RESUMO
BACKGROUND: Cancer patients often have weakened immune systems, resulting in a lower response to vaccines, especially those receiving immunosuppressive oncological treatment (OT). We aimed to assess the impact of OT on the humoral and T-cell response to the B.1 lineage and Omicron variant following COVID-19 vaccination in patients with solid and hematological neoplasms. METHODS: We conducted a prospective study on cancer patients, stratified into OT and non-OT groups, who received a two-dose series of the COVID-19 mRNA vaccine and a booster six months later. The outcomes measured were the humoral (anti-SARS-CoV-2 S IgG titers and ACE2-S interaction inhibition capacity) and cellular (SARS-CoV-2 S-specific T-cell spots per million PBMCs) responses against the B.1 lineage and Omicron variant. These responses were evaluated four weeks after the second dose (n = 98) and eight weeks after the booster dose (n = 71). RESULTS: The humoral response after the second vaccine dose against the B.1 lineage and Omicron variant was significantly weaker in the OT group compared to the non-OT group (q-value<0.05). A booster dose of the mRNA-1273 vaccine significantly improved the humoral response in the OT group, making it comparable to the non-OT group. The mRNA-1273 vaccine, designed for the original Wuhan strain, elicited a weaker humoral response against the Omicron variant compared to the B.1 lineage, regardless of oncological treatment or vaccine dose. In contrast, T-cell responses against SARS-CoV-2, including the Omicron variant, were already present after the second vaccine dose and were not significantly affected by oncological treatments. CONCLUSIONS: Cancer patients, particularly those receiving immunosuppressive oncological treatments, should require booster doses and adapted COVID-19 vaccines for new SARS-CoV-2 variants like Omicron. Future studies should evaluate the durability of the immune response and the efficacy of individualized regimens.
Assuntos
Anticorpos Antivirais , Vacinas contra COVID-19 , COVID-19 , Neoplasias , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Humanos , Estudos Prospectivos , Masculino , COVID-19/imunologia , COVID-19/prevenção & controle , Feminino , Pessoa de Meia-Idade , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Glicoproteína da Espícula de Coronavírus/imunologia , SARS-CoV-2/imunologia , Idoso , Neoplasias/imunologia , Anticorpos Antivirais/sangue , Linfócitos T/imunologia , Imunização Secundária , Vacinação , Adulto , Imunidade Humoral , Imunoglobulina G/sangue , Hospedeiro Imunocomprometido , Imunidade CelularRESUMO
OBJECTIVES: This study analyzed the association of TNFAIP3-interacting protein 1 (TNIP1) polymorphisms with the symptomatic human respiratory syncytial virus (HRSV) infection and bronchiolitis in infants. METHODS: A case-control study was conducted involving 129 hospitalized infants with symptomatic HRSV infection (case group) and 161 healthy infants (control group) in South Africa (2016-2018). Six TNIP1 polymorphisms (rs869976, rs4958881, rs73272842, rs3792783, rs17728338, and rs999011) were genotyped. Genetic associations were evaluated using logistic regression adjusted by age and gender. RESULTS: Both rs73272842 G and rs999011 C alleles were associated with reduced odds for symptomatic HRSV infection (adjusted odd ratio [aOR] = 0.68 [95% confidence interval {CI} = 0.48-0.96] and aOR = 0.36 [95% CI = 0.19-0.68], respectively] and bronchiolitis (aOR = 0.71 [95% CI = 0.50-1.00] and aOR = 0.38 [95% CI = 0.22-0.66], respectively). The significance of these associations was validated using the BCa Bootstrap method (P <0.05). The haplotype GC (composed of rs73272842 and rs999011) was associated with reduced odds of symptomatic HRSV infection (aOR = 0.53 [95% CI = 0.37-0.77]) and bronchiolitis (aOR = 0.62 [95% CI = 0.46-0.84]), which were validated by the BCa Bootstrap method (P = 0.002 for both). CONCLUSION: TNIP1 rs73272842 G allele and rs999011 C allele were associated with reduced odds of symptomatic HRSV infection and the development of bronchiolitis in infants, suggesting that TNIP1 polymorphisms could impact susceptibility to HRSV illness.
Assuntos
Bronquiolite , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Humanos , Lactente , Infecções por Vírus Respiratório Sincicial/genética , Vírus Sincicial Respiratório Humano/genética , Estudos de Casos e Controles , África do Sul/epidemiologia , Bronquiolite/genética , Polimorfismo de Nucleotídeo Único , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genéticaRESUMO
OBJECTIVES: We analyzed the expression of inflammatory and antiviral genes in the nasopharynx of SARS-CoV-2 infected patients and their association with the severity of COVID-19 pneumonia. METHODS: We conducted a cross-sectional study on 223 SARS-CoV-2 infected patients. Clinical data were collected from medical records, and nasopharyngeal samples were collected in the first 24 hours after admission to the emergency room. The gene expression of eight proinflammatory/antiviral genes (plasminogen activator urokinase receptor [PLAUR], interleukin [IL]-6, IL-8, interferon [IFN]-ß, IFN-stimulated gene 15 [ISG15], retinoic acid-inducible gene I [RIG-I], C-C motif ligand 5 [CCL5], and chemokine C-X-C motif ligand 10 [CXCL10]) were quantified by real-time polymerase chain reaction. Outcome variables were: (i) pneumonia; (ii) severe pneumonia or acute respiratory distress syndrome. Statistical analysis was performed using multivariate logistic regression analyses. RESULTS: We enrolled 84 mild, 88 moderate, and 51 severe/critical cases. High expression of PLAUR (adjusted odds ratio [aOR] = 1.25; P = 0.032, risk factor) and low expression of CXCL10 (aOR = 0.89; P = 0.048, protective factor) were associated with pneumonia. Furthermore, lower values of ISG15 (aOR = 0.88, P = 0.021), RIG-I (aOR = 0.87, P = 0.034), CCL5 (aOR = 0.73, P <0.001), and CXCL10 (aOR = 0.84, P = 0.002) were risk factors for severe pneumonia/acute respiratory distress syndrome. CONCLUSION: An unbalanced early innate immune response to SARS-CoV-2 in the nasopharynx, characterized by high expression of PLAUR and low expression of antiviral genes (ISG15 and RIG-I), and chemokines (CCL5 and CXCL10), was associated with COVID-19 severity.
Assuntos
COVID-19 , Pneumonia , Síndrome do Desconforto Respiratório , Humanos , COVID-19/genética , SARS-CoV-2 , Estudos Transversais , Ligantes , Quimiocinas/genética , Antivirais , Imunidade Inata , Interleucina-6 , NasofaringeRESUMO
OBJECTIVES: We aimed to assess the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and factors associated with seropositivity and asymptomatic coronavirus disease 2019 (COVID-19) among people with HIV (PWH). METHODS: This was a cross-sectional study carried out within the cohort of the Spanish HIV Research Network. Participants were consecutive PWH with plasma collected from 1st April to 30th September 2020. We determined SARS-CoV-2 antibodies (Abs) in plasma. Illness severity (NIH criteria) was assessed by a review of medical records and, if needed, participant interviews. Multivariable logistic regression analysis was used to identify predictors of seropositivity among the following variables: sex, age, country of birth, education level, comorbidities (hypertension, chronic heart disease, diabetes mellitus, non-AIDS-related cancer, chronic kidney disease, cirrhosis), route of HIV acquisition, prior AIDS, CD4+ cell count, HIV viral load, nucleoside/nucleotide reverse transcriptase inhibitor (N [t]RTI) backbone, type of third antiretroviral drug, and month of sample collection. RESULTS: Of 1076 PWH (88.0% males, median age 43 years, 97.7% on antiretroviral therapy, median CD4+ 688 cells/mm3, 91.4% undetectable HIV viral load), SARS-CoV-2 Abs were detected in 91 PWH, a seroprevalence of 8.5% (95%CI 6.9-10.3%). Forty-five infections (45.0%) were asymptomatic. Variables independently associated with SARS-CoV-2 seropositivity were birth in Latin American countries versus Spain (adjusted odds ratio (aOR) 2.30, 95%CI 1.41-3.76, p 0.001), and therapy with tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) versus tenofovir alafenamide (TAF)/FTC as the N(t)RTI backbone (aOR 0.49, 95%CI 0.26-0.94, p 0.031). CONCLUSIONS: Many SARS-CoV-2 infections among PWH were asymptomatic, and birth in Latin American countries increased the risk of SARS-CoV-2 seropositivity. Our analysis, adjusted by comorbidities and other variables, suggests that TDF/FTC may prevent SARS-CoV-2 infection among PWH.
Assuntos
Fármacos Anti-HIV , COVID-19 , Infecções por HIV , Adulto , Fármacos Anti-HIV/uso terapêutico , COVID-19/diagnóstico , COVID-19/epidemiologia , Estudos Transversais , Emtricitabina/uso terapêutico , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Masculino , Prevalência , Inibidores da Transcriptase Reversa/uso terapêutico , Estudos Soroepidemiológicos , Espanha/epidemiologia , Tenofovir/uso terapêuticoRESUMO
Viral infections induce substantial metabolic changes in infected cells to optimize viral production while cells develop countermeasures to restrict that infection. Human respiratory syncytial virus (HRSV) is an infectious pathogen that causes severe lower respiratory tract infections (LRTI) in infants, the elderly, and immunocompromised adults for which no effective treatment or vaccine is currently available. In this study, variations in metabolite levels at different time points post-HRSV infection of epithelial cells were studied by untargeted metabolomics using liquid chromatography/mass spectrometry analysis of methanol cell extracts. Numerous metabolites were significantly upregulated after 18 hours post-infection, including nucleotides, amino acids, amino and nucleotide sugars, and metabolites of the central carbon pathway. In contrast, most lipid classes were downregulated. Additionally, increased levels of oxidized glutathione and polyamines were associated with oxidative stress in infected cells. These results show how HRSV infection influences cell metabolism to produce the energy and building blocks necessary for virus reproduction, suggesting potential therapeutic interventions against this virus.
Assuntos
Células Epiteliais/metabolismo , Células Epiteliais/virologia , Vírus Sincicial Respiratório Humano/fisiologia , Células A549 , Aminoácidos/metabolismo , Carbono/metabolismo , Humanos , Cinética , Metabolômica , Nucleotídeos/metabolismo , Estresse OxidativoRESUMO
Human respiratory syncytial virus (HRSV) infection is a common cause of severe lower respiratory tract diseases such as bronchiolitis and pneumonia. Both virus replication and the associated inflammatory immune response are believed to be behind these pathologies. So far, no vaccine or effective treatment is available for this viral infection. With the aim of finding new strategies to counteract HRSV replication and modulate the immune response, specific small interfering RNAs (siRNAs) were generated targeting the mRNA coding for the viral fusion (F) protein or nucleoprotein (N), or for two proteins involved in intracellular immune signaling, which are named tripartite motif-containing protein 25 (TRIM25) and retinoic acid-inducible gene-I (RIG-I). Furthermore, two additional bispecific siRNAs were designed that silenced F and TRIM25 (TRIM25/HRSV-F) or N and RIG-I (RIG-I/HRSV-N) simultaneously. All siRNAs targeting N or F, but not those silencing TRIM25 or RIG-I alone, significantly reduced viral titers. However, while siRNAs targeting F inhibited only the expression of the F mRNA and protein, the siRNAs targeting N led to a general inhibition of viral mRNA and protein expression. The N-targeting siRNAs also induced a drastic decrease in the expression of genes of the innate immune response. These results show that both virus replication and the early innate immune response can be regulated by targeting distinct viral products with siRNAs, which may be related to the different role of each protein in the life cycle of the virus.
Assuntos
Imunidade Inata , RNA Interferente Pequeno/metabolismo , Vírus Sincicial Respiratório Humano/imunologia , Vírus Sincicial Respiratório Humano/fisiologia , Replicação Viral/fisiologia , Sequência de Bases , Linhagem Celular Tumoral , Regulação Viral da Expressão Gênica , Inativação Gênica , Genoma Viral , Humanos , Imunidade Inata/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/metabolismo , Vírus Sincicial Respiratório Humano/genética , Vírus Sincicial Respiratório Humano/crescimento & desenvolvimento , Proteínas Virais/genética , Proteínas Virais/metabolismoRESUMO
BACKGROUND: TNFAIP3 is a crucial hepatoprotective factor due to its anti-inflammatory, anti-apoptotic, anti-oxidant and pro-regenerative functions. The aim of this study was to analyze the associations between genetic variants upstream of TNFAIP3 (rs675520, rs9376293 and rs6920220) and liver fibrosis severity and inflammation in HIV/HCV-coinfected patients. METHODS: A cross-sectional study was carried out in 215 HIV/HCV-coinfected patients, who underwent a liver biopsy. TNFAIP3 polymorphisms were genotyped using GoldenGate® assay. Outcome variables were: a) liver fibrosis (Metavir score) [fibrosis stage (F0, F1, F2, F3 and F4) and advanced fibrosis and cirrhosis (Fâ¯≥â¯3 and F4, respectively)]; b) non-invasive indexes [FIB-4, APRI, and their cut-offs (FIB-4â¯≥â¯3.25 and APRI≥1.5)]; c) inflammation-related biomarkers (leptin, HGF, NGF, sFasL, sFas, MIF, HA, Ang-2, TIMP1, MMP1 and MMP2). RESULTS: Patients with rs675520 AG/GG genotypes had decreased odds of having cirrhosis (F4) and advanced fibrosis (FIB-4â¯≥â¯3.25 and APRI≥1.5) [adjusted Odd Ratio (aOR)â¯=â¯0.30 (pâ¯=â¯0.025), aORâ¯=â¯0.20 (pâ¯=â¯0.014), and aORâ¯=â¯0.34 (pâ¯=â¯0.017), respectively] and lower levels of FIB-4 and APRI [adjusted arithmetic mean ratio (aAMR)â¯=â¯0.76 (pâ¯=â¯0.003) and aAMRâ¯=â¯0.72 (pâ¯=â¯0.006), respectively]. Patients with rs9376293 CT/CC genotypes had decreased odds of APRI≥1.5 [aORâ¯=â¯0.39 (pâ¯=â¯0.030)] and lower levels of APRI [aAMRâ¯=â¯0.77 (pâ¯=â¯0.018)]. Patients with rs6920220 AG/AA genotypes had higher odds of having FIB-4â¯≥â¯3.25 [aORâ¯=â¯3.72 (pâ¯=â¯0.043)]. Moreover, rs675520 AG/GG genotypes, compared to AA genotype, were associated with lower levels of leptin and NGF (pâ¯=â¯0.002 and pâ¯=â¯0.001, respectively) and higher levels of sFas, MIF, TIMP1 and MMP2 (pâ¯=â¯0.004, pâ¯=â¯0.007, pâ¯=â¯0.020 and pâ¯=â¯0.036, respectively). Also, rs9376293 CT/CC genotypes were related to lower leptin levels (pâ¯=â¯0.026) and higher sFas, MIF, TIMP1 and MMP2 levels (pâ¯=â¯0.029, pâ¯=â¯0.040, pâ¯=â¯0.022 and pâ¯=â¯0.024, respectively). CONCLUSIONS: Genetic variants upstream of TNFAIP3 were associated with the liver fibrosis severity and inflammation in HIV/HCV-coinfected patients.
Assuntos
Cromossomos Humanos Par 6 , Coinfecção , Variação Genética , Infecções por HIV/complicações , Hepatite C Crônica/complicações , Hepatopatias/diagnóstico , Hepatopatias/etiologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Adulto , Alelos , Biomarcadores , Biópsia , Estudos Transversais , Feminino , Predisposição Genética para Doença , Genótipo , Infecções por HIV/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Desequilíbrio de Ligação , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Masculino , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de DoençaRESUMO
TRIM25 is an E3 ubiquitin ligase enzyme that is involved in various cellular processes, including regulation of the innate immune response against viruses. TRIM25-mediated ubiquitination of the cytosolic pattern recognition receptor RIG-I is an essential step for initiation of the intracellular antiviral response and has been thoroughly documented. In recent years, however, additional roles of TRIM25 in early innate immunity are emerging, including negative regulation of RIG-I, activation of the melanoma differentiation-associated protein 5-mitochondrial antiviral signaling protein-TRAF6 antiviral axis and modulation of p53 levels and activity. In addition, the ability of TRIM25 to bind RNA may uncover new mechanisms by which this molecule regulates intracellular signaling and/or RNA virus replication.