neutrófilo , Neutrófilos/metabolismo , Pneumonia/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Superóxido Dismutase/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Encéfalo/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/imunologia , Células Cultivadas , Modelos Animais de Doenças , Humanos , Imunidade Inata , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/patologia , Neutrófilos/imunologia , Pneumonia/enzimologia , Pneumonia/genética , Pneumonia/imunologia , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Transdução de Sinais , Superóxido Dismutase/genética
17.
Epidemiol Infect ; 148: e164, 2020 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-32713370

RESUMO

The emergence of 2019 novel coronavirus disease (COVID-19) is currently a global concern. In this study, our goal was to explore the changing expression levels of acute-phase reaction proteins (APRPs) in the serum of COVID-19 patients and to elucidate the immunological characteristics of COVID-19. In the study design, we recruited 72 COVID-19 patients, including 22 cases of mild degree, 38 cases of moderate degree and 12 cases of severe degree. We also recruited 20 patients with community-acquired pneumonia (CAP) and 20 normal control subjects as a comparison. Fasting venous blood was taken to detect the content of complement 3 (C3), complement 4 (C4), C-reactive protein (CRP), serum amyloid A (SAA) and prealbumin (PA). When compared the COVID-19 group with the CAP and normal control groups, respectively, the mean value of CRP and SAA in the COVID-19 group (including mild, moderate and severe patients) had increased significantly (P < 0.01), whereas the mean values of C3, C4 and PA decreased (P < 0.01). For the asymptomatic or mild symptomatic patients with COVID-19, the actual aggravation of disease may be more advanced than the clinical appearances. Meanwhile, the statistical analyses indicated that the development of COVID-19 brought about a significant increase in the content of CRP and SAA (P < 0.01), and a decline in the content of C3, C4 and PA (P < 0.01). These findings suggested that the changes in the level of APRPs could be used as indicators to identify the degree and progression of COVID-19, and the significant changes might demonstrate the aggravation of disease. This study provided a new approach to improve the clinical management plan and prognosis of COVID-19.


Assuntos
Proteínas da Fase Aguda/análise , Proteínas da Fase Aguda/biossíntese , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Adulto , Idoso , Proteína C-Reativa/análise , Proteína C-Reativa/biossíntese , Estudos de Casos e Controles , Infecções Comunitárias Adquiridas/sangue , Infecções Comunitárias Adquiridas/imunologia , Complemento C3/análise , Complemento C3/biossíntese , Complemento C4/análise , Complemento C4/biossíntese , Infecções por Coronavirus/sangue , Infecções por Coronavirus/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia/sangue , Pneumonia/imunologia , Pneumonia Viral/sangue , Pneumonia Viral/imunologia , Pré-Albumina/análise , Pré-Albumina/biossíntese , Prognóstico , Proteína Amiloide A Sérica/análise , Proteína Amiloide A Sérica/biossíntese , Índice de Gravidade de Doença , Adulto Jovem
18.
PLoS One ; 15(7): e0236744, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730309

RESUMO

Repeated exposures to environmental allergens in susceptible individuals drive the development of type 2 inflammatory conditions such as asthma, which have been traditionally considered to be mainly mediated by Th2 cells. However, emerging evidence suggest that a new innate cell type, group 2 innate lymphoid cells (ILC2), plays a central role in initiating and amplifying a type 2 response, even in the absence of adaptive immunity. At present, the regulatory mechanisms for controlling ILC2 activation remain poorly understood. Here we report that respiratory delivery of immunogenic extracellular RNA (exRNAs) derived from RNA- and DNA-virus infected cells, was able to activate a protective response against acute type 2 lung immunopathology and airway hyperresponsiveness (AHR) induced by IL-33 and a fungal allergen, A. flavus, in mice. Mechanistically, we found that the innate immune responses triggered by exRNAs had a potent suppressive effect in vivo on the proliferation and function of ILC2 without the involvement of adaptive immunity. We further provided the loss-of-function genetic evidence that the TLR3- and MAVS-mediated signaling axis is essential for the inhibitory effects of exRNAs in mouse lungs. Thus, our results indicate that the host detection of extracellular immunostimulatory RNAs generated during respiratory viral infections have an important function in the regulation of ILC2-driven acute lung inflammation.


Assuntos
Armadilhas Extracelulares/imunologia , Imunidade Inata/imunologia , Linfócitos/imunologia , Pneumonia/imunologia , RNA/imunologia , Hipersensibilidade Respiratória/imunologia , Imunidade Adaptativa , Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Alérgenos/imunologia , Alérgenos/metabolismo , Animais , Citocinas/metabolismo , Armadilhas Extracelulares/metabolismo , Interleucina-33/imunologia , Interleucina-33/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pneumonia/metabolismo , Pneumonia/patologia , RNA/metabolismo , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia , Transdução de Sinais , Células Th2/imunologia , Células Th2/metabolismo , Receptor 3 Toll-Like/fisiologia
19.
J Vis Exp ; (160)2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32658184

RESUMO

Immune cell expansion, activation, and trafficking to the lungs, which are controlled by the expression of multiple cytokines and chemokines, may be altered by severe brain injury. This is evidenced by the fact that pneumonia is a major cause of mortality in patients who have suffered from ischemic stroke. The goal of this protocol is to describe the use of multicolor flow cytometric analysis to identify 13 types of immune cells in the lungs of mice, including alveolar macrophages, interstitial macrophages, CD103+ or CD11b+ dendritic cells (DCs), plasmacytoid DCs, eosinophils, monocytes/monocyte-derived cells, neutrophils, lymphoid-derived  T and B cells, NK cells, and NKT cells, following ischemic stroke induction by transient middle cerebral artery occlusion. Moreover, we describe the preparation of lung homogenates using a bead homogenization method, to determine the expression levels of 13 different cytokines or chemokines simultaneously by multiplex bead arrays coupled with flow cytometric analysis. This protocol can also be used to investigate the pulmonary immune response in other disease settings, such as infectious lung disease or allergic disease.


Assuntos
Citometria de Fluxo , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Animais , Movimento Celular/imunologia , Quimiocinas/metabolismo , Células Dendríticas/imunologia , Pulmão/citologia , Macrófagos/metabolismo , Camundongos , Pneumonia/imunologia
20.
Cell Mol Immunol ; 17(9): 995-997, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32612152

Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Terapia de Alvo Molecular/métodos , Pneumonia Viral/imunologia , Pneumonia/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Antivirais/uso terapêutico , Apirase/antagonistas & inibidores , Apirase/genética , Apirase/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Betacoronavirus/imunologia , Estudos de Casos e Controles , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Subfamília C de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília C de Receptores Semelhantes a Lectina de Células NK/imunologia , Pandemias , Pneumonia/tratamento farmacológico , Pneumonia/genética , Pneumonia/virologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/genética , Síndrome Respiratória Aguda Grave/virologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia
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