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1.
Nat Commun ; 12(1): 2055, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824342

RESUMO

Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations.


Assuntos
Antivirais/farmacologia , /virologia , Reações Cruzadas/imunologia , Imunoensaio/métodos , Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Citocinas/metabolismo , Células HEK293 , Pessoal de Saúde , Humanos , Imunoglobulina G/imunologia , Memória Imunológica , Interferon gama/metabolismo , Pandemias , Peptídeos/metabolismo , /efeitos dos fármacos
2.
Cell ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33852911

RESUMO

Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.

3.
Nat Commun ; 12(1): 1951, 2021 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-33782398

RESUMO

Serological detection of antibodies to SARS-CoV-2 is essential for establishing rates of seroconversion in populations, and for seeking evidence for a level of antibody that may be protective against COVID-19 disease. Several high-performance commercial tests have been described, but these require centralised laboratory facilities that are comparatively expensive, and therefore not available universally. Red cell agglutination tests do not require special equipment, are read by eye, have short development times, low cost and can be applied at the Point of Care. Here we describe a quantitative Haemagglutination test (HAT) for the detection of antibodies to the receptor binding domain of the SARS-CoV-2 spike protein. The HAT has a sensitivity of 90% and specificity of 99% for detection of antibodies after a PCR diagnosed infection. We will supply aliquots of the test reagent sufficient for ten thousand test wells free of charge to qualified research groups anywhere in the world.


Assuntos
Anticorpos Antivirais/análise , /diagnóstico , Testes de Hemaglutinação/métodos , Glicoproteína da Espícula de Coronavírus/imunologia , Testes de Aglutinação/métodos , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , /imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Humanos , Sistemas Automatizados de Assistência Junto ao Leito , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Soroconversão
4.
Cell ; 184(9): 2348-2361.e6, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33730597

RESUMO

The race to produce vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began when the first sequence was published, and this forms the basis for vaccines currently deployed globally. Independent lineages of SARS-CoV-2 have recently been reported: UK, B.1.1.7; South Africa, B.1.351; and Brazil, P.1. These variants have multiple changes in the immunodominant spike protein that facilitates viral cell entry via the angiotensin-converting enzyme-2 (ACE2) receptor. Mutations in the receptor recognition site on the spike are of great concern for their potential for immune escape. Here, we describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor-binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K, although K417N and N501Y act together against some important antibody classes. In a number of cases, it would appear that convalescent and some vaccine serum offers limited protection against this variant.


Assuntos
/sangue , /imunologia , Animais , Anticorpos Monoclonais/imunologia , /terapia , Chlorocebus aethiops , Ensaios Clínicos como Assunto , Células HEK293 , Humanos , Imunização Passiva , Modelos Moleculares , Mutação/genética , Testes de Neutralização , Ligação Proteica , /genética , Células Vero
5.
Cell ; 184(8): 2201-2211.e7, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33743891

RESUMO

SARS-CoV-2 has caused over 2 million deaths in little over a year. Vaccines are being deployed at scale, aiming to generate responses against the virus spike. The scale of the pandemic and error-prone virus replication is leading to the appearance of mutant viruses and potentially escape from antibody responses. Variant B.1.1.7, now dominant in the UK, with increased transmission, harbors 9 amino acid changes in the spike, including N501Y in the ACE2 interacting surface. We examine the ability of B.1.1.7 to evade antibody responses elicited by natural SARS-CoV-2 infection or vaccination. We map the impact of N501Y by structure/function analysis of a large panel of well-characterized monoclonal antibodies. B.1.1.7 is harder to neutralize than parental virus, compromising neutralization by some members of a major class of public antibodies through light-chain contacts with residue 501. However, widespread escape from monoclonal antibodies or antibody responses generated by natural infection or vaccination was not observed.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , /imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Células CHO , Chlorocebus aethiops , Cricetulus , Células HEK293 , Humanos , Pandemias , Ligação Proteica , Relação Estrutura-Atividade , Células Vero
6.
Cell ; 184(8): 2183-2200.e22, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33756110

RESUMO

Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50 < 0.1 µg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Sítios de Ligação de Anticorpos , Células CHO , Chlorocebus aethiops , Cricetulus , Epitopos , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Ligação Proteica , Estrutura Terciária de Proteína , Células Vero
7.
Infect Immun ; 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649051

RESUMO

Shigella is a leading cause of moderate-to-severe diarrhea globally and the causative agent of shigellosis and bacillary dysentery. Associated with 80-165 million cases of diarrhea and over 13% of diarrheal deaths, in many regions Shigella exposure is ubiquitous while infection is heterogenous. To characterize host-genetic susceptibility to Shigella-associated diarrhea, we performed two independent genome-wide association studies (GWAS) including Bangladeshi infants from the PROVIDE and CBC birth cohorts in Dhaka, Bangladesh. Cases were infants with Shigella-associated diarrhea (n=143) and controls were infants with no Shigella-associated diarrhea in the first 13 months of life (n=446). Shigella-associated diarrhea was identified via qPCR Ct distributions for the ipaH gene, carried by all four Shigella species and enteroinvasive Escherichia coli Host GWAS were performed under an additive genetic model. A joint analysis identified protective loci on chromosomes 11 (rs582240, within the KRT18P59 pseudogene, P=6.40x10-8, OR=0.43) and 8 (rs12550437, within the lincRNA RP11-115J16.1, P=1.49x10-7, OR=0.48). Conditional analyses identified two previously suggestive loci, a protective locus on chromosome 7 (rs10266841, within the 3'-UTR of CYTH3, Pconditional=1.48x10-7, OR=0.44) and a risk-associated locus on chromosome 10 (rs2801847, an intronic variant within MPP7, Pconditional=8.37x10-8, OR=5.51). These loci have all been indirectly linked to bacterial Type 3 Secretion System (T3SS) activity, its components, and bacterial effectors delivered into host cells. Host genetic factors that may affect bacterial T3SS activity and are associated with the host response to Shigella-associated diarrhea may provide insight into vaccine and drug development efforts for Shigella-associated diarrheal disease.

8.
Nat Med ; 27(4): 653-658, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33619371

RESUMO

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.


Assuntos
Ferro/deficiência , Malária/complicações , Absorção Fisiológica , Adolescente , África , Criança , Pré-Escolar , Feminino , Geografia , Hepcidinas/metabolismo , Humanos , Lactente , Masculino , Análise da Randomização Mendeliana , Traço Falciforme/complicações
9.
Wellcome Open Res ; 5: 181, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33283055

RESUMO

Background: Laboratory diagnosis of SARS-CoV-2 infection (the cause of COVID-19) uses PCR to detect viral RNA (vRNA) in respiratory samples. SARS-CoV-2 RNA has also been detected in other sample types, but there is limited understanding of the clinical or laboratory significance of its detection in blood. Methods: We undertook a systematic literature review to assimilate the evidence for the frequency of vRNA in blood, and to identify associated clinical characteristics. We performed RT-PCR in serum samples from a UK clinical cohort of acute and convalescent COVID-19 cases (n=212), together with convalescent plasma samples collected by NHS Blood and Transplant (NHSBT) (n=462 additional samples). To determine whether PCR-positive blood samples could pose an infection risk, we attempted virus isolation from a subset of RNA-positive samples. Results: We identified 28 relevant studies, reporting SARS-CoV-2 RNA in 0-76% of blood samples; pooled estimate 10% (95%CI 5-18%). Among serum samples from our clinical cohort, 27/212 (12.7%) had SARS-CoV-2 RNA detected by RT-PCR. RNA detection occurred in samples up to day 20 post symptom onset, and was associated with more severe disease (multivariable odds ratio 7.5). Across all samples collected ≥28 days post symptom onset, 0/494 (0%, 95%CI 0-0.7%) had vRNA detected. Among our PCR-positive samples, cycle threshold (ct) values were high (range 33.5-44.8), suggesting low vRNA copy numbers. PCR-positive sera inoculated into cell culture did not produce any cytopathic effect or yield an increase in detectable SARS-CoV-2 RNA. There was a relationship between RT-PCR negativity and the presence of total SARS-CoV-2 antibody (p=0.02). Conclusions: vRNA was detectable at low viral loads in a minority of serum samples collected in acute infection, but was not associated with infectious SARS-CoV-2 (within the limitations of the assays used). This work helps to inform biosafety precautions for handling blood products from patients with current or previous COVID-19.

10.
EBioMedicine ; 62: 103123, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33248371

RESUMO

BACKGROUND: Antibodies against the HPV16 oncoprotein E6 are promising biomarkers for HPV16-driven oropharyngeal cancer (HPV16-OPC) due to their high sensitivity and specificity, and prospective manifestation. In previous studies, 0•7% of controls without HPV-associated malignancies were HPV16 E6 seropositive of which only a minority is expected to develop HPV16-driven cancer. We aimed to characterise HPV16 E6 antibodies in individuals without HPV-associated malignancies. METHODS: We analysed serum antibodies against HPV16 E6, E7, L1 and HPV18 L1 in a random sample (n = 9,695) of the prospective UK Biobank cohort (UKB). Excluding individuals with potentially HPV-associated malignancies (n = 192), we assessed risk factors for seropositivity by logistic regression. FINDINGS: In individuals without potentially HPV-associated malignancies (n = 9,503), the HPV16 E6 seroprevalence was 0•8%. Seropositivity against HPV16 E6 and all other HPV antigens was strongly associated with sexual behaviour. The seroprevalence of HPV16 E6, L1 and HPV18 L1 increased with the number of lifetime sex partners (ptrend<0•005), and all HPV antibodies were associated with same-sex intercourse (ORE6 3•1, 95%CI 1•4-6•9; reference category: no same-sex intercourse). HPV16 E6 and L1 seropositivity were associated with young age (≤17 years) at sexual debut (ORE6 2•0, 95%CI 1•1-3•7) compared with individuals reporting sexual debut at age ≥20 years. INTERPRETATION: This is the first study characterising HPV16 E6 antibodies in the general UK population. Their strong association with sexual behaviour, and overlapping risk factor profiles with other HPV antibodies support their relevance for HPV16-OPC disease prediction. However, additional risk stratification will be required to identify individuals at highest risk to develop HPV16-OPC.

11.
Am J Clin Nutr ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184625

RESUMO

BACKGROUND: The number of gluten-free diet followers without celiac disease (CD) is increasing. However, little is known about the characteristics of these individuals. OBJECTIVES: We address this issue by investigating a wide range of genetic and phenotypic characteristics in association with following a gluten-free diet. METHODS: The cross-sectional association between lifestyle and health-related characteristics and following a gluten-free diet was investigated in 124,447 women and men aged 40-69 y from the population-based UK Biobank study. A genome-wide association study (GWAS) of following a gluten-free diet was performed. RESULTS: A total of 1776 (1.4%) participants reported following a gluten-free diet. Gluten-free diet followers were more likely to be women, nonwhite, highly educated, living in more socioeconomically deprived areas, former smokers, have lost weight in the past year, have poorer self-reported health, and have made dietary changes as a result of illness. Conversely, these individuals were less likely to consume alcohol daily, be overweight or obese, have hypertension, or use cholesterol-lowering medication. Participants with hospital inpatient diagnosed blood and immune mechanism disorders (OR: 1.62; 95% CI: 1.18, 2.21) and non-CD digestive system diseases (OR: 1.58; 95% CI: 1.42, 1.77) were more likely to follow a gluten-free diet. The GWAS demonstrated that no genetic variants were associated with being a gluten-free diet follower. CONCLUSIONS: Gluten-free diet followers have a better cardiovascular risk profile than non-gluten-free diet followers but poorer self-reported health and a higher prevalence of blood and immune disorders and digestive conditions. Reasons for following a gluten-free diet warrant further investigation.

12.
Euro Surveill ; 25(42)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33094717

RESUMO

SARS-CoV-2 IgG screening of 1,000 antenatal serum samples in the Oxford area, United Kingdom, between 14 April and 15 June 2020, yielded a 5.3% seroprevalence, mirroring contemporaneous regional data. Among the 53 positive samples, 39 showed in vitro neutralisation activity, correlating with IgG titre (Pearson's correlation p<0.0001). While SARS-CoV-2 seroprevalence in pregnancy cohorts could potentially inform population surveillance, clinical correlates of infection and immunity in pregnancy, and antenatal epidemiology evolution over time need further study.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Imunoglobulina G/sangue , Pandemias , Pneumonia Viral/epidemiologia , Vigilância da População , Complicações Infecciosas na Gravidez/sangue , Primeiro Trimestre da Gravidez/sangue , Adolescente , Adulto , Estudos de Coortes , Infecções por Coronavirus/sangue , Inglaterra/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pessoa de Meia-Idade , Pneumonia Viral/sangue , Gravidez , Diagnóstico Pré-Natal , Prevalência , Estudos Soroepidemiológicos , Método Simples-Cego , Adulto Jovem
13.
Euro Surveill ; 25(42)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33094713

RESUMO

BackgroundThe progression and geographical distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United Kingdom (UK) and elsewhere is unknown because typically only symptomatic individuals are diagnosed. We performed a serological study of blood donors in Scotland in the spring of 2020 to detect neutralising antibodies to SARS-CoV-2 as a marker of past infection and epidemic progression.AimOur objective was to determine if sera from blood bank donors can be used to track the emergence and progression of the SARS-CoV-2 epidemic.MethodsA pseudotyped SARS-CoV-2 virus microneutralisation assay was used to detect neutralising antibodies to SARS-CoV-2. The study comprised samples from 3,500 blood donors collected in Scotland between 17 March and 18 May 2020. Controls were collected from 100 donors in Scotland during 2019.ResultsAll samples collected on 17 March 2020 (n = 500) were negative in the pseudotyped SARS-CoV-2 virus microneutralisation assay. Neutralising antibodies were detected in six of 500 donors from 23 to 26 March. The number of samples containing neutralising antibodies did not significantly rise after 5-6 April until the end of the study on 18 May. We found that infections were concentrated in certain postcodes, indicating that outbreaks of infection were extremely localised. In contrast, other areas remained comparatively untouched by the epidemic.ConclusionAlthough blood donors are not representative of the overall population, we demonstrated that serosurveys of blood banks can serve as a useful tool for tracking the emergence and progression of an epidemic such as the SARS-CoV-2 outbreak.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Betacoronavirus/imunologia , Doadores de Sangue , Infecções por Coronavirus/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Vigilância da População , Adulto , Análise por Conglomerados , Infecções por Coronavirus/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Geografia Médica , Humanos , Concentração Inibidora 50 , Masculino , Modelos Imunológicos , Testes de Neutralização , Pneumonia Viral/sangue , Prevalência , Escócia/epidemiologia , Sensibilidade e Especificidade , Estudos Soroepidemiológicos , População Urbana
14.
Nat Immunol ; 21(11): 1336-1345, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32887977

RESUMO

The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide-MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.


Assuntos
Antígenos Virais/imunologia , Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/prevenção & controle , Epitopos de Linfócito T/imunologia , Humanos , Epitopos Imunodominantes/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Glicoproteína da Espícula de Coronavírus/imunologia , Reino Unido , Vacinas Virais/imunologia
15.
Elife ; 92020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32820721

RESUMO

We conducted voluntary Covid-19 testing programmes for symptomatic and asymptomatic staff at a UK teaching hospital using naso-/oro-pharyngeal PCR testing and immunoassays for IgG antibodies. 1128/10,034 (11.2%) staff had evidence of Covid-19 at some time. Using questionnaire data provided on potential risk-factors, staff with a confirmed household contact were at greatest risk (adjusted odds ratio [aOR] 4.82 [95%CI 3.45-6.72]). Higher rates of Covid-19 were seen in staff working in Covid-19-facing areas (22.6% vs. 8.6% elsewhere) (aOR 2.47 [1.99-3.08]). Controlling for Covid-19-facing status, risks were heterogenous across the hospital, with higher rates in acute medicine (1.52 [1.07-2.16]) and sporadic outbreaks in areas with few or no Covid-19 patients. Covid-19 intensive care unit staff were relatively protected (0.44 [0.28-0.69]), likely by a bundle of PPE-related measures. Positive results were more likely in Black (1.66 [1.25-2.21]) and Asian (1.51 [1.28-1.77]) staff, independent of role or working location, and in porters and cleaners (2.06 [1.34-3.15]).


Assuntos
Infecções por Coronavirus/epidemiologia , Pessoal de Saúde/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Infecções Assintomáticas/epidemiologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Feminino , Hospitais de Ensino/estatística & dados numéricos , Humanos , Incidência , Transmissão de Doença Infecciosa do Paciente para o Profissional/estatística & dados numéricos , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Risco , Inquéritos e Questionários , Reino Unido/epidemiologia , Adulto Jovem
16.
Nat Commun ; 11(1): 3849, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737300

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR = 5.71(1.58-7.12)), HIV positivity (OR = 2.22(1.32-3.73)) and living in a more rural area (OR = 1.38(1.01-1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p = 6.64 × 10-09). For EBV, associations are identified for VCA (rs71542439, p = 1.15 × 10-12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p = 5.24 × 10-44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission.


Assuntos
Anticorpos Antivirais/biossíntese , Resistência à Doença/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Henipavirus/genética , Interações Hospedeiro-Patógeno/genética , Sarcoma de Kaposi/genética , Adolescente , Adulto , Antígenos Virais/genética , Antígenos Virais/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Coinfecção , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , HIV/genética , HIV/imunologia , HIV/patogenicidade , Cadeias alfa de HLA-DQ/genética , Cadeias alfa de HLA-DQ/imunologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/imunologia , Infecções por Henipavirus/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Herpesvirus Humano 8/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , População Rural , Sarcoma de Kaposi/epidemiologia , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/virologia , Uganda/epidemiologia , População Urbana
17.
Nature ; 583(7817): 572-577, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32641827

RESUMO

The possibility of voyaging contact between prehistoric Polynesian and Native American populations has long intrigued researchers. Proponents have pointed to the existence of New World crops, such as the sweet potato and bottle gourd, in the Polynesian archaeological record, but nowhere else outside the pre-Columbian Americas1-6, while critics have argued that these botanical dispersals need not have been human mediated7. The Norwegian explorer Thor Heyerdahl controversially suggested that prehistoric South American populations had an important role in the settlement of east Polynesia and particularly of Easter Island (Rapa Nui)2. Several limited molecular genetic studies have reached opposing conclusions, and the possibility continues to be as hotly contested today as it was when first suggested8-12. Here we analyse genome-wide variation in individuals from islands across Polynesia for signs of Native American admixture, analysing 807 individuals from 17 island populations and 15 Pacific coast Native American groups. We find conclusive evidence for prehistoric contact of Polynesian individuals with Native American individuals (around AD 1200) contemporaneous with the settlement of remote Oceania13-15. Our analyses suggest strongly that a single contact event occurred in eastern Polynesia, before the settlement of Rapa Nui, between Polynesian individuals and a Native American group most closely related to the indigenous inhabitants of present-day Colombia.


Assuntos
Fluxo Gênico/genética , Genoma Humano/genética , Migração Humana/história , Índios Centro-Americanos/genética , Índios Sul-Americanos/genética , Ilhas , Grupo com Ancestrais Oceânicos/genética , América Central/etnologia , Colômbia/etnologia , Europa (Continente)/etnologia , Genética Populacional , História Medieval , Humanos , Polimorfismo de Nucleotídeo Único/genética , Polinésia , América do Sul/etnologia , Fatores de Tempo
18.
Sci Rep ; 10(1): 9004, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488134

RESUMO

Rheumatic heart disease (RHD), an autoinflammatory heart disease, was recently declared a global health priority by the World Health Organization. Here we report a genome-wide association study (GWAS) of RHD susceptibility in 1,163 South Asians (672 cases; 491 controls) recruited in India and Fiji. We analysed directly obtained and imputed genotypes, and followed-up associated loci in 1,459 Europeans (150 cases; 1,309 controls) from the UK Biobank study. We identify a novel susceptibility signal in the class III region of the human leukocyte antigen (HLA) complex in the South Asian dataset that clearly replicates in the Europeans (rs201026476; combined odds ratio 1.81, 95% confidence intervals 1.51-2.18, P = 3.48×10-10). Importantly, this signal remains despite conditioning on the lead class I and class II variants (P = 0.00033). These findings suggest the class III region is a key determinant of RHD susceptibility offering important new insight into pathogenesis while partly explaining the inconsistency of earlier reports.

19.
Clin Infect Dis ; 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32507899

RESUMO

BACKGROUND: Iron deficiency (ID) and malaria are common causes of ill-health and disability among children living in sub-Saharan Africa. Although iron is critical for the acquisition of humoral immunity, little is known about the effects of ID on antibody responses to Plasmodium falciparum malaria. METHODS: The study included 1,794 Kenyan and Ugandan children aged 0-7 years. We measured biomarkers of iron and inflammation, and antibodies to P falciparum antigens including apical merozoite antigen 1 (anti-AMA-1) and merozoite surface antigen 1 (anti-MSP-1) in cross-sectional and longitudinal studies. RESULTS: The overall prevalence of ID was 31%. ID was associated with lower anti-AMA-1 and anti-MSP-1 antibody levels in pooled analyses adjusted for age, gender, study site, inflammation and P falciparum parasitemia (adjusted mean difference on a log-transformed scale (ß) -0.46; 95 CI -0.66, -0.25 P <0.0001; ß -0.33; 95 CI -0.50, -0.16 P <0.0001, respectively). Additional covariates for malaria exposure index, previous malaria episodes, and time since last malaria episode, were available for individual cohorts. Meta-analysis was used to allow for these adjustments giving ß -0.34; -0.52, -0.16 for anti-AMA-1 antibodies and ß -0.26; -0.41, -0.11 for anti-MSP-1 antibodies. Low transferrin saturation was similarly associated with reduced anti-AMA1 antibody levels. Lower AMA-1 and MSP-1 specific antibody levels persisted over time in iron-deficient children. CONCLUSIONS: Reduced levels of P. falciparum-specific antibodies in iron-deficient children might reflect impaired acquisition of immunity to malaria and/or reduced malaria exposure. Strategies to prevent and treat ID may influence antibody responses to malaria for children living in sub-Saharan Africa.

20.
bioRxiv ; 2020 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-32577665

RESUMO

COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFNγ based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4 + and/or CD8 + epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8 + T cells than spike-specific CD8 + T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8 + to CD4 + T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.

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