RESUMO
BACKGROUND: A distinct phenotype in Coronavirus disease 2019 (Covid-19) was observed in severe patients, consisting of a highly impaired interferon (IFN) type I response, an exacerbated inflammatory response. OBJECTIVE: The aim of the present study was to investigate a possible association of single nucleotide polymorphisms (SNPs), in five genes related to the immune response, rs3775291 in TLR3; rs2292151 in TICAM1; rs1758566 in IFNA1; rs1800629 in TNF, and rs1800795 in IL6 with the severity of Covid-19. METHODS: A cross-sectional study was performed, with non-severe and severe/critical patients diagnosed with Covid-19, by two public hospitals in Brazil. In total, 300 patients were genotyped for the SNPs, 150 with the non-severe form of the disease and 150 with severe/critical form. RESULTS: The T/T genotype of TLR3 in recessive model shows 58% of protection against severe/critical Covid-19; as well as the genotypes G/A+A/A of TICAM1 in dominant model with 60% of protection, and in a codominant model G/A with 57% and A/A with 71% of protection against severe/critical Covid-19. Comparing severe and critical cases, the T/C genotype of IFNA1 in the codominant model and TC+C/C in the dominant model showed twice the risk of critical Covid-19. CONCLUSION: We can conclude that rs3775291, rs2292151 and rs1758566 can influence the COVID-19 severity.
Assuntos
COVID-19 , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , SARS-CoV-2 , Índice de Gravidade de Doença , Receptor 3 Toll-Like , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Brasil/epidemiologia , COVID-19/genética , COVID-19/virologia , Estudos Transversais , Genótipo , Interferon Tipo I/genética , Interferon-alfa , SARS-CoV-2/genética , Receptor 3 Toll-Like/genéticaRESUMO
Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by SARS-CoV-2. According to the World Health Organization (WHO), there have been over 760 million reported cases and over 6 million deaths caused by this disease worldwide. The severity of COVID-19 is based on symptoms presented by the patient and is divided as asymptomatic, mild, moderate, severe, and critical. The manifestations are interconnected with genetic variations. The innate immunity is the quickest response mechanism of an organism against viruses. Type I interferon pathway plays a key role in antiviral responses due to viral replication inhibition in infected cells and adaptive immunity stimulation induced by interferon molecules. Thus, variants in type I interferon pathway's genes are being studied in different COVID-19 manifestations. This review summarizes the role of variants in type I interferon pathway's genes on prognosis and severity progression of COVID-19.
Assuntos
COVID-19 , Interferon Tipo I , Humanos , Interferon Tipo I/genética , COVID-19/genética , SARS-CoV-2/genética , Imunidade Adaptativa , Replicação do DNARESUMO
The innate immune system is the first line of defense against pathogens such as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The type I-interferon (IFN) response activation during the initial steps of infection is essential to prevent viral replication and tissue damage. SARS-CoV and SARS-CoV-2 can inhibit this activation, and individuals with a dysregulated IFN-I response are more likely to develop severe disease. Several mutations in different variants of SARS-CoV-2 have shown the potential to interfere with the immune system. Here, we evaluated the buffy coat transcriptome of individuals infected with Gamma or Delta variants of SARS-CoV-2. The Delta transcriptome presents more genes enriched in the innate immune response and Gamma in the adaptive immune response. Interactome and enriched promoter analysis showed that Delta could activate the INF-I response more effectively than Gamma. Two mutations in the N protein and one in the nsp6 protein found exclusively in Gamma have already been described as inhibitors of the interferon response pathway. This indicates that the Gamma variant evolved to evade the IFN-I response. Accordingly, in this work, we showed one of the mechanisms that variants of SARS-CoV-2 can use to avoid or interfere with the host Immune system.
Assuntos
COVID-19 , Interferon Tipo I , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , Humanos , Interferon Tipo I/genética , SARS-CoV-2 , Transcriptoma , COVID-19/genéticaRESUMO
Since late 2016, a yellow fever virus (YFV) variant carrying a set of nine amino acid variations has circulated in South America. Three of them were mapped on the methyltransferase (MTase) domain of viral NS5 protein. To assess whether these changes affected viral infectivity, we synthesized YFV carrying the MTase of circulating lineage as well as its isoform with the residues of the previous strains (NS5 K101R, NS5 V138I, and NS5 G173S). We observed a slight difference in viral growth properties and plaque phenotype between the two synthetic YFVs. However, the MTase polymorphisms associated with the Brazilian strain of YFV (2016-2019) confer more susceptibility to the IFN-I. In addition, in vitro MTase assay revealed that the interaction between the YFV MTase and the methyl donor molecule (SAM) is altered in the Brazilian MTase variant. Altogether, the results reported here describe that the MTase carrying the molecular signature of the Brazilian YFV circulating since 2016 might display a slight decrease in its catalytic activity but virtually no effect on viral fitness in the parameters comprised in this study. The most marked influence of these residues stands in the immune escape against the antiviral response mediated by IFN-I.
Assuntos
Interferon Tipo I , Vírus da Febre Amarela , Vírus da Febre Amarela/fisiologia , Interferon Tipo I/genética , Aminoácidos , Evasão da Resposta Imune , Brasil , Metiltransferases/metabolismo , Proteínas não Estruturais Virais/genéticaRESUMO
Interferons (IFNs) are a group of cytokines with antiviral, antiproliferative, antiangiogenic, and immunomodulatory activities. Type I IFNs amplify and propagate the antiviral response by interacting with their receptors, IFNAR1 and IFNAR2. In COVID-19, the IFNAR2 (interferon alpha and beta receptor subunit 2) gene has been associated with the severity of the disease, but the soluble receptor (sIFNAR2) levels have not been investigated. We aimed to evaluate the association of IFNAR2 variants (rs2236757, rs1051393, rs3153, rs2834158, and rs2229207) with COVID-19 mortality and to assess if there was a relation between the genetic variants and/or the clinical outcome, with the levels of sIFNAR2 in plasma samples from hospitalized individuals with severe COVID-19. We included 1,202 subjects with severe COVID-19. The genetic variants were determined by employing Taqman® assays. The levels of sIFNAR2 were determined with ELISA in plasma samples from a subgroup of 351 individuals. The rs2236757, rs3153, rs1051393, and rs2834158 variants were associated with mortality risk among patients with severe COVID-19. Higher levels of sIFNAR2 were observed in survivors of COVID-19 compared to the group of non-survivors, which was not related to the studied IFNAR2 genetic variants. IFNAR2, both gene, and soluble protein, are relevant in the clinical outcome of patients hospitalized with severe COVID-19.
Assuntos
COVID-19 , Interferon Tipo I , Receptor de Interferon alfa e beta , COVID-19/genética , COVID-19/mortalidade , Hospitalização , Humanos , Interferon Tipo I/genética , Interferon-alfa/genética , Receptor de Interferon alfa e beta/genéticaRESUMO
In salmon farming, viruses are responsible for outbreaks that produce significant economic losses for which there is a lack of control tools other than vaccines. Type I interferon has been successfully used for treating some chronic viral infections in humans. However, its application in salmonids depends on the proper design of a vehicle that allows its massive administration, ideally orally. In mammals, administration of recombinant probiotics capable of expressing cytokines has shown local and systemic therapeutic effects. In this work, we evaluate the use of Lactococcus lactis as a type I Interferon expression system in Atlantic salmon, and we analyze its ability to stimulate the antiviral immune response against IPNV, in vivo and in vitro. The interferon expressed in L. lactis, even though it was located mainly in the bacterial cytoplasm, was functional, stimulating Mx and PKR expression in CHSE-214 cells, and reducing the IPNV viral load in SHK-1 cells. In vivo, the oral administration of this L. lactis producer of Interferon I increases Mx and PKR expression, mainly in the spleen, and to a lesser extent, in the head kidney. The oral administration of this strain also reduces the IPNV viral load in Atlantic salmon specimens challenged with this pathogen. Our results show that oral administration of L. lactis producing Interferon I induces systemic effects in Atlantic salmon, allowing to stimulate the antiviral immune response. This probiotic could have effects against a wide variety of viruses that infect Atlantic salmon and also be effective in other salmonids due to the high identity among their type I interferons.
Assuntos
Infecções por Birnaviridae/prevenção & controle , Proteínas de Peixes/metabolismo , Imunidade Inata , Vírus da Necrose Pancreática Infecciosa/patogenicidade , Interferon Tipo I/metabolismo , Lactococcus lactis/metabolismo , Probióticos , Salmo salar/microbiologia , Animais , Infecções por Birnaviridae/imunologia , Infecções por Birnaviridae/microbiologia , Infecções por Birnaviridae/virologia , Linhagem Celular , Proteínas de Peixes/genética , Pesqueiros , Interações Hospedeiro-Patógeno , Vírus da Necrose Pancreática Infecciosa/crescimento & desenvolvimento , Vírus da Necrose Pancreática Infecciosa/imunologia , Interferon Tipo I/genética , Lactococcus lactis/genética , Lactococcus lactis/imunologia , Proteínas de Resistência a Myxovirus/metabolismo , Salmo salar/genética , Salmo salar/imunologia , Salmo salar/virologia , Carga Viral , eIF-2 Quinase/metabolismoRESUMO
St. Louis encephalitis virus (SLEV) is a neglected mosquito-borne flavivirus that causes severe neurological disease in humans. SLEV replication in the central nervous system (CNS) induces the local production of interferons (IFNs), which are attributed to host protection. The antiviral response to SLEV infection in the CNS is not completely understood, which led us to characterize the roles of IFNs using mouse models of St. Louis encephalitis. We infected mice deficient in type I IFN receptor (ABR-/-) or deficient in Type II IFN (IFNγ-/-) and assessed the contribution of each pathway to disease development. We found that type I and II IFNs play different roles in SLEV infection. Deficiency in type I IFN signaling was associated to an early and increased mortality, uncontrolled SLEV replication and impaired ISG expression, leading to increased proinflammatory cytokine production and brain pathology. Conversely, IFNγ-/- mice were moderately resistant to SLEV infection. IFNγ deficiency caused no changes to viral load or SLEV-induced encephalitis and did not change the expression of ISGs in the brain. We found that type I IFN is essential for the control of SLEV replication whereas type II IFN was not associated with protection in this model.
Assuntos
Encéfalo/imunologia , Encéfalo/virologia , Vírus da Encefalite de St. Louis/imunologia , Encefalite de St. Louis/imunologia , Interferon Tipo I/imunologia , Interferon gama/imunologia , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Interferon Tipo I/genética , Interferon gama/genética , Camundongos , Camundongos Endogâmicos C57BL , Carga Viral , Replicação Viral/imunologiaRESUMO
BACKGROUND: More than 300 million people carry a diagnosis of asthma, with data to suggest that they are at a higher risk for infection or adverse outcomes from severe acute respiratory syndrome coronavirus 2. Asthma is remarkably heterogeneous, and it is currently unclear how patient-intrinsic factors may relate to coronavirus disease 2019. OBJECTIVE: We sought to identify and characterize subsets of patients with asthma at increased risk for severe acute respiratory syndrome coronavirus 2 infection. METHODS: Participants from 2 large asthma cohorts were stratified using clinically relevant parameters to identify factors related to angiotensin-converting enzyme-2 (ACE2) expression within bronchial epithelium. ACE-2-correlated gene signatures were used to interrogate publicly available databases to identify upstream signaling events and novel therapeutic targets. RESULTS: Stratifying by type 2 inflammatory biomarkers, we identified subjects who demonstrated low peripheral blood eosinophils accompanied by increased expression of the severe acute respiratory syndrome coronavirus 2 receptor ACE2 in bronchial epithelium. Genes highly correlated with ACE2 overlapped with type 1 and 2 IFN signatures, normally induced by viral infections. T-cell recruitment and activation within bronchoalveolar lavage cells of ACE2-high subjects was reciprocally increased. These patients demonstrated characteristics corresponding to risk factors for severe coronavirus disease 2019, including male sex, history of hypertension, low peripheral blood, and elevated bronchoalveolar lavage lymphocytes. CONCLUSIONS: ACE2 expression is linked to upregulation of viral response genes in a subset of type 2-low patients with asthma with characteristics resembling known risk factors for severe coronavirus disease 2019. Therapies targeting the IFN family and T-cell-activating factors may therefore be of benefit in a subset of patients.
Assuntos
Asma/epidemiologia , Asma/genética , Infecções por Coronavirus/epidemiologia , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/epidemiologia , Receptores Virais/genética , Adolescente , Adulto , Enzima de Conversão de Angiotensina 2 , Asma/classificação , Asma/imunologia , Betacoronavirus/genética , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Brônquios/imunologia , Brônquios/patologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19 , Estudos de Coortes , Infecções por Coronavirus/virologia , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Interferon gama/genética , Interferon gama/imunologia , Masculino , Pessoa de Meia-Idade , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/virologia , Mapeamento de Interação de Proteínas , Receptores Virais/imunologia , Fatores de Risco , SARS-CoV-2 , Índice de Gravidade de Doença , Linfócitos T/classificação , Linfócitos T/imunologia , Linfócitos T/patologia , Transcriptoma , Estados Unidos/epidemiologiaRESUMO
Type I interferon (IFN-I) pathway plays a central role in the systemic lupus erythematosus (SLE) pathogenesis. Recent data suggest that SLE is associated with variants in IFN-I genes, such as tyrosine kinase 2 (TYK2), which is crucial in anti-viral immunity. Here, five TYK2 single nucleotide polymorphisms (SNPs) were genotyped in 368 childhood-onset SLE Mexican patients and 516 sex-matched healthy controls. Allele frequencies were also estimated in four indigenous groups. SLE protection was associated with TYK2 risk infection variants affecting residually its catalytic domain, rs12720356 (OR = 0.308; p = 0.041) and rs34536443 (OR = 0.370; p = 0.034), but not with rs2304256, rs12720270, and rs280500. This association was replicated in a 506 adult-onset SLE patients sample (OR = 0.250; p = 0.005, and OR = 0.277; p = 0.008, respectively). The minor alleles of both associated SNPs had a lower frequency in Mestizos than in Spaniards and were absent or rare in indigenous, suggesting that the presence of these alleles in the Mexican Mestizo population was derived from the Spaniards. For the first time, we report genetic variants with a protective effect in childhood- and adult-onset SLE Mexican population. Our results suggest that the frequency of IFN-I alleles associated with SLE, may have been shaped in populations exposed to infectious diseases for long periods, and this could be an explanation why Native American ancestry is associated with a higher SLE prevalence and an earlier onset.
Assuntos
Lúpus Eritematoso Sistêmico/patologia , TYK2 Quinase/genética , Adulto , Alelos , Estudos de Casos e Controles , Domínio Catalítico , Criança , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Interferon Tipo I/genética , Desequilíbrio de Ligação , Lúpus Eritematoso Sistêmico/genética , Masculino , México , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco , TYK2 Quinase/química , TYK2 Quinase/metabolismoRESUMO
For those with leprosy, the extent of host infection by Mycobacterium leprae and the progression of the disease depend on the ability of mycobacteria to shape a safe environment for its replication during early interaction with host cells. Thus, variations in key genes such as those in pattern recognition receptors (NOD2 and TLR1), autophagic flux (PARK2, LRRK2, and RIPK2), effector immune cytokines (TNF and IL12), and environmental factors, such as nutrition, have been described as critical determinants for infection and disease progression. While parkin-mediated autophagy is observed as being essential for mycobacterial clearance, leprosy patients present a prominent activation of the type I IFN pathway and its downstream genes, including OASL, CCL2, and IL10. Activation of this host response is related to a permissive phenotype through the suppression of IFN-γ response and negative regulation of autophagy. Finally, modulation of host metabolism was observed during mycobacterial infection. Both changes in lipid and glucose homeostasis contribute to the persistence of mycobacteria in the host. M. leprae-infected cells have an increased glucose uptake, nicotinamide adenine dinucleotide phosphate generation by pentose phosphate pathways, and downregulation of mitochondrial activity. In this review, we discussed new pathways involved in the early mycobacteria-host interaction that regulate innate immune pathways or metabolism and could be new targets to host therapy strategies.