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1.
Life Sci ; 259: 118389, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32898522

RESUMO

AIMS: Adenosine triphosphate (ATP) is released at a high concentration in the tumor microenvironment. The overexpression of ectonucleotidases in non-small-cell lung cancer (NSCLC), metabolizing ΑΤP to the immunosuppressive adenosine, is studied. MATERIALS AND METHODS: We examined the expression of the ectonucleotidases CD73 and CD39 in NSCLC in parallel with immunological parameters and markers of hypoxia and anaerobic metabolism. In vitro experiments with A549 and H1299 lung cancer cell lines were also conducted. RESULTS: CD73 and CD39 were not expressed by normal bronchial and alveolar epithelium. In contrast, these were overexpressed by cancer cells, cancer-associated fibroblasts (CAFs), and tumor-infiltrating lymphocytes (TILs). High CD73 cancer cell expression was directly linked with lactate dehydrogenase LDH5 and with hypoxia-inducible factor HIF1α expression by cancer cells. The expression of CD39 by CAFs was directly linked with PD-L1 expression by cancer cells. A significant abundance of FOXP3+ and PD-1+ TILs was noted in tumors with high CD73 and CD39 stroma expression. In in vitro experiments, hypoxia and acidity induced CD73 mRNA and protein levels in cancer cell lines. Exposure of cancer cell lines to adenosine induced the expression of PD-L1 and LDHA mRNA and protein levels. CONCLUSION: Ectonucleotidases are up-regulated in cancer cells, CAFs, and TILs in lung tumors. Such overexpression is linked with regulatory TIL-phenotype and PD-L1 up-regulation by cancer cells. Overexpression of LDH5 is up-regulated by adenosine, creating a vicious cycle, as the high amounts of ATP produced by LDH5-mediated anaerobic glycolysis promote the production of adenosine by a tumor microenvironment rich in ectonucleotidases.


Assuntos
5'-Nucleotidase/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Hipóxia/etiologia , Neoplasias Pulmonares/metabolismo , Adenosina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/metabolismo , Tolerância Imunológica , Neoplasias Pulmonares/enzimologia , Masculino , Pessoa de Meia-Idade
2.
Nat Commun ; 11(1): 4454, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901001

RESUMO

Chronic viral infections are often associated with impaired CD8+ T cell function, referred to as exhaustion. Although the molecular and cellular circuits involved in CD8+ T cell exhaustion are well defined, with sustained presence of antigen being one important parameter, how much T cell receptor (TCR) signaling is actually ongoing in vivo during established chronic infection is unclear. Here, we characterize the in vivo TCR signaling of virus-specific exhausted CD8+ T cells in a mouse model, leveraging TCR signaling reporter mice in combination with transcriptomics. In vivo signaling in exhausted cells is low, in contrast to their in vitro signaling potential, and despite antigen being abundantly present. Both checkpoint blockade and adoptive transfer of naïve target cells increase TCR signaling, demonstrating that engagement of co-inhibitory receptors curtails CD8+ T cell signaling and function in vivo.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Coriomeningite Linfocítica/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transferência Adotiva , Animais , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/virologia , Doença Crônica , Citotoxicidade Imunológica , Modelos Animais de Doenças , Regulação para Baixo , Tolerância Imunológica , Imunidade Celular , Técnicas In Vitro , Ativação Linfocitária , Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Receptor de Morte Celular Programada 1/imunologia , RNA-Seq , Transdução de Sinais/imunologia
3.
Anesth Analg ; 131(4): 993-999, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32925314

RESUMO

BACKGROUND: The cellular immune system is of pivotal importance with regard to the response to severe infections. Monocytes/macrophages are considered key immune cells in infections and downregulation of the surface expression of monocytic human leukocyte antigen-DR (mHLA-DR) within the major histocompatibility complex class II reflects a state of immunosuppression, also referred to as injury-associated immunosuppression. As the role of immunosuppression in coronavirus disease 2019 (COVID-19) is currently unclear, we seek to explore the level of mHLA-DR expression in COVID-19 patients. METHODS: In a preliminary prospective monocentric observational study, 16 COVID-19-positive patients (75% male, median age: 68 [interquartile range 59-75]) requiring hospitalization were included. The median Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score in 9 intensive care unit (ICU) patients with acute respiratory failure was 30 (interquartile range 25-32). Standardized quantitative assessment of HLA-DR on monocytes (cluster of differentiation 14+ cells) was performed using calibrated flow cytometry at baseline (ICU/hospital admission) and at days 3 and 5 after ICU admission. Baseline data were compared to hospitalized noncritically ill COVID-19 patients. RESULTS: While normal mHLA-DR expression was observed in all hospitalized noncritically ill patients (n = 7), 89% (8 of 9) critically ill patients with COVID-19-induced acute respiratory failure showed signs of downregulation of mHLA-DR at ICU admission. mHLA-DR expression at admission was significantly lower in critically ill patients (median, [quartiles]: 9280 antibodies/cell [6114, 16,567]) as compared to the noncritically ill patients (30,900 antibodies/cell [26,777, 52,251]), with a median difference of 21,508 antibodies/cell (95% confidence interval [CI], 14,118-42,971), P = .002. Reduced mHLA-DR expression was observed to persist until day 5 after ICU admission. CONCLUSIONS: When compared to noncritically ill hospitalized COVID-19 patients, ICU patients with severe COVID-19 disease showed reduced mHLA-DR expression on circulating CD14+ monocytes at ICU admission, indicating a dysfunctional immune response. This immunosuppressive (monocytic) phenotype remained unchanged over the ensuing days after ICU admission. Strategies aiming for immunomodulation in this population of critically ill patients should be guided by an immune-monitoring program in an effort to determine who might benefit best from a given immunological intervention.


Assuntos
Infecções por Coronavirus/imunologia , Estado Terminal , Antígenos HLA-DR/biossíntese , Antígenos HLA-DR/imunologia , Tolerância Imunológica/imunologia , Pneumonia Viral/imunologia , APACHE , Idoso , Anticorpos/análise , Anticorpos/imunologia , Infecções por Coronavirus/terapia , Cuidados Críticos , Regulação para Baixo/imunologia , Feminino , Humanos , Imunoterapia , Receptores de Lipopolissacarídeos/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Pandemias , Pneumonia Viral/terapia , Estudos Prospectivos , Insuficiência Respiratória/imunologia , Insuficiência Respiratória/fisiopatologia
5.
Nat Commun ; 11(1): 3912, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32764562

RESUMO

Immunotherapy has emerged as a promising approach to treat cancer, however, its efficacy in highly malignant brain-tumors, glioblastomas (GBM), is limited. Here, we generate distinct imageable syngeneic mouse GBM-tumor models and utilize RNA-sequencing, CyTOF and correlative immunohistochemistry to assess immune-profiles in these models. We identify immunologically-inert and -active syngeneic-tumor types and show that inert tumors have an immune-suppressive phenotype with numerous exhausted CD8 T cells and resident macrophages; fewer eosinophils and SiglecF+ macrophages. To mimic the clinical-settings of first line of GBM-treatment, we show that tumor-resection invigorates an anti-tumor response via increasing T cells, activated microglia and SiglecF+ macrophages and decreasing resident macrophages. A comparative CyTOF analysis of resected-tumor samples from GBM-patients and mouse GBM-tumors show stark similarities in one of the mouse GBM-tumors tested. These findings guide informed choices for use of GBM models for immunotherapeutic interventions and offer a potential to facilitate immune-therapies in GBM patients.


Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Tolerância Imunológica , Imunofenotipagem , Imunoterapia , Isoenxertos , Linfócitos do Interstício Tumoral/classificação , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Microambiente Tumoral/imunologia
6.
Obes Facts ; 13(4): 439-452, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32791497

RESUMO

Accumulating evidence suggests that obesity is a major risk factor for the initiation, progression, and outcomes of coronavirus disease 2019 (COVID-19). The European Association for the Study of Obesity (EASO), as a scientific and medical society dedicated to the promotion of health and well-being, is greatly concerned about the concomitant obesity and COVID-19 pandemics and their impact on health and society at large. In this perspective, we will address the inherent immunological perturbations and alterations in the renin-angiotensin-aldosterone system in patients with obesity and COVID-19, and discuss how these impairments may underlie the increased susceptibility and more detrimental outcomes of COVID-19 in people with obesity. Clearly, this has important implications for preventive measures, vaccination, and future therapeutic strategies to combat COVID-19. Furthermore, we will highlight important knowledge gaps and provide suggestions for future research and recommendations for policy actions. Since many new reports on COVID-19 rapidly appear, the present perspective should be seen as a focus for discussion to drive forward further understanding, research initiatives, and clinical management of COVID-19.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Obesidade/complicações , Obesidade/imunologia , Pneumonia Viral/imunologia , Coronavirus , Infecções por Coronavirus/terapia , Suscetibilidade a Doenças , Humanos , Tolerância Imunológica/imunologia , Imunocompetência/imunologia , Pandemias , Peptidil Dipeptidase A , Pneumonia Viral/terapia , Prognóstico , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco
7.
J Immunol ; 205(8): 1990-1997, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32826281

RESUMO

The recent outbreak of COVID-19 has emerged as a major global health concern. Although susceptible to infection, recent evidence indicates mostly asymptomatic or mild presentation of the disease in infants, children, and adolescents. Similar observations were made for acute respiratory infections caused by other coronaviruses (severe acute respiratory syndrome and Middle East respiratory syndrome). These observations suggest that the immune system behaves differently in children than adults. Recent developments in the field demonstrated fundamental differences in the neonatal immune system as compared with adults, whereby infants respond to microorganisms through biased immune tolerance rather than resistance strategies. Similarly, more frequent/recent vaccinations in children and younger populations may result in trained immunity. Therefore, the physiological abundance of certain immunosuppressive cells, a tightly regulated immune system, and/or exposure to attenuated vaccines may enhance trained immunity to limit excessive immune reaction to COVID-19 in the young.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Sistema Imunitário/imunologia , Tolerância Imunológica , Pneumonia Viral/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Suscetibilidade a Doenças , Humanos , Imunossupressores/uso terapêutico , Lactente , Recém-Nascido , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Vacinas Atenuadas/imunologia , Internalização do Vírus
8.
Nat Commun ; 11(1): 4011, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32782249

RESUMO

Tryptophan catabolism by the enzymes indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase 2 (IDO/TDO) promotes immunosuppression across different cancer types. The tryptophan metabolite L-Kynurenine (Kyn) interacts with the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) to drive the generation of Tregs and tolerogenic myeloid cells and PD-1 up-regulation in CD8+ T cells. Here, we show that the AHR pathway is selectively active in IDO/TDO-overexpressing tumors and is associated with resistance to immune checkpoint inhibitors. We demonstrate that IDO-Kyn-AHR-mediated immunosuppression depends on an interplay between Tregs and tumor-associated macrophages, which can be reversed by AHR inhibition. Selective AHR blockade delays progression in IDO/TDO-overexpressing tumors, and its efficacy is improved in combination with PD-1 blockade. Our findings suggest that blocking the AHR pathway in IDO/TDO expressing tumors would overcome the limitation of single IDO or TDO targeting agents and constitutes a personalized approach to immunotherapy, particularly in combination with immune checkpoint inhibitors.


Assuntos
Cinurenina/imunologia , Macrófagos/imunologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Linfócitos T Reguladores/imunologia , Animais , Resistencia a Medicamentos Antineoplásicos , Humanos , Tolerância Imunológica , Imunoterapia , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Camundongos , Neoplasias/imunologia , Neoplasias/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais , Triptofano Oxigenase/genética , Triptofano Oxigenase/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral
9.
Proc Natl Acad Sci U S A ; 117(32): 19408-19414, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32719138

RESUMO

Untoward effector CD4+ T cell responses are kept in check by immune regulatory mechanisms mediated by CD4+ and CD8+ T cells. CD4+ T helper 17 (Th17) cells, characterized by IL-17 production, play important roles in the pathogenesis of autoimmune diseases (such as arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, among others) and in the host response to infection and cancer. Here, we demonstrate that human CD4+ T cells cells exposed to a Th17-differentiating milieu are significantly more resistant to immune suppression by CD8+ T cells compared to control Th0 cells. This resistance is mediated, in part, through the action of IL-17A, IL-17F, and IL-17AF heterodimer through their receptors (IL-17RA and IL-17RC) on CD4+ T cells themselves, but not through their action on CD8+ T cells or APC. We further show that IL-17 can directly act on non-Th17 effector CD4+ T cells to induce suppressive resistance, and this resistance can be reversed by blockade of IL-1ß, IL-6, or STAT3. These studies reveal a role for IL-17 cytokines in mediating CD4-intrinsic immune resistance. The pathways induced in this process may serve as a critical target for future investigation and immunotherapeutic intervention.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Tolerância Imunológica/imunologia , Interleucina-17/imunologia , Células Th17/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Humanos , Interleucina-17/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia
10.
Proc Natl Acad Sci U S A ; 117(28): 16339-16345, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601217

RESUMO

We present a technique to construct a simplification of a feature network which can be used for interactive data exploration, biological hypothesis generation, and the detection of communities or modules of cofunctional features. These are modules of features that are not necessarily correlated, but nevertheless exhibit common function in their network context as measured by similarity of relationships with neighboring features. In the case of genetic networks, traditional pathway analyses tend to assume that, ideally, all genes in a module exhibit very similar function, independent of relationships with other genes. The proposed technique explicitly relaxes this assumption by employing the comparison of relational profiles. For example, two genes which always activate a third gene are grouped together even if they never do so concurrently. They have common, but not identical, function. The comparison is driven by an average of a certain computationally efficient comparison metric between Gaussian mixture models. The method has its basis in the local connection structure of the network and the collection of joint distributions of the data associated with nodal neighborhoods. It is benchmarked on networks with known community structures. As the main application, we analyzed the gene regulatory network in lung adenocarcinoma, finding a cofunctional module of genes including the pregnancy-specific glycoproteins (PSGs). About 20% of patients with lung, breast, uterus, and colon cancer in The Cancer Genome Atlas (TCGA) have an elevated PSG+ signature, with associated poor group prognosis. In conjunction with previous results relating PSGs to tolerance in the immune system, these findings implicate the PSGs in a potential immune tolerance mechanism of cancers.


Assuntos
Biologia Computacional/métodos , Tolerância Imunológica/genética , Neoplasias/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Modelos Estatísticos , Neoplasias/imunologia , Glicoproteínas beta 1 Específicas da Gravidez/genética , Prognóstico
11.
PLoS Pathog ; 16(7): e1008599, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32692767

RESUMO

Heme oxygenase (HO-1) mediates the enzymatic cleavage of heme, a molecule with proinflammatory and prooxidant properties. HO-1 activity deeply impacts host capacity to tolerate infection through reduction of tissue damage or affecting resistance, the ability of the host to control pathogen loads. In this Review, we will discuss the contribution of HO-1 in different and complex protozoan infections, such as malaria, leishmaniasis, Chagas disease, and toxoplasmosis. The complexity of these infections and the pleiotropic effects of HO-1 constitute an interesting area of study and an opportunity for drug development.


Assuntos
Heme Oxigenase-1/metabolismo , Infecções por Protozoários/enzimologia , Animais , Humanos , Tolerância Imunológica/fisiologia
12.
Nat Commun ; 11(1): 3734, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709894

RESUMO

Medullary thymic epithelial cells (mTEC) contribute to the development of T cell tolerance by expressing and presenting tissue-restricted antigens (TRA), so that developing T cells can assess the self-reactivity of their antigen receptors prior to leaving the thymus. mTEC are a heterogeneous population of cells that differentially express TRA. Whether mTEC subsets induce distinct autoreactive T cell fates remains unclear. Here, we establish bacterial artificial chromosome (BAC)-transgenic mouse lines with biased mTEClo or mTEChi expression of model antigens. The transgenic lines support negative selection of antigen-specific thymocytes depending on antigen dose. However, model antigen expression predominantly by mTEClo supports TCRαß+ CD8αα intraepithelial lymphocyte development; meanwhile, mTEChi-restricted expression preferentially induces Treg differentiation of antigen-specific cells in these models to impact control of infectious agents and tumor growth. In summary, our data suggest that mTEC subsets may have a function in directing distinct mechanisms of T cell tolerance.


Assuntos
Antígenos/imunologia , Diferenciação Celular/imunologia , Células Epiteliais/imunologia , Linfócitos T/imunologia , Timo/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos/metabolismo , Infecções Bacterianas , Medula Óssea , Linhagem Celular Tumoral , Feminino , Tolerância Imunológica , Linfonodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T/metabolismo , Timócitos/imunologia , Fatores de Transcrição/genética
15.
Proc Natl Acad Sci U S A ; 117(29): 17156-17165, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32611812

RESUMO

Semi-invariant natural killer T (iNKT) cells are self-reactive lymphocytes, yet how this lineage attains self-tolerance remains unknown. iNKT cells constitutively express high levels of Nr4a1-encoded Nur77, a transcription factor that integrates signal strength downstream of the T cell receptor (TCR) within activated thymocytes and peripheral T cells. The function of Nur77 in iNKT cells is unknown. Here we report that sustained Nur77 overexpression (Nur77tg) in mouse thymocytes abrogates iNKT cell development. Introgression of a rearranged Vα14-Jα18 TCR-α chain gene into the Nur77tg (Nur77tg;Vα14tg) mouse rescued iNKT cell development up to the early precursor stage, stage 0. iNKT cells in bone marrow chimeras that reconstituted thymic cellularity developed beyond stage 0 precursors and yielded IL-4-producing NKT2 cell subset but not IFN-γ-producing NKT1 cell subset. Nonetheless, the developing thymic iNKT cells that emerged in these chimeras expressed the exhaustion marker PD1 and responded poorly to a strong glycolipid agonist. Thus, Nur77 integrates signals emanating from the TCR to control thymic iNKT cell tolerance induction, terminal differentiation, and effector functions.


Assuntos
Diferenciação Celular , Tolerância Imunológica , Células T Matadoras Naturais , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/imunologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Receptores de Antígenos de Linfócitos T , Timócitos
16.
Chin J Traumatol ; 23(4): 187-189, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32669221

RESUMO

The COVID-19 pandemic is still raging across the world. Everyday thousands of infected people lost their lives. What is worse, there is no specific medicine and we do not know when the end of the pandemic will come. The nearest global pandemic is the 1918 influenza, which caused about 50 million deaths and partly terminate the World War Ⅰ. We believe that no matter the virus H1N1 for the 1918 influenza or 2019-nCoV for COVID-19, they are essentially the same and the final cause of death is sepsis. The definition and diagnostic/management criteria of sepsis have been modified several times but the mortality rate has not been improved until date. Over decades, researchers focus either on the immunosuppression or on the excessive inflammatory response following trauma or body exposure to harmful stimuli. But the immune response is very complex with various regulating factors involved in, such as neurotransmitter, endocrine hormone, etc. Sepsis is not a kind of disease, instead a misbalance of the body following infection, trauma or other harmful stimulation. Therefore we should re-think sepsis comprehensively with the concept of systemic biology, i.e. inflammationomics.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/epidemiologia , Pneumonia Viral/epidemiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Humanos , Tolerância Imunológica , Inflamação/complicações , Influenza Humana/complicações , Influenza Humana/imunologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Sepse/etiologia
17.
Endocrinology ; 161(9)2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730568

RESUMO

Severe outcomes and death from the novel coronavirus disease 2019 (COVID-19) appear to be characterized by an exaggerated immune response with hypercytokinemia leading to inflammatory infiltration of the lungs and acute respiratory distress syndrome. Risk of severe COVID-19 outcomes is consistently lower in women than men worldwide, suggesting that female biological sex is instrumental in protection. This mini-review discusses the immunomodulatory and anti-inflammatory actions of high physiological concentrations of the steroids 17ß-estradiol (E2) and progesterone (P4). We review how E2 and P4 favor a state of decreased innate immune inflammatory response while enhancing immune tolerance and antibody production. We discuss how the combination of E2 and P4 may improve the immune dysregulation that leads to the COVID-19 cytokine storm. It is intended to stimulate novel consideration of the biological forces that are protective in women compared to men, and to therapeutically harness these factors to mitigate COVID-19 morbidity and mortality.


Assuntos
Infecções por Coronavirus/imunologia , Estradiol/imunologia , Imunomodulação/imunologia , Pneumonia Viral/imunologia , Progesterona/imunologia , Formação de Anticorpos/imunologia , Betacoronavirus , Anticoncepcionais Orais Hormonais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Síndrome da Liberação de Citocina/imunologia , Reposicionamento de Medicamentos , Estradiol/uso terapêutico , Terapia de Reposição de Estrogênios , Estrogênios/uso terapêutico , Feminino , Humanos , Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Masculino , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Progesterona/uso terapêutico , Progestinas/uso terapêutico , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Índice de Gravidade de Doença , Fatores Sexuais
18.
PLoS Pathog ; 16(7): e1008622, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32634175

RESUMO

Listeria monocytogenes is a facultative intracellular bacterial pathogen that escapes from phagosomes and induces a robust adaptive immune response in mice, while mutants unable to escape phagosomes fail to induce a robust adaptive immune response and suppress the immunity to wildtype bacteria when co-administered. The capacity to suppress immunity can be reversed by blocking IL-10. In this study, we sought to understand the host receptors that lead to secretion of IL-10 in response to phagosome-confined L. monocytogenes (Δhly), with the ultimate goal of generating strains that fail to induce IL-10. We conducted a transposon screen to identify Δhly L. monocytogenes mutants that induced significantly more or less IL-10 secretion in bone marrow-derived macrophages (BMMs). A transposon insertion in lgt, which encodes phosphatidylglycerol-prolipoprotein diacylglyceryl transferase and is essential for the formation of lipoproteins, induced significantly reduced IL-10 secretion. Mutants with transposon insertions in pgdA and oatA, which encode peptidoglycan N-acetylglucosamine deacetylase and O-acetyltransferase, are sensitive to lysozyme and induced enhanced IL-10 secretion. A ΔhlyΔpgdAΔoatA strain was killed in BMMs and induced enhanced IL-10 secretion that was dependent on Unc93b1, a trafficking molecule required for signaling of nucleic acid-sensing TLRs. These data revealed that nucleic acids released by bacteriolysis triggered endosomal TLR-mediated IL-10 secretion. Secretion of IL-10 in response to infection with the parental strain was mostly TLR2-dependent, while IL-10 secretion in response to lysozyme-sensitive strains was dependent on TLR2 and Unc93b1. In mice, the IL-10 response to vacuole-confined L. monocytogenes was also dependent on TLR2 and Unc93b1. Co-administration of Δhly and ΔactA resulted in suppressed immunity in WT mice, but not in mice with mutations in Unc93b1. These data revealed that secretion of IL-10 in response to L. monocytogenes infection in vitro is mostly TLR2-dependent and immune suppression by phagosome-confined bacteria in vivo is mostly dependent on endosomal TLRs.


Assuntos
Tolerância Imunológica/imunologia , Interleucina-10/metabolismo , Listeriose/imunologia , Receptores Toll-Like/imunologia , Animais , Endossomos/imunologia , Endossomos/metabolismo , Interleucina-10/imunologia , Listeria monocytogenes/imunologia , Listeriose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fagossomos/imunologia , Fagossomos/metabolismo , Receptor 2 Toll-Like/imunologia , Receptor 2 Toll-Like/metabolismo , Receptores Toll-Like/metabolismo
20.
J Infect Public Health ; 13(10): 1397-1404, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32712106

RESUMO

Secondary bacterial infections are commonly associated with prior or concomitant respiratory viral infections. Viral infections damage respiratory airways and simultaneously defects both innate and acquired immune response that provides a favorable environment for bacterial growth, adherence, and facilitates invasion into healthy sites of the respiratory tract. Understanding the molecular mechanism of viral-induced secondary bacterial infections will provide us a chance to develop novel and effective therapeutic approaches for disease prevention. The present study describes details about the secondary bacterial infection during viral infections and their immunological changes.The outcome of discussion avails an opportunity to understand possible secondary bacterial infections associated with novel SARS-CoV-2, presently causing pandemic outbreak COVID-19.


Assuntos
Infecções Bacterianas/imunologia , Infecções Bacterianas/virologia , Infecções por Coronavirus/imunologia , Influenza Humana/imunologia , Pneumonia Viral/imunologia , Imunidade Adaptativa , Bactérias/crescimento & desenvolvimento , Aderência Bacteriana , Betacoronavirus , Infecções por Coronavirus/complicações , Humanos , Tolerância Imunológica , Imunidade Inata , Inflamação/complicações , Influenza Humana/complicações , Interações Microbianas , Pandemias , Gravidade do Paciente , Pneumonia Viral/complicações
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