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2.
Proc Natl Acad Sci U S A ; 118(29)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34193524

RESUMO

Successfully combating the COVID-19 pandemic depends on mass vaccination with suitable vaccines to achieve herd immunity. Here, we describe COVI-VAC, the only live attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine currently in clinical development. COVI-VAC was developed by recoding a segment of the viral spike protein with synonymous suboptimal codon pairs (codon-pair deoptimization), thereby introducing 283 silent (point) mutations. In addition, the furin cleavage site within the spike protein was deleted from the viral genome for added safety of the vaccine strain. Except for the furin cleavage site deletion, the COVI-VAC and parental SARS-CoV-2 amino acid sequences are identical, ensuring that all viral proteins can engage with the host immune system of vaccine recipients. COVI-VAC was temperature sensitive in vitro yet grew robustly (>107 plaque forming units/mL) at the permissive temperature. Tissue viral loads were consistently lower, lung pathology milder, and weight loss reduced in Syrian golden hamsters (Mesocricetus auratus) vaccinated intranasally with COVI-VAC compared to those inoculated with wild-type (WT) virus. COVI-VAC inoculation generated spike IgG antibody levels and plaque reduction neutralization titers similar to those in hamsters inoculated with WT virus. Upon challenge with WT virus, COVI-VAC vaccination reduced lung challenge viral titers, resulted in undetectable virus in the brain, and protected hamsters from almost all SARS-CoV-2-associated weight loss. Highly attenuated COVI-VAC is protective at a single intranasal dose in a relevant in vivo model. This, coupled with its large-scale manufacturing potential, supports its potential use in mass vaccination programs.


Assuntos
Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/farmacologia , COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Animais , Anticorpos Antivirais/imunologia , COVID-19/epidemiologia , Chlorocebus aethiops , Feminino , Humanos , Masculino , Mesocricetus , Pandemias , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinação , Vacinas Atenuadas/imunologia , Células Vero
3.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206395

RESUMO

The innate immune system's natural killer (NK) cells exert their cytolytic function against a variety of pathological challenges, including tumors and virally infected cells. Their activation depends on net signaling mediated via inhibitory and activating receptors that interact with specific ligands displayed on the surfaces of target cells. The CD94/NKG2C heterodimer is one of the NK activating receptors and performs its function by interacting with the trimeric ligand comprised of the HLA-E/ß2m/nonameric peptide complex. Here, simulations of the all-atom multi-microsecond molecular dynamics in five immune complexes provide atomistic insights into the receptor-ligand molecular recognition, as well as the molecular events that facilitate the NK cell activation. We identify NKG2C, the HLA-Eα2 domain, and the nonameric peptide as the key elements involved in the molecular machinery of signal transduction via an intertwined hydrogen bond network. Overall, the study addresses the complex intricacies that are necessary to understand the mechanisms of the innate immune system.


Assuntos
Complexo Antígeno-Anticorpo/química , Antígenos de Histocompatibilidade Classe I/química , Modelos Moleculares , Subfamília C de Receptores Semelhantes a Lectina de Células NK/química , Subfamília D de Receptores Semelhantes a Lectina de Células NK/química , Peptídeos/química , Sequência de Aminoácidos , Complexo Antígeno-Anticorpo/imunologia , Complexo Antígeno-Anticorpo/metabolismo , Sítios de Ligação , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ligação de Hidrogênio , Ligantes , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Subfamília D de Receptores Semelhantes a Lectina de Células NK/metabolismo , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Relação Estrutura-Atividade
4.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206399

RESUMO

Key features of chronic lymphocytic leukemia (CLL) are defects in the immune system and the ability of leukemic cells to evade immune defenses and induce immunosuppression, resulting in increased susceptibility to infections and disease progression. Several immune effectors are impaired in CLL, including T and natural killer (NK) cells. The role of T cells in defense against CLL and in CLL progression and immunotherapy has been extensively studied. Less is known about the role of NK cells in this leukemia, and data on NK cell alterations in CLL are contrasting. Besides studies showing that NK cells have intrinsic defects in CLL, there is a large body of evidence indicating that NK cell dysfunctions in CLL mainly depend on the escape mechanisms employed by leukemic cells. In keeping, it has been shown that NK cell functions, including antibody-dependent cellular cytotoxicity (ADCC), can be retained and/or restored after adequate stimulation. Therefore, due to their preserved ADCC function and the reversibility of CLL-related dysfunctions, NK cells are an attractive source for novel immunotherapeutic strategies in this disease, including chimeric antigen receptor (CAR) therapy. Recently, satisfying clinical responses have been obtained in CLL patients using cord blood-derived CAR-NK cells, opening new possibilities for further exploring NK cells in the immunotherapy of CLL. However, notwithstanding the promising results of this clinical trial, more evidence is needed to fully understand whether and in which CLL cases NK cell-based immunotherapy may represent a valid, alternative/additional therapeutic option for this leukemia. In this review, we provide an overview of the current knowledge about phenotypic and functional alterations of NK cells in CLL and the mechanisms by which CLL cells circumvent NK cell-mediated immunosurveillance. Additionally, we discuss the potential relevance of using NK cells in CLL immunotherapy.


Assuntos
Suscetibilidade a Doenças , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucemia Linfocítica Crônica de Células B/etiologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Biomarcadores , Comunicação Celular , Gerenciamento Clínico , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/terapia , Ligantes , Ligação Proteica , Receptores de Células Matadoras Naturais/genética , Receptores de Células Matadoras Naturais/metabolismo , Resultado do Tratamento , Evasão Tumoral/genética , Evasão Tumoral/imunologia
5.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206478

RESUMO

Prevalences of Campylobacter (C.) jejuni infections are progressively rising globally. Given that probiotic feed additives, such as the commercial product Aviguard®, have been shown to be effective in reducing enteropathogens, such as Salmonella, in vertebrates, including livestock, we assessed potential anti-pathogenic and immune-modulatory properties of Aviguard® during acute C. jejuni-induced murine enterocolitis. Therefore, microbiota-depleted IL-10-/- mice were infected with C. jejuni strain 81-176 by gavage and orally treated with Aviguard® or placebo from day 2 to 4 post-infection. The applied probiotic bacteria could be rescued from the intestinal tract of treated mice, but with lower obligate anaerobic bacterial counts in C. jejuni-infected as compared to non-infected mice. Whereas comparable gastrointestinal pathogen loads could be detected in both groups until day 6 post-infection, Aviguard® treatment resulted in improved clinical outcome and attenuated apoptotic cell responses in infected large intestines during acute campylobacteriosis. Furthermore, less distinct pro-inflammatory immune responses could be observed not only in the intestinal tract, but also in extra-intestinal compartments on day 6 post-infection. In conclusion, we show here for the first time that Aviguard® exerts potent disease-alleviating effects in acute C. jejuni-induced murine enterocolitis and might be a promising probiotic treatment option for severe campylobacteriosis in humans.


Assuntos
Infecções por Campylobacter/microbiologia , Infecções por Campylobacter/terapia , Campylobacter jejuni/fisiologia , Enterocolite/microbiologia , Enterocolite/terapia , Probióticos/uso terapêutico , Animais , Biomarcadores , Infecções por Campylobacter/diagnóstico , Citocinas/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Enterocolite/diagnóstico , Microbioma Gastrointestinal , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunidade , Mediadores da Inflamação/metabolismo , Interleucina-10/deficiência , Jejuno/microbiologia , Jejuno/patologia , Camundongos , Camundongos Knockout
6.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206505

RESUMO

Myosins are a remarkable superfamily of actin-based motor proteins that use the energy derived from ATP hydrolysis to translocate actin filaments and to produce force. Myosins are abundant in different types of tissues and involved in a large variety of cellular functions. Several classes of the myosin superfamily are expressed in the nervous system; among them, non-muscle myosin II (NM II) is expressed in both neurons and non-neuronal brain cells, such as astrocytes, oligodendrocytes, endothelial cells, and microglia. In the nervous system, NM II modulates a variety of functions, such as vesicle transport, phagocytosis, cell migration, cell adhesion and morphology, secretion, transcription, and cytokinesis, as well as playing key roles during brain development, inflammation, repair, and myelination functions. In this review, we will provide a brief overview of recent emerging roles of NM II in resting and activated microglia cells, the principal regulators of immune processes in the central nervous system (CNS) in both physiological and pathological conditions. When stimulated, microglial cells react and produce a number of mediators, such as pro-inflammatory cytokines, free radicals, and nitric oxide, that enhance inflammation and contribute to neurodegenerative diseases. Inhibition of NM II could be a new therapeutic target to treat or to prevent CNS diseases.


Assuntos
Microglia/metabolismo , Miosina Tipo II/metabolismo , Animais , Biomarcadores , Movimento Celular/imunologia , Citoesqueleto/metabolismo , Humanos , Microglia/imunologia , Fagocitose/imunologia
7.
Viruses ; 13(7)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208954

RESUMO

There are some reports and case series addressing Coronavirus Disease 2019 (COVID-19) infections during pregnancy in upper income countries, but there are few data on pregnant women with comorbid conditions in low and middle income Countries. This study evaluated the proportion and the maternal and neonatal outcomes associated with SARS-CoV-2 infection among pregnant women with comorbidities. Participants were recruited consecutively in order of admission to a maternity for pregnant women with comorbidities. Sociodemographic, clinical, and laboratory data were prospectively collected during hospitalization. Pregnant women were screened at entry: nasopharyngeal swabs were tested by RT-PCR; serum samples were tested for IgG antibodies against spike protein by ELISA. From April to June 2020, 115 eligible women were included in the study. The proportion of SARS-CoV-2 infection was 28.7%. The rate of obesity was 60.9%, vascular hypertension 40.0%, and HIV 21.7%. The most common clinical presentations were ageusia (21.2%), anosmia (18.2%), and fever (18.2%). Prematurity was higher among mothers who had a SARS-CoV-2 infection based on RT-PCR. There were two cases of fetal demise. We found a high proportion of COVID-19 among pregnant women with comorbidities. This underscores the importance of antenatal care during the pandemic to implement universal SARS-CoV-2 screening, precautionary measures, and the rollout of vaccination programs for pregnant women.


Assuntos
COVID-19/epidemiologia , Imunoglobulina G/sangue , Complicações Infecciosas na Gravidez/epidemiologia , Complicações Infecciosas na Gravidez/virologia , SARS-CoV-2/imunologia , Adulto , COVID-19/imunologia , Estudos de Coortes , Comorbidade , Feminino , Hospitalização , Humanos , Recém-Nascido , Transmissão Vertical de Doenças Infecciosas , Obesidade/complicações , Obesidade/virologia , Projetos Piloto , Gravidez , Gestantes , SARS-CoV-2/genética , Adulto Jovem
8.
Viruses ; 13(7)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209034

RESUMO

Host plasma membrane protein SERINC5 is incorporated into budding retrovirus particles where it blocks subsequent entry into susceptible target cells. Three structurally unrelated proteins encoded by diverse retroviruses, human immunodeficiency virus type 1 (HIV-1) Nef, equine infectious anemia virus (EIAV) S2, and ecotropic murine leukemia virus (MLV) GlycoGag, disrupt SERINC5 antiviral activity by redirecting SERINC5 from the site of virion assembly on the plasma membrane to an internal RAB7+ endosomal compartment. Pseudotyping retroviruses with particular glycoproteins, e.g., vesicular stomatitis virus glycoprotein (VSV G), renders the infectivity of particles resistant to inhibition by virion-associated SERINC5. To better understand viral determinants for SERINC5-sensitivity, the effect of SERINC5 was assessed using HIV-1, MLV, and Mason-Pfizer monkey virus (M-PMV) virion cores, pseudotyped with glycoproteins from Arenavirus, Coronavirus, Filovirus, Rhabdovirus, Paramyxovirus, and Orthomyxovirus genera. SERINC5 restricted virions pseudotyped with glycoproteins from several retroviruses, an orthomyxovirus, a rhabdovirus, a paramyxovirus, and an arenavirus. Infectivity of particles pseudotyped with HIV-1, amphotropic-MLV (A-MLV), or influenza A virus (IAV) glycoproteins, was decreased by SERINC5, whether the core was provided by HIV-1, MLV, or M-PMV. In contrast, particles pseudotyped with glycoproteins from M-PMV, parainfluenza virus 5 (PIV5), or rabies virus (RABV) were sensitive to SERINC5, but only with particular retroviral cores. Resistance to SERINC5 did not correlate with reduced SERINC5 incorporation into particles, route of viral entry, or absolute infectivity of the pseudotyped virions. These findings indicate that some non-retroviruses may be sensitive to SERINC5 and that, in addition to the viral glycoprotein, the retroviral core influences sensitivity to SERINC5.


Assuntos
Interações Hospedeiro-Patógeno , Proteínas de Membrana/genética , Proteínas do Envelope Viral , Vírion/metabolismo , Vírus/metabolismo , Células HEK293 , HIV-1/metabolismo , Humanos , Vírus da Leucemia Murina/metabolismo , Proteínas de Membrana/imunologia , Retroviridae/classificação , Retroviridae/metabolismo , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Vírion/genética , Internalização do Vírus , Vírus/química , Vírus/classificação , Vírus/genética
9.
Viruses ; 13(7)2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209711

RESUMO

In stark contrast to the rapid development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an effective human immunodeficiency virus (HIV) vaccine is still lacking. Furthermore, despite virologic suppression and CD4 T-cell count normalization with antiretroviral therapy (ART), people living with HIV (PLWH) still exhibit increased morbidity and mortality compared to the general population. Such differences in health outcomes are related to higher risk behaviors, but also to HIV-related immune activation and viral coinfections. Among these coinfections, cytomegalovirus (CMV) latent infection is a well-known inducer of long-term immune dysregulation. Cytomegalovirus contributes to the persistent immune activation in PLWH receiving ART by directly skewing immune response toward itself, and by increasing immune activation through modification of the gut microbiota and microbial translocation. In addition, through induction of immunosenescence, CMV has been associated with a decreased response to infections and vaccines. This review provides a comprehensive overview of the influence of CMV on the immune system, the mechanisms underlying a reduced response to vaccines, and discuss new therapeutic advances targeting CMV that could be used to improve vaccine response in PLWH.


Assuntos
Coinfecção/virologia , Infecções por Citomegalovirus/virologia , Citomegalovirus/imunologia , Infecções por HIV/virologia , Vacinas/imunologia , Animais , Fármacos Anti-HIV/uso terapêutico , Ensaios Clínicos como Assunto , Citomegalovirus/patogenicidade , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/imunologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/patologia , Trato Gastrointestinal/virologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Imunossenescência , Inflamação , Infecção Latente/imunologia , Infecção Latente/virologia , Camundongos , Vacinas/administração & dosagem
10.
Nat Commun ; 12(1): 4196, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234131

RESUMO

Monoclonal antibodies targeting a variety of epitopes have been isolated from individuals previously infected with SARS-CoV-2, but the relative contributions of these different antibody classes to the polyclonal response remains unclear. Here we use a yeast-display system to map all mutations to the viral spike receptor-binding domain (RBD) that escape binding by representatives of three potently neutralizing classes of anti-RBD antibodies with high-resolution structures. We compare the antibody-escape maps to similar maps for convalescent polyclonal plasmas, including plasmas from individuals from whom some of the antibodies were isolated. While the binding of polyclonal plasma antibodies are affected by mutations across multiple RBD epitopes, the plasma-escape maps most resemble those of a single class of antibodies that target an epitope on the RBD that includes site E484. Therefore, although the human immune system can produce antibodies that target diverse RBD epitopes, in practice the polyclonal response to infection is skewed towards a single class of antibodies targeting an epitope that is already undergoing rapid evolution.


Assuntos
Anticorpos Antivirais/imunologia , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Sítios de Ligação , COVID-19/imunologia , Epitopos , Antígenos HLA/imunologia , Humanos , Evasão da Resposta Imune/genética , Modelos Moleculares , Mutação , Testes de Neutralização , Domínios Proteicos , SARS-CoV-2/química , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/química
11.
Nat Commun ; 12(1): 4226, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244481

RESUMO

RIFIN, a large family of Plasmodium variant surface antigens, plays a crucial role in malaria pathogenesis by mediating immune suppression through activation of inhibitory receptors such as LAIR1, and antibodies with LAIR1 inserts have been identified that bind infected erythrocytes through RIFIN. However, details of RIFIN-mediated LAIR1 recognition and receptor activation have been unclear. Here, we use negative-stain EM to define the architecture of LAIR1-inserted antibodies and determine crystal structures of RIFIN-variable 2 (V2) domain in complex with a LAIR1 domain. These structures reveal the LAIR1-binding region of RIFIN to be hydrophobic and membrane-distal, to exhibit extensive structural diversity, and to interact with RIFIN-V2 in a one-to-one fashion. Through structural and sequence analysis of various LAIR1 constructs, we identify essential elements of RIFIN-binding on LAIR1. Furthermore, a structure-derived LAIR1-binding sequence signature ascertained >20 LAIR1-binding RIFINs, including some from P. falciparum field strains and Plasmodium species infecting gorillas and chimpanzees.


Assuntos
Antígenos de Protozoários/ultraestrutura , Malária Falciparum/imunologia , Proteínas de Membrana/ultraestrutura , Plasmodium falciparum/imunologia , Proteínas de Protozoários/ultraestrutura , Receptores Imunológicos/ultraestrutura , Anticorpos Antiprotozoários/genética , Anticorpos Antiprotozoários/metabolismo , Variação Antigênica/genética , Antígenos de Protozoários/imunologia , Antígenos de Protozoários/metabolismo , Cristalografia por Raios X , Humanos , Malária Falciparum/parasitologia , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Mutação , Plasmodium falciparum/metabolismo , Domínios Proteicos/genética , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo
12.
Nutrients ; 13(6)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34207960

RESUMO

Psoriasis is an immune-mediated systemic disease that may be treated with probiotics. In this study, probiotic strains that could or could not decrease interleukin (IL)-17 levels were applied to imiquimod (IMQ)-induced psoriasis-like mice via oral administration. Bifidobacteriumadolescentis CCFM667, B. breve CCFM1078, Lacticaseibacillusparacasei CCFM1074, and Limosilactobacillus reuteri CCFM1132 ameliorated psoriasis-like pathological characteristics and suppressed the release of IL-23/T helper cell 17 (Th17) axis-related inflammatory cytokines, whereas B. animalis CCFM1148, L. paracasei CCFM1147, and L. reuteri CCFM1040 neither alleviated the pathological characteristics nor reduced the levels of inflammatory cytokines. All effective strains increased the contents of short-chain fatty acids, which were negatively correlated with the levels of inflammatory cytokines. By performing 16S rRNA gene sequencing, the diversity of gut microbiota in psoriasis-like mice was found to decrease, but all effective strains made some specific changes to the composition of gut microbiota compared to the ineffective strains. Furthermore, except for B. breve CCFM1078, all other effective strains decreased the abundance of the family Rikenellaceae, which was positively correlated with psoriasis-like pathological characteristics and was negatively correlated with propionate levels. These findings demonstrated effects of strain-specificity, and how probiotics ameliorated psoriasis and provide new possibilities for the treatment of psoriasis.


Assuntos
Microbioma Gastrointestinal , Probióticos/uso terapêutico , Psoríase/dietoterapia , Psoríase/microbiologia , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Bifidobacterium/fisiologia , Citocinas/imunologia , Citocinas/metabolismo , Ácidos Graxos Voláteis/metabolismo , Fezes/microbiologia , Feminino , Imiquimode , Interleucinas/análise , Interleucinas/metabolismo , Lactobacillaceae/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Probióticos/farmacologia , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Células Th17/imunologia
13.
Nat Commun ; 12(1): 4098, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215730

RESUMO

Tumor infiltration by T cells is paramount for effective anti-cancer immune responses. We hypothesized that the T cell receptor (TCR) repertoire of tumor infiltrating T lymphocytes could therefore be indicative of the functional state of these cells and determine disease course at different stages in cancer progression. Here we show that the diversity of the TCR of tumor infiltrating T cell at baseline is prognostic in various cancers, whereas the TCR clonality of T cell infiltrating metastatic melanoma pre-treatment is predictive for activity and efficacy of PD1 blockade immunotherapy.


Assuntos
Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Biópsia , Estudos de Coortes , Feminino , Humanos , Imunoterapia , Masculino , Melanoma/patologia , Melanoma/terapia , Pessoa de Meia-Idade , Prognóstico , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Taxa de Sobrevida
14.
Nat Commun ; 12(1): 4117, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226537

RESUMO

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.


Assuntos
COVID-19/complicações , COVID-19/imunologia , Síndrome da Liberação de Citocina/complicações , Monócitos/patologia , Ativação de Neutrófilo , Idoso , Células Apresentadoras de Antígenos/imunologia , COVID-19/sangue , COVID-19/virologia , Estudos de Casos e Controles , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/virologia , Citocinas/sangue , Armadilhas Extracelulares/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença
15.
Nat Commun ; 12(1): 4144, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34230476

RESUMO

To investigate the duration of humoral immune response in convalescent coronavirus disease 2019 (COVID-19) patients, we conduct a 12-month longitudinal study through collecting a total of 1,782 plasma samples from 869 convalescent plasma donors in Wuhan, China and test specific antibody responses. The results show that positive rate of IgG antibody against receptor-binding domain of spike protein (RBD-IgG) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the COVID-19 convalescent plasma donors exceeded 70% for 12 months post diagnosis. The level of RBD-IgG decreases with time, with the titer stabilizing at 64.3% of the initial level by the 9th month. Moreover, male plasma donors produce more RBD-IgG than female, and age of the patients positively correlates with the RBD-IgG titer. A strong positive correlation between RBD-IgG and neutralizing antibody titers is also identified. These results facilitate our understanding of SARS-CoV-2-induced immune memory to promote vaccine and therapy development.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Imunoglobulina G/sangue , Receptores Virais/imunologia , SARS-CoV-2/imunologia , Adulto , Animais , Doadores de Sangue , COVID-19/terapia , Linhagem Celular , China , Chlorocebus aethiops , Convalescença , Feminino , Humanos , Imunidade Humoral/imunologia , Imunização Passiva , Memória Imunológica/imunologia , Estudos Longitudinais , Masculino , Fatores Sexuais , Glicoproteína da Espícula de Coronavírus/imunologia , Células Vero
16.
Nat Commun ; 12(1): 4193, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234122

RESUMO

Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.


Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/imunologia , Neoplasias Nasofaríngeas/imunologia , Evasão Tumoral/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/imunologia , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p15/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Regulação Viral da Expressão Gênica/imunologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Metionina Adenosiltransferase/antagonistas & inibidores , Metionina Adenosiltransferase/metabolismo , Camundongos , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/virologia , Nasofaringe/imunologia , Nasofaringe/patologia , Nasofaringe/cirurgia , Nasofaringe/virologia , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Deleção de Sequência , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Evasão Tumoral/efeitos dos fármacos , Sequenciamento Completo do Genoma , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Nat Commun ; 12(1): 4175, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234126

RESUMO

Although we can now measure single-cell signaling responses with multivariate, high-throughput techniques our ability to interpret such measurements is still limited. Even interpretation of dose-response based on single-cell data is not straightforward: signaling responses can differ significantly between cells, encompass multiple signaling effectors, and have dynamic character. Here, we use probabilistic modeling and information-theory to introduce fractional response analysis (FRA), which quantifies changes in fractions of cells with given response levels. FRA can be universally performed for heterogeneous, multivariate, and dynamic measurements and, as we demonstrate, quantifies otherwise hidden patterns in single-cell data. In particular, we show that fractional responses to type I interferon in human peripheral blood mononuclear cells are very similar across different cell types, despite significant differences in mean or median responses and degrees of cell-to-cell heterogeneity. Further, we demonstrate that fractional responses to cytokines scale linearly with the log of the cytokine dose, which uncovers that heterogeneous cellular populations are sensitive to fold-changes in the dose, as opposed to additive changes.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Interferon Tipo I/metabolismo , Leucócitos Mononucleares/metabolismo , Modelos Imunológicos , Células 3T3 , Animais , Voluntários Saudáveis , Humanos , Interferon Tipo I/imunologia , Leucócitos Mononucleares/imunologia , Camundongos , Modelos Estatísticos , Cultura Primária de Células , Transdução de Sinais/imunologia , Análise de Célula Única , Software
18.
Nat Commun ; 12(1): 4210, 2021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244522

RESUMO

Neutralizing antibodies (nAbs) to SARS-CoV-2 hold powerful potentials for clinical interventions against COVID-19 disease. However, their common genetic and biologic features remain elusive. Here we interrogate a total of 165 antibodies from eight COVID-19 patients, and find that potent nAbs from different patients have disproportionally high representation of IGHV3-53/3-66 usage, and therefore termed as public antibodies. Crystal structural comparison of these antibodies reveals they share similar angle of approach to RBD, overlap in buried surface and binding residues on RBD, and have substantial spatial clash with receptor angiotensin-converting enzyme-2 (ACE2) in binding to RBD. Site-directed mutagenesis confirms these common binding features although some minor differences are found. One representative antibody, P5A-3C8, demonstrates extraordinarily protective efficacy in a golden Syrian hamster model against SARS-CoV-2 infection. However, virus escape analysis identifies a single natural mutation in RBD, namely K417N found in B.1.351 variant from South Africa, abolished the neutralizing activity of these public antibodies. The discovery of public antibodies and shared escape mutation highlight the intricate relationship between antibody response and SARS-CoV-2, and provide critical reference for the development of antibody and vaccine strategies to overcome the antigenic variation of SARS-CoV-2.


Assuntos
Enzima de Conversão de Angiotensina 2/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Receptores Virais/imunologia , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Sítios de Ligação/imunologia , COVID-19/imunologia , Cricetinae , Modelos Animais de Doenças , Epitopos/imunologia , Feminino , Humanos , Masculino , Testes de Neutralização , Receptores de Antígenos de Linfócitos B/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia
19.
Virulence ; 12(1): 1771-1794, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34251989

RESUMO

Coronavirus disease 2019 (COVID-19) is a highly infectious viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Laboratory findings from a significant number of patients with COVID-19 indicate the occurrence of leukocytopenia, specifically lymphocytopenia. Moreover, infected patients can experience contrasting outcomes depending on lymphocytopenia status. Patients with resolved lymphocytopenia are more likely to recover, whereas critically ill patients with signs of unresolved lymphocytopenia develop severe complications, sometimes culminating in death. Why immunodepression manifests in patients with COVID-19 remains unclear. Therefore, the evaluation of clinical symptoms and laboratory findings from infected patients is critical for understanding the disease course and its consequences. In this review, we take a logical approach to unravel the reasons for immunodepression in patients with COVID-19. Following the footprints of the virus within host tissues, from entry to exit, we extrapolate the mechanisms underlying the phenomenon of immunodepression.


Assuntos
COVID-19/imunologia , Tolerância Imunológica , SARS-CoV-2/patogenicidade , COVID-19/patologia , Morte Celular , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Citocinas/metabolismo , Humanos , Imunidade , Linfopenia/imunologia , Linfopenia/patologia , SARS-CoV-2/fisiologia , Replicação Viral
20.
Sci Rep ; 11(1): 14275, 2021 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253751

RESUMO

SARS-CoV-2 infection is characterized by a highly variable clinical course with patients experiencing asymptomatic infection all the way to requiring critical care support. This variation in clinical course has led physicians and scientists to study factors that may predispose certain individuals to more severe clinical presentations in hopes of either identifying these individuals early in their illness or improving their medical management. We sought to understand immunogenomic differences that may result in varied clinical outcomes through analysis of T-cell receptor sequencing (TCR-Seq) data in the open access ImmuneCODE database. We identified two cohorts within the database that had clinical outcomes data reflecting severity of illness and utilized DeepTCR, a multiple-instance deep learning repertoire classifier, to predict patients with severe SARS-CoV-2 infection from their repertoire sequencing. We demonstrate that patients with severe infection have repertoires with higher T-cell responses associated with SARS-CoV-2 epitopes and identify the epitopes that result in these responses. Our results provide evidence that the highly variable clinical course seen in SARS-CoV-2 infection is associated to certain antigen-specific responses.


Assuntos
COVID-19/imunologia , Epitopos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , SARS-CoV-2/imunologia , Infecções Assintomáticas/epidemiologia , COVID-19/patologia , COVID-19/virologia , Aprendizado Profundo , Humanos , Receptores de Antígenos de Linfócitos T/genética , SARS-CoV-2/patogenicidade , Linfócitos T/imunologia , Linfócitos T/virologia
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