RESUMO
The Coronaviridae are a family of viruses that cause disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E), and glycosaminoglycans (for OC43). Additionally, we identified phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol kinases and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle and the development of host-directed therapies.
Assuntos
COVID-19/genética , Infecções por Coronavirus/genética , Coronavirus/fisiologia , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno , SARS-CoV-2/fisiologia , Células A549 , Animais , Vias Biossintéticas/efeitos dos fármacos , COVID-19/virologia , Linhagem Celular , Chlorocebus aethiops , Colesterol/biossíntese , Colesterol/metabolismo , Análise por Conglomerados , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Resfriado Comum/genética , Resfriado Comum/virologia , Coronavirus/classificação , Infecções por Coronavirus/virologia , Técnicas de Inativação de Genes , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Camundongos , Fosfatidilinositóis/biossíntese , Células Vero , Internalização do Vírus/efeitos dos fármacos , Replicação ViralRESUMO
Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.
Assuntos
Asma/imunologia , Redes Reguladoras de Genes/imunologia , Transcriptoma/imunologia , Viroses/imunologia , Adolescente , Asma/genética , Asma/virologia , Estudos de Casos e Controles , Criança , Resfriado Comum/genética , Resfriado Comum/imunologia , Resfriado Comum/virologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Viroses/genética , Viroses/virologiaRESUMO
The ability to directly uncover the contributions of genes to a given phenotype is fundamental for biology research. However, ostensibly homogeneous cell populations exhibit large clonal variance that can confound analyses and undermine reproducibility. Here we used genome-saturated mutagenesis to create a biobank of over 100,000 individual haploid mouse embryonic stem (mES) cell lines targeting 16,970 genes with genetically barcoded, conditional and reversible mutations. This Haplobank is, to our knowledge, the largest resource of hemi/homozygous mutant mES cells to date and is available to all researchers. Reversible mutagenesis overcomes clonal variance by permitting functional annotation of the genome directly in sister cells. We use the Haplobank in reverse genetic screens to investigate the temporal resolution of essential genes in mES cells, and to identify novel genes that control sprouting angiogenesis and lineage specification of blood vessels. Furthermore, a genome-wide forward screen with Haplobank identified PLA2G16 as a host factor that is required for cytotoxicity by rhinoviruses, which cause the common cold. Therefore, clones from the Haplobank combined with the use of reversible technologies enable high-throughput, reproducible, functional annotation of the genome.
Assuntos
Bancos de Espécimes Biológicos , Genômica/métodos , Haploidia , Células-Tronco Embrionárias Murinas/metabolismo , Mutação , Animais , Vasos Sanguíneos/citologia , Linhagem da Célula/genética , Resfriado Comum/genética , Resfriado Comum/virologia , Genes Essenciais/genética , Testes Genéticos , Células HEK293 , Homozigoto , Humanos , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Neovascularização Fisiológica/genética , Fosfolipases A2 Independentes de Cálcio/genética , Fosfolipases A2 Independentes de Cálcio/metabolismo , Rhinovirus/patogenicidadeRESUMO
Severe acute respiratory coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is of zoonotic origin. Evolutionary analyses assessing whether coronaviruses similar to SARS-CoV-2 infected ancestral species of modern-day animal hosts could be useful in identifying additional reservoirs of potentially dangerous coronaviruses. We reasoned that if a clade of species has been repeatedly exposed to a virus, then their proteins relevant for viral entry may exhibit adaptations that affect host susceptibility or response. We perform comparative analyses across the mammalian phylogeny of angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, in order to uncover evidence for selection acting at its binding interface with the SARS-CoV-2 spike protein. We uncover that in rodents there is evidence for adaptive amino acid substitutions at positions comprising the ACE2-spike interaction interface, whereas the variation within ACE2 proteins in primates and some other mammalian clades is not consistent with evolutionary adaptations. We also analyze aminopeptidase N (APN), the receptor for the human coronavirus 229E, a virus that causes the common cold, and find evidence for adaptation in primates. Altogether, our results suggest that the rodent and primate lineages may have had ancient exposures to viruses similar to SARS-CoV-2 and HCoV-229E, respectively.
Assuntos
COVID-19/genética , COVID-19/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/virologia , SARS-CoV-2/genética , Adaptação Fisiológica/genética , Substituição de Aminoácidos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/fisiologia , Animais , Antígenos CD13/genética , Antígenos CD13/fisiologia , Resfriado Comum/genética , Resfriado Comum/virologia , Biologia Computacional , Coronavirus Humano 229E/genética , Coronavirus Humano 229E/fisiologia , Evolução Molecular , Genômica , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/fisiologia , Especificidade de Hospedeiro/genética , Especificidade de Hospedeiro/fisiologia , Humanos , Mamíferos/genética , Mamíferos/virologia , Filogenia , Domínios e Motivos de Interação entre Proteínas/genética , Receptores Virais/genética , Receptores Virais/fisiologia , SARS-CoV-2/fisiologia , Seleção Genética , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/fisiologia , Internalização do VírusRESUMO
Rhinovirus (RV) is the most prevalent human respiratory virus and is responsible for at least half of all common colds. RV infections may result in a broad spectrum of effects that range from asymptomatic infections to severe lower respiratory illnesses. The basis for inter-individual variation in the response to RV infection is not well understood. In this study, we explored whether host genetic variation is associated with variation in gene expression response to RV infections between individuals. To do so, we obtained genome-wide genotype and gene expression data in uninfected and RV-infected peripheral blood mononuclear cells (PBMCs) from 98 individuals. We mapped local and distant genetic variation that is associated with inter-individual differences in gene expression levels (eQTLs) in both uninfected and RV-infected cells. We focused specifically on response eQTLs (reQTLs), namely, genetic associations with inter-individual variation in gene expression response to RV infection. We identified local reQTLs for 38 genes, including genes with known functions in viral response (UBA7, OAS1, IRF5) and genes that have been associated with immune and RV-related diseases (e.g., ITGA2, MSR1, GSTM3). The putative regulatory regions of genes with reQTLs were enriched for binding sites of virus-activated STAT2, highlighting the role of condition-specific transcription factors in genotype-by-environment interactions. Overall, we suggest that the 38 loci associated with inter-individual variation in gene expression response to RV-infection represent promising candidates for affecting immune and RV-related respiratory diseases.
Assuntos
Resfriado Comum/genética , Loci Gênicos , Variação Genética , Transcriptoma , 2',5'-Oligoadenilato Sintetase/genética , 2',5'-Oligoadenilato Sintetase/metabolismo , Adulto , Resfriado Comum/metabolismo , Feminino , Perfilação da Expressão Gênica , Interação Gene-Ambiente , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Integrina alfa2/genética , Integrina alfa2/metabolismo , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Transcrição STAT2/genética , Fator de Transcrição STAT2/metabolismo , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismoRESUMO
To better understand the systemic response to naturally acquired acute respiratory viral infections, we prospectively enrolled 1610 healthy adults in 2009 and 2010. Of these, 142 subjects were followed for detailed evaluation of acute viral respiratory illness. We examined peripheral blood gene expression at 7 timepoints: enrollment, 5 illness visits and the end of each year of the study. 133 completed all study visits and yielded technically adequate peripheral blood microarray gene expression data. Seventy-three (55%) had an influenza virus infection, 64 influenza A and 9 influenza B. The remaining subjects had a rhinovirus infection (N = 32), other viral infections (N = 4), or no viral agent identified (N = 24). The results, which were replicated between two seasons, showed a dramatic upregulation of interferon pathway and innate immunity genes. This persisted for 2-4 days. The data show a recovery phase at days 4 and 6 with differentially expressed transcripts implicated in cell proliferation and repair. By day 21 the gene expression pattern was indistinguishable from baseline (enrollment). Influenza virus infection induced a higher magnitude and longer duration of the shared expression signature of illness compared to the other viral infections. Using lineage and activation state-specific transcripts to produce cell composition scores, patterns of B and T lymphocyte depressions accompanied by a major activation of NK cells were detected in the acute phase of illness. The data also demonstrate multiple dynamic gene modules that are reorganized and strengthened following infection. Finally, we examined pre- and post-infection anti-influenza antibody titers defining novel gene expression correlates.
Assuntos
Influenza Humana/genética , Influenza Humana/imunologia , Infecções Respiratórias/genética , Infecções Respiratórias/imunologia , Adolescente , Adulto , Estudos de Coortes , Resfriado Comum/genética , Resfriado Comum/imunologia , Feminino , Humanos , Vírus da Influenza A/imunologia , Vírus da Influenza B/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real , Rhinovirus/imunologia , Transcrição Gênica , Transcriptoma , Adulto JovemRESUMO
Human rhinovirus (RV) infections are the principle cause of common colds and precipitate asthma and COPD exacerbations. There is currently no RV vaccine, largely due to the existence of â¼150 strains. We aimed to define highly conserved areas of the RV proteome and test their usefulness as candidate antigens for a broadly cross-reactive vaccine, using a mouse infection model. Regions of the VP0 (VP4+VP2) capsid protein were identified as having high homology across RVs. Immunization with a recombinant VP0 combined with a Th1 promoting adjuvant induced systemic, antigen specific, cross-serotype, cellular and humoral immune responses. Similar cross-reactive responses were observed in the lungs of immunized mice after infection with heterologous RV strains. Immunization enhanced the generation of heterosubtypic neutralizing antibodies and lung memory T cells, and caused more rapid virus clearance. Conserved domains of the RV capsid therefore induce cross-reactive immune responses and represent candidates for a subunit RV vaccine.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Proteínas do Capsídeo/imunologia , Pulmão/imunologia , Rhinovirus/imunologia , Animais , Asma/imunologia , Asma/virologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/farmacologia , Resfriado Comum/genética , Resfriado Comum/imunologia , Resfriado Comum/prevenção & controle , Reações Cruzadas , Feminino , Humanos , Imunização , Pulmão/virologia , Camundongos , Doença Pulmonar Obstrutiva Crônica/imunologia , Doença Pulmonar Obstrutiva Crônica/virologia , Rhinovirus/genética , Vacinas ViraisRESUMO
Low socioeconomic status (SES) during childhood and adolescence has been found to predict greater susceptibility to common cold viruses in adults. Here, we test whether low childhood SES is associated with shorter leukocyte telomere length in adulthood, and whether telomere length mediates the association between childhood SES and susceptibility to acute upper respiratory disease in adulthood. At baseline, 196 healthy volunteers reported whether they currently owned their home and, for each year of their childhood, whether their parents owned the family home. Volunteers also had blood drawn for assessment of specific antibody to the challenge virus, and for CD8+ CD28- T-lymphocyte telomere length (in a subset, n=135). They were subsequently quarantined in a hotel, exposed to a virus (rhinovirus [RV] 39) that causes a common cold and followed for infection and illness (clinical cold) over five post-exposure days. Lower childhood SES as measured by fewer years of parental home ownership was associated with shorter adult CD8+ CD28- telomere length and with an increased probability of developing infection and clinical illness when exposed to a common cold virus in adulthood. These associations were independent of adult SES, age, sex, race, body mass, neuroticism, and childhood family characteristics. Associations with infections and colds were also independent of pre-challenge viral-specific antibody and season. Further analyses do not support mediating roles for smoking, alcohol consumption or physical activity but suggest that CD8+ CD28- cell telomere length may act as a partial mediator of the associations between childhood SES and infection and childhood SES and colds.
Assuntos
Resfriado Comum/genética , Infecções Respiratórias/genética , Telômero , Adolescente , Adulto , Antígenos CD28/imunologia , Antígenos CD8/imunologia , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rhinovirus/patogenicidade , Fatores Socioeconômicos , Linfócitos T/imunologia , Linfócitos T/ultraestrutura , Homeostase do Telômero , Adulto JovemRESUMO
IMPORTANCE: Although leukocyte telomere length is associated with mortality and many chronic diseases thought to be manifestations of age-related functional decline, it is not known whether it relates to acute disease in younger healthy populations. OBJECTIVE: To determine whether shorter telomeres in leukocytes, especially CD8CD28- T cells, are associated with decreased resistance to upper respiratory infection and clinical illness in young to midlife adults. DESIGN, SETTING, AND PARTICIPANTS: Between 2008 and 2011, telomere length was assessed in peripheral blood mononuclear cells (PBMCs) and T-cell subsets (CD4, CD8CD28+, CD8CD28-) from 152 healthy 18- to 55-year-old residents of Pittsburgh, Pennsylvania. Participants were subsequently quarantined (single rooms), administered nasal drops containing a common cold virus (rhinovirus 39), and monitored for 5 days for development of infection and clinical illness. MAIN OUTCOME MEASURES: Infection (virus shedding or 4-fold increase in virus-specific antibody titer) and clinical illness (verified infection plus objective signs of illness). RESULTS: Rates of infections and clinical illness were 69% (n = 105) and 22% (n = 33), respectively. Shorter telomeres were associated with greater odds of infection, independent of prechallenge virus-specific antibody, demographics, contraceptive use, season, and body mass index (PBMC: odds ratio [OR] per 1-SD decrease in telomere length, 1.71 [95% CI, 1.08-2.72]; n = 128 [shortest tertile 77% infected; middle, 66%; longest, 57%]; CD4: OR, 1.76 [95% CI, 1.15-2.70]; n = 146 [shortest tertile 80% infected; middle, 71%; longest, 54%]; CD8CD28+: OR, 1.93 [95% CI, 1.21-3.09], n = 132 [shortest tertile 84% infected; middle, 64%; longest, 58%]; CD8CD28-: OR, 2.02 [95% CI, 1.29-3.16]; n = 144 [shortest tertile 77% infected; middle, 75%; longest, 50%]). CD8CD28- was the only cell population in which shorter telomeres were associated with greater risk of clinical illness (OR, 1.69 [95% CI, 1.01-2.84]; n = 144 [shortest tertile, 26%; middle, 22%; longest, 13%]). The association between CD8CD28- telomere length and infection increased with age (CD8CD28- telomere length × age interaction, b = 0.09 [95% CI, 0.02-0.16], P = .01, n = 144). CONCLUSION AND RELEVANCE: In this preliminary study among a cohort of healthy 18- to 55-year-olds, shorter CD8CD28- T-cell telomere length was associated with increased risk for experimentally induced acute upper respiratory infection and clinical illness.
Assuntos
Resfriado Comum/genética , Infecções Respiratórias/genética , Encurtamento do Telômero , Adolescente , Adulto , Fatores Etários , Antígenos CD28 , Antígenos CD8 , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Infecções Respiratórias/virologia , Rhinovirus , Risco , Linfócitos T , Adulto JovemRESUMO
BACKGROUND: Risk factors for severe human rhinovirus (HRV)-associated infant illness are unknown. OBJECTIVES: We sought to examine the role of HRV infection in infant respiratory tract illness and assess viral and host risk factors for HRV-associated disease severity. METHODS: We used a prospective cohort of term, previously healthy infants enrolled during an inpatient or outpatient visit for acute upper or lower respiratory tract illness during the fall-spring months of 2004-2008. Illness severity was determined by using an ordinal bronchiolitis severity score, with higher scores indicating more severe disease. HRV was identified by means of real-time RT-PCR. The VP4/VP2 region from HRV-positive specimens was sequenced to determine species. RESULTS: Of 630 infants with bronchiolitis or upper respiratory tract illnesses (URIs), 162 (26%) had HRV infection; HRV infection was associated with 18% of cases of bronchiolitis and 47% of cases of URI. Among infants with HRV infection, 104 (64%) had HRV infection alone. Host factors associated with more severe HRV-associated illness included a maternal and family history of atopy (median score of 3.5 [interquartile range [IQR], 1.0-7.8] vs 2.0 [IQR, 1.0-5.2] and 3.5 [IQR, 1.0-7.5] vs 2.0 [IQR, 0-4.0]). In adjusted analyses maternal history of atopy conferred an increase in the risk for more severe HRV-associated bronchiolitis (odds ratio, 2.39; 95% CI, 1.14-4.99; P = .02). In a similar model maternal asthma was also associated with greater HRV-associated bronchiolitis severity (odds ratio, 2.49, 95% CI, 1.10-5.67; P = .03). Among patients with HRV infection, 35% had HRVA, 6% had HRVB, and 30% had HRVC. CONCLUSION: HRV infection was a frequent cause of bronchiolitis and URIs among previously healthy term infants requiring hospitalization or unscheduled outpatient visits. Substantial viral genetic diversity was seen among the patients with HRV infection, and predominant groups varied by season and year. Host factors, including maternal atopy, were associated with more severe infant HRV-associated illness.
Assuntos
Resfriado Comum/fisiopatologia , Resfriado Comum/virologia , Bronquiolite/fisiopatologia , Bronquiolite/virologia , Resfriado Comum/genética , Feminino , Humanos , Hipersensibilidade Imediata/imunologia , Lactente , Masculino , Mães , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rhinovirus , Fatores de RiscoRESUMO
BACKGROUND: Uteroglobin-Related Protein 1 (UGRP1) is a secretoglobulin protein which has been suggested to play a role in lung inflammation and allergic diseases. UGRP1 has also been shown to be an important pneumoprotein, with diagnostic potential as a biomarker of lung damage. Previous genetic studies evaluating the association between variations on UGRP1 and allergic phenotypes have yielded mixed results. The aim of this present study was to identify genetic polymorphisms in UGRP1 and investigate if they were associated with asthma and allergic rhinitis in the Singapore Chinese population. METHODS: Resequencing of the UGRP1 gene was conducted on 40 randomly selected individuals from Singapore of ethnic Chinese origin. The polymorphisms identified were then tagged and genotyped in a population of 1893 Singapore Chinese individuals. Genetic associations were evaluated in this population comparing 795 individuals with allergic rhinitis, 718 with asthma (of which 337 had both asthma and allergic rhinitis) and 717 healthy controls with no history of allergy or allergic diseases. RESULTS: By resequencing the UGRP1 gene within our population, we identified 11 novel and 16 known single nucleotide polymorphisms (SNPs). TagSNPs were then genotyped, revealing a significant association between rs7726552 and allergic rhinitis (Odds Ratio: 0.81, 95% Confidence Interval: 0.66-0.98, P = 0.039). This association remained statistically significant when it was analyzed genotypically or when stratified according to haplotypes. When variations on UGRP1 were evaluated against asthma, no association was observed. CONCLUSION: This study documents the association between polymorphisms in UGRP1 and allergic rhinitis, suggesting a potential role in its pathogenesis.
Assuntos
Asma/genética , Resfriado Comum , Rinite Alérgica Perene/genética , Uteroglobina/genética , Povo Asiático/etnologia , Asma/metabolismo , Estudos de Casos e Controles , Mapeamento Cromossômico , Resfriado Comum/genética , Resfriado Comum/metabolismo , Genótipo , Humanos , Pulmão/metabolismo , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Secretoglobinas , Singapura/epidemiologiaRESUMO
BACKGROUND: In adults and children with respiratory syncytial virus (RSV) infection, a polymorphism in the interleukin 6 (IL-6) promoter at position -174 predicts illness magnitude. In addition, polymorphisms in the interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma) genes are associated with immune responsiveness and the frequency of complications. Here, the effect of these polymorphisms on illness and seroconversion during infection with rhinovirus type 39 (RV39) was evaluated. METHODS: Seventy-two adults were genotyped for the selected polymorphisms, experimentally exposed to RV39, and followed to track infection, seroconversion, and symptoms and signs of illness. Regression analysis was used to determine whether these polymorphisms predicted seroconversion and illness magnitude in 57 infected subjects. RESULTS: The low-production IL-6 -174 phenotype (C/C genotype) was associated with greater symptom magnitudes, and the IFN-gamma phenotype +874 predicted the frequency of seroconversion. No relationship between the IL-10 or TNF-alpha polymorphisms and any measured outcome was documented. The concentration of IL-6 protein, as measured in nasal wash fluids from subjects, was positively correlated with symptom magnitude, but it was independent of the IL-6 -174 genotypes representing the high- and low-production phenotypes. CONCLUSIONS: These results document statistically significant associations between the IL-6 -174 and IFN-gamma +874 polymorphisms and specific responses to experimental RV39 infection. For the IL-6 -174 polymorphism, the results replicate those for experimental RSV infection.
Assuntos
Resfriado Comum/genética , Predisposição Genética para Doença , Interferon gama/genética , Interleucina-6/genética , Polimorfismo de Nucleotídeo Único , Rhinovirus/imunologia , Adulto , Resfriado Comum/imunologia , Feminino , Genótipo , Humanos , Interferon gama/imunologia , Masculino , Índice de Gravidade de Doença , Adulto JovemRESUMO
In the spring of 2020, we and others hypothesized that T cells in COVID-19 patients may recognize identical protein fragments shared between the coronaviruses of the common cold and COVID-19 and thereby confer cross-virus immune memory. Here, we look at this issue by screening studies that, since that time, have experimentally addressed COVID-19 associated T cell specificities. Currently, the identical T cell epitope shared between COVID-19 and common cold coronaviruses most convincingly identified as immunogenic is the CD8 + T cell epitope VYIGDPAQL if presented by the MHC class I allele HLA-A*24:02. The HLA-A*24:02 allele is found in the majority of Japanese individuals and several indigenous populations in Asia, Oceania, and the Americas. In combination with histories of common cold infections, HLA-A*24:02 may affect their protection from COVID-19.
Assuntos
COVID-19 , Resfriado Comum , Resfriado Comum/genética , Epitopos de Linfócito T/genética , Humanos , Japão , SARS-CoV-2RESUMO
The beta-coronavirus SARS-CoV-2 induces severe disease (COVID-19) mainly in elderly persons with risk factors, whereas the majority of patients experience a mild course of infection. As the circulating common cold coronaviruses OC43 and HKU1 share some homologous sequences with SARS-CoV-2, beta-coronavirus cross-reactive T-cell responses could influence the susceptibility to SARS-CoV-2 infection and the course of COVID-19. To investigate the role of beta-coronavirus cross-reactive T-cells, we analyzed the T-cell response against a 15 amino acid long peptide (SCoV-DP15: DLSPRWYFYYLGTGP) from the SARS-CoV-2 nucleoprotein sequence with a high homology to the corresponding sequence (QLLPRWYFYYLGTGP) in OC43 and HKU1. SCoV-DP15-specific T-cells were detected in 4 out of 23 (17.4%) SARS-CoV-2-seronegative healthy donors. As HIV-1 infection is a potential risk factor for COVID-19, we also studied a cohort of HIV-1-infected patients on antiretroviral therapy. 44 out of these 116 HIV-1-infected patients (37.9%) showed a specific recognition of the SCoV-DP15 peptide or of shorter peptides within SCoV-DP15 by CD4+ T-cells and/or by CD8+ T-cells. We could define several new cross-reactive HLA-I-restricted epitopes in the SARS-CoV-2 nucleoprotein such as SPRWYFYYL (HLA-B*07, HLA-B*35), DLSPRWYFYY (HLA-A*02), LSPRWYFYY (HLA-A*29), WYFYYLGTGP and WYFYYLGT. Epitope specific CD8+ T-cell lines recognized corresponding epitopes within OC43 and HKU1 to a similar degree or even at lower peptide concentrations suggesting that they were induced by infection with OC43 or HKU1. Our results confirm that SARS-CoV-2-seronegative subjects can target SARS-CoV-2 not only by beta-coronavirus cross-reactive CD4+ T-cells but also by cross-reactive CD8+ cytotoxic T-cells (CTL). The delineation of cross-reactive T-cell epitopes contributes to an efficient epitope-specific immunomonitoring of SARS-CoV-2-specific T-cells. Further prospective studies are needed to prove a protective role of cross-reactive T-cells and their restricting HLA alleles for control of SARS-CoV-2 infection. The frequent observation of SARS-CoV-2-reactive T-cells in HIV-1-infected subjects could be a reason that treated HIV-1 infection does not seem to be a strong risk factor for the development of severe COVID-19.
Assuntos
Linfócitos T CD4-Positivos/imunologia , COVID-19/imunologia , Resfriado Comum/imunologia , Epitopos de Linfócito T/imunologia , Nucleoproteínas/imunologia , SARS-CoV-2/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Linfócitos T CD4-Positivos/patologia , COVID-19/genética , COVID-19/patologia , Linhagem Celular , Resfriado Comum/genética , Resfriado Comum/patologia , Reações Cruzadas , Epitopos de Linfócito T/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nucleoproteínas/genética , SARS-CoV-2/genética , Linfócitos T Citotóxicos/patologiaRESUMO
PURPOSE OF REVIEW: Asthma is the most common chronic disease in pediatric age. Childhood-onset asthma, as opposed to adult-onset asthma, is typically characterized by a personal and often a family history of atopy and related markers of type 2-mediated inflammation. However, the interplay between atopy and asthma development is more complex than a linear dose-response relationship. RECENT FINDINGS: Family and personal history of atopic diseases have been confirmed as major risk factors for asthma occurrence and persistence in children. Early life and multiple sensitizations to aeroallergens significantly increase the risk of asthma development in school age. Early life lower respiratory tract viral infections, especially caused by rhinovirus, also increase the susceptibility to atopic asthma in childhood. Human rhinovirus type C receptor CDHR3 polymorphisms have been shown to affect receptor epithelial expression, activation, and asthma development and exacerbation severity in children. Atopic sensitization and respiratory viral infections can synergistically enhance the susceptibility to asthma through multiple mechanisms, including the IgE-mediated inhibition of innate antiviral responses to rhinovirus. Emerging evidence shows that several nonatopic factors are also involved in the asthma pathogenesis in genetically predisposed individuals, including early life exposure to environmental factors, and lung and gut microbiome composition. SUMMARY: The current review outlines recent data on the complex role of atopy in asthma pathogenesis and persistence, and addresses new research topics such as the role of epigenetics and the lung microbiome.
Assuntos
Alérgenos/imunologia , Asma/imunologia , Resfriado Comum/complicações , Exposição Ambiental/efeitos adversos , Hipersensibilidade Imediata/complicações , Alérgenos/efeitos adversos , Asma/genética , Asma/microbiologia , Proteínas Relacionadas a Caderinas , Caderinas/genética , Caderinas/metabolismo , Criança , Doença Crônica , Resfriado Comum/genética , Resfriado Comum/imunologia , Resfriado Comum/virologia , Relação Dose-Resposta Imunológica , Predisposição Genética para Doença , Humanos , Hipersensibilidade Imediata/imunologia , Hipersensibilidade Imediata/microbiologia , Imunidade Inata , Imunoglobulina E/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Pulmão/imunologia , Pulmão/microbiologia , Anamnese , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microbiota/imunologia , Polimorfismo de Nucleotídeo Único , Mucosa Respiratória/imunologia , Mucosa Respiratória/microbiologia , Rhinovirus/imunologiaRESUMO
Infectious diseases have a profound impact on our health and many studies suggest that host genetics play a major role in the pathogenesis of most of them. We perform 23 genome-wide association studies for common infections and infection-associated procedures, including chickenpox, shingles, cold sores, mononucleosis, mumps, hepatitis B, plantar warts, positive tuberculosis test results, strep throat, scarlet fever, pneumonia, bacterial meningitis, yeast infections, urinary tract infections, tonsillectomy, childhood ear infections, myringotomy, measles, hepatitis A, rheumatic fever, common colds, rubella and chronic sinus infection, in over 200,000 individuals of European ancestry. We detect 59 genome-wide significant (P < 5 × 10-8) associations in genes with key roles in immunity and embryonic development. We apply fine-mapping analysis to dissect associations in the human leukocyte antigen region, which suggests important roles of specific amino acid polymorphisms in the antigen-binding clefts. Our findings provide an important step toward dissecting the host genetic architecture of response to common infections.Susceptibility to infectious diseases is, among others, influenced by the genetic landscape of the host. Here, Tian and colleagues perform genome-wide association studies for 23 common infections and find 59 risk loci for 17 of these, both within the HLA region and non-HLA loci.
Assuntos
Antígenos HLA/genética , Infecções/genética , População Branca/genética , Candidíase Vulvovaginal/genética , Estudos de Casos e Controles , Varicela/genética , Doença Crônica , Resfriado Comum/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hepatite A/genética , Hepatite B/genética , Herpes Labial/genética , Herpes Zoster/genética , Humanos , Mononucleose Infecciosa/genética , Masculino , Sarampo/genética , Meningites Bacterianas/genética , Ventilação da Orelha Média , Caxumba/genética , Otite Média/genética , Otite Média/cirurgia , Faringite/genética , Pneumonia/genética , Febre Reumática/genética , Rubéola (Sarampo Alemão)/genética , Escarlatina/genética , Sinusite/genética , Infecções Estreptocócicas/genética , Tonsilectomia , Tonsilite/genética , Tonsilite/cirurgia , Teste Tuberculínico , Tuberculose/diagnóstico , Tuberculose/genética , Infecções Urinárias/genética , Verrugas/genéticaRESUMO
The epidemiology of common cold and the role of some predisposing factors were studied by examining 2065 healthy children, aged 2.5-6 years. The examination included a questionnaire, completed by the parents, a general physical examination, a clinical E.N.T.-examination and various technical investigations. The mean annual incidence of common cold was 2.43 (as was reported by the parents) and 5 when taking into consideration the time span between the last episode of common cold and the date of examination. Mucoid and purulent rhinitis were less frequently found in older children. A positive history of upper respiratory tract infections in the parents showed to be the most important risk factor for the occurrence of infectious rhinitis in the children. The higher the weight of the child, the lower the incidence of common cold and the fewer pathological rhinoscopical findings. Children with a head circumference below the 2.5 percentile had the highest incidence of infectious rhinitis. Humid housing conditions showed to be connected with a higher incidence of infectious rhinitis. Children of parents with a higher profession had more rhinitis than children of labourers. Smoking habits of the parents had only little effect on the rhinological status of children.