Search Results (28)

Recent studies have shown that long noncoding RNAs (lncRNAs) play pivotal roles in the development and progression of cancer. In the present study, we aimed to identify lncRNAs associated with lymph node metastasis in pancreatic ductal adenocarcinoma (PDAC). We analyzed data from The Cancer Genome Atlas (TCGA) database to screen for genes overexpressed in primary PDAC tumors with lymph node metastasis. Our screen revealed 740 genes potentially associated with lymph node metastasis, among which were multiple lncRNA genes located in the HOXA locus, including HOXA11-AS. Elevated expression of HOXA11-AS was associated with more advanced tumor stages and shorter overall survival in PDAC patients. HOXA11-AS knockdown suppressed proliferation and migration of PDAC cells. RNA-sequencing analysis revealed that HOXA11-AS knockdown upregulated interferon lambda (IFNL) family genes and downregulated high-mobility group box (HMGB) family genes in PDAC cells. Moreover, HMGB3 knockdown suppressed proliferation and migration by PDAC cells. These results suggest that HOXA11-AS contributes to PDAC progression, at least in part, through regulation of IFNL and HMGB family genes and that HOXA11 AS is a potential therapeutic target in PDAC. Full article

The rs12979860 polymorphism, related to the IFNL4 gene, is suggested as a factor that impacts fibrosis progression in hepatitis C virus (HCV) infection and exhibits a wide distribution pattern across global populations. In this retrospective cross-sectional study, we aimed to investigate the frequency of this variant in an Amazonian population from Brazil, as well as its association with liver fibrosis development and its staging in HCV carriers. Our results show a significant association of the TT genotype in the sample of patients with HCV (OR = 2.291; 95% CI = 1.088–4.826; p = 0.033) and the greater frequency of the T allele (62.1%), which is similar to the those of African populational groups. Populational genetics analysis showed significant differences in allele frequencies on global levels. The frequency of the C allele in the study population (37.8%) was like that of the African population (39.7%), and differed from all other populations, which ranged from 62.5% to 92.9%. These findings suggest that rs12979860 plays a role in susceptibility to hepatitis C. Additionally, they allow us to propose that the response to hepatitis C infection in this group may resemble that of the African population. Full article

It is heavily suggested that one IFNL4 gene polymorphism, rs12979860 (T/C), exerts influence on the outcome of HBV infection, with the rs12979860-T allele being classified as a risk predictor, and the rs12979860-C allele being classified as a protective one. This study investigated whether the rs12979860 IFNL4 gene polymorphism presented any association with the clinical severity for HBV carriers in an admixed population in Northern Brazil. A total of 69 samples were investigated from infected people from the city of Belém-Pará. The rs12979860-T allele was positively associated with HBV infection, suggesting a higher risk of chronicity. This research’s importance is that the polymorphism influence was investigated in a population of HBV carriers with a heterogeneous genetic profile, formed through the extensive admixture of different ethnic groups, including Europeans, Africans, and Natives with indigenous heritage. This analysis is particularly important since highly mixed populations do not always follow the same association patterns previously established by studies using populations classified as more genetically homogeneous, due to a different formation process. Full article

Since the discovery of the polymorphic nature of the IFNL4 gene, its variants have been investigated and associated with several viral diseases, with an emphasis on hepatitis C. However, the impacts of these variants on mixed-race and native populations in the northern region of Brazil are scarce. We investigated three variants of the IFNL4 gene in populations from this location, which were among the 14 most frequent variants in worldwide populations, and compared the frequencies obtained to populational data from the 1000 Genomes Project, gnomAD and ABraOM databases. Our results demonstrate that mixed-race and native populations from the northern region of Brazil present frequencies like those of European and Asian groups for the rs74597329 and rs11322783 variants, and like all populations presented for the rs4803221 variant. These data reinforce the role of world populations in shaping the genetic profile of Brazilian populations, indicate patterns of illness according to the expressed genotype, and infer an individual predisposition to certain diseases. Full article

Porcine epidemic diarrhea virus (PEDV) has led to significant economic losses in the global porcine industry since the emergence of variant strains in 2010. The high mutability of coronaviruses endows PEDV with the ability to evade the host immune response, which impairs the effectiveness of vaccines. In our previous study, we generated a highly cell-passaged PEDV strain, CT-P120, which showed promise as a live attenuated vaccine candidate by providing satisfactory protection against variant PEDV infection in piglets. However, the mechanism by which the attenuated CT-P120 adapts to cells during passage, resulting in increased replication efficiency, remains unclear. To address this question, we conducted a comparative transcriptomic analysis of Vero E6 cells infected with either the original parental strain (CT-P10) or the cell-attenuated strain (CT-P120) of PEDV at 6, 12, and 24 h post-infection. Compared to CT-P10, CT-P120 infection resulted in a significant decrease in the number of differentially expressed genes (DEGs) at each time point. Functional enrichment analysis of genes revealed the activation of various innate immune-related pathways by CT-P10, notably attenuated during CT-P120 infection. To validate these results, we selected eight genes (TRAF3, IRF3, IFNL1, ISG15, NFKB1, MAP2K3, IL1A, and CCL2) involved in antiviral processes and confirmed their mRNA expression patterns using RT-qPCR, in line with the transcriptomic data. Subsequent protein-level analysis of selected genes via Western blotting and enzyme-linked immunosorbent assay corroborated these results, reinforcing the robustness of our findings. Collectively, our research elucidates the strategies underpinning PEDV attenuation and immune evasion, providing invaluable insights for the development of effective PEDV vaccines. Full article

Interferon lambdas (IFNLs) are innate immune cytokines that induce antiviral cellular responses by signaling through a heterodimer composed of IL10RB and the interferon lambda receptor 1 (IFNLR1). Multiple IFNLR1 transcriptional variants are expressed in vivo and are predicted to encode distinct protein isoforms whose function is not fully established. IFNLR1 isoform 1 has the highest relative transcriptional expression and encodes the full-length functional form that supports canonical IFNL signaling. IFNLR1 isoforms 2 and 3 have lower relative expression and are predicted to encode signaling-defective proteins. To gain insight into IFNLR1 function and regulation, we explored how altering relative expression of IFNLR1 isoforms influenced the cellular response to IFNLs. To achieve this, we generated and functionally characterized stable HEK293T clones expressing doxycycline-inducible FLAG-tagged IFNLR1 isoforms. Minimal FLAG-IFNLR1 isoform 1 overexpression markedly increased IFNL3-dependent expression of antiviral and pro-inflammatory genes, a phenotype that could not be further augmented by expressing higher levels of FLAG-IFNLR1 isoform 1. Expression of low levels of FLAG-IFNLR1 isoform 2 led to partial induction of antiviral genes, but not pro-inflammatory genes, after IFNL3 treatment, a phenotype that was largely abrogated at higher FLAG-IFNLR1 isoform 2 expression levels. Expression of FLAG-IFNLR1 isoform 3 partially augmented antiviral gene expression after IFNL3 treatment. In addition, FLAG-IFNLR1 isoform 1 significantly reduced cellular sensitivity to the type-I IFN IFNA2 when overexpressed. These results identify a unique influence of canonical and non-canonical IFNLR1 isoforms on mediating the cellular response to interferons and provide insight into possible pathway regulation in vivo. Full article

Although advanced age, male sex, and some comorbidities impact the clinical course of COVID-19, these factors only partially explain the inter-individual variability in disease severity. Some studies have shown that genetic polymorphisms contribute to COVID-19 severity; however, the results are inconclusive. Thus, we investigated the association between polymorphisms in ACE1, ACE2, DPP9, IFIH1, IFNAR2, IFNL4, TLR3, TMPRSS2, and TYK2 and the clinical course of COVID-19. A total of 694 patients with COVID-19 were categorized as: (1) ward inpatients (moderate symptoms) or patients admitted at the intensive care unit (ICU; severe symptoms); and (2) survivors or non-survivors. In females, the rs1990760/IFIH1 T/T genotype was associated with risk of ICU admission and death. Moreover, the rs1799752/ACE1 Ins and rs12329760/TMPRSS2 T alleles were associated with risk of ICU admission. In non-white patients, the rs2236757/IFNAR2 A/A genotype was associated with risk of ICU admission, while the rs1799752/ACE1 Ins/Ins genotype, rs2236757/IFNAR2 A/A genotype, and rs12329760/TMPRSS2 T allele were associated with risk of death. Moreover, some of the analyzed polymorphisms interact in the risk of worse COVID-19 outcomes. In conclusion, this study shows an association of rs1799752/ACE1, rs1990760/IFIH1, rs2236757/IFNAR2, rs12329760/TMPRSS2, and rs2304256/TYK2 polymorphisms with worse COVID-19 outcomes, especially among female and non-white patients. Full article

The persistence of high-risk (HR) human papillomavirus (HPV) genotypes is a prerequisite of cervical cancer. It is not clear whether and how bacterial vaginosis (BV) and sexually transmitted infections (STIs) cause higher rates of persistent HPV infection. This study aimed to characterize mucosal innate immunity to HPV, comparing different conditions. Specifically, expression levels of genes coding for Toll-like receptors (TLR)7 and 9, several type III Interferon-related genes (IFNL1, 2, 3, their specific receptor subunit IFNLR1, and the IFN-stimulated gene ISG15). Chemokines CCL5 and CCL20 were measured in cervical cells positive, or not, for HPV, BV, and STIs. HPV DNA was detected in 51/120 (42.5%) enrolled women, two/third were HR-HPV genotypes. More than 50% of samples were BV- and/or STI-positive. HPV-positive women had BV, but not other STIs, more frequently than the HPV-negative. TLR9 and IFNL1 mRNAs were expressed in the LR, but much less in the HR HPV infection. Enhanced levels of TLR9, TLR7, IFNL2, and IFNLR1 were observed in HPV-positive women with BV and STI. TLR9-increased expression was associated with HPV persistence in previous studies; hence, bacterial coinfections may enhance this risk. Prospective measurements of type III IFNs and IFNLR1 are warranted to evaluate whether this response may act as a double-edged sword in infected epithelia. Full article

Type III and type I interferon have similar mechanisms of action, and their different receptors lead to different distributions in tissue. On mucosal surfaces, type III interferon exhibits strong antiviral activity. Porcine epidemic diarrhea virus (PEDV) is an economically important enteropathogenic coronavirus, which can cause a high incidence rate and mortality in piglets. Here, we demonstrate that porcine interferon lambda 1 (pIFNL1) and porcine interferon lambda 3 (pIFNL3) can inhibit the proliferation of vesicular stomatitis virus with an enhanced green fluorescent protein (VSV-EGFP) in different cells, and also show strong antiviral activity when PEDV infects Vero cells. Both forms of pIFNLs were shown to be better than porcine interferon alpha (pIFNα), the antiviral activity of pIFNL1 is lower than that of pIFNL3. Therefore, our results provide experimental evidence for the inhibition of PEDV infection by pIFNLs, which may provide a promising treatment for the prevention and treatment of Porcine epidemic diarrhea (PED) in piglets. Full article

Given the role of pharmacogenomics in the large variability observed in drug efficacy/safety, an assessment about the pharmacogenomic profile of patients prior to drug prescription or dose adjustment is paramount to improve adherence to treatment and prevent adverse drug reaction events. A population commonly underrepresented in pharmacogenomic studies is the Native American populations, which have a unique genetic profile due to a long process of geographic isolation and other genetic and evolutionary processes. Here, we describe the pharmacogenetic variability of Native American populations regarding 160 pharmacogenes involved in absorption, distribution, metabolism, and excretion processes and biological pathways of different therapies. Data were obtained through complete exome sequencing of individuals from 12 different Amerindian groups of the Brazilian Amazon. The study reports a total of 3311 variants; of this, 167 are exclusive to Amerindian populations, and 1183 are located in coding regions. Among these new variants, we found non-synonymous coding variants in the DPYD and the IFNL4 genes and variants with high allelic frequencies in intronic regions of the MTHFR, TYMS, GSTT1, and CYP2D6 genes. Additionally, 332 variants with either high or moderate (disruptive or non-disruptive impact in protein effectiveness, respectively) significance were found with a minimum of 1% frequency in the Amazonian Amerindian population. The data reported here serve as scientific basis for future design of specific treatment protocols for Amazonian Amerindian populations as well as for populations admixed with them, such as the Northern Brazilian population. Full article

HLA-B*57:01 is an HLA allelic variant associated with positive outcomes during viral infections through interactions with T cells and NK cells, but severe disease in persons treated with the anti-HIV-1 drug abacavir. The role of HLA-B*57:01 in the context of HSV infection is unknown. We identified an HLA-B*57:01-restricted CD8 T-cell epitope in the ICP22 (US1) protein of HSV-2. CD8 T cells reactive to the HSV-2 ICP22 epitope recognized the orthologous HSV-1 peptide, but not closely related peptides in human IFNL2 or IFNL3. Abacavir did not alter the CD8 T-cell recognition of the HSV or self-derived peptides. Unexpectedly, a tetramer of HSV-2 ICP22 epitope (228–236) and HLA-B*57:01 bound both CD8 T cells and NK cells. Tetramer specificity for KIR3DL1 was confirmed using KIR3DL1 overexpression on non-human primate cells lacking human KIR and studies with blocking anti-KIR3DL1 antibody. Interaction with KIR3DL1 was generalizable to donors lacking the HLA-B*57:01 genotype or HSV seropositivity. These findings suggest a mechanism for the recognition of HSV infection by NK cells or KIR-expressing T cells via KIR3DL1. Full article

Type III interferons (IFN-III), also known as IFN-Lambda, have a pivotal role during SARS-CoV-2 infection. IFN-Lambda response among individuals is heterogeneous and its association with COVID-19 symptoms severity needs to be further clarified. We analyzed the genotype frequencies of IFNL4 single nucleotide polymorphism (SNP) rs11322783 in patients with COVID-19 (n = 128), in comparison with a validated data set of European healthy controls (n = 14152). The IFNL4 SNP was also analyzed according to the haematological and clinical parameters of patients with COVID-19. The distributions of IFNL4 genotypes among SARS-CoV-2 positive patients [TT/TT 41.4% (n = 53), TT/ΔG 47.7% (n = 61) and ΔG/ΔG 10.9% (n = 14)] and healthy controls were comparable. Different levels of white blood cells (p = 0.036) and neutrophils (p = 0.042) were found in the IFNL4 different genotypes in patients with COVID-19; the ΔG/ΔG genotype was more represented in the groups with low white blood cells and neutrophils. There were no differences in major inflammation parameters (C-reactive protein, D-dimer, Albumin, and Lactate-dehydrogenase (LDH)] and survival rate according to the IFNL4 genotypes. In conclusion, although patients with COVID-19 did not exhibit a different distribution of the IFNL4 SNP, the ΔG/ΔG genotype was associated with a lower count of immune cell populations. These findings need to be confirmed in larger groups of patients with COVID-19 and the role of IFNL4 SNP needs to be also investigated in other respiratory viral infections. Full article

The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1–9 ligands for 6–24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection. Full article

Growth is an important heritable economic trait for dromedaries and necessary for planning a successful breeding program. Until now, genome-wide association studies (GWAS) and QTL-mapping have identified significant single nucleotide polymorphisms (SNPs) associated with growth in domestic animals, but in dromedaries, the number of studies is very low. This project aimed to find biological themes affecting growth in dromedaries. In the first step, 99 candidate SNPs were chosen from a previously established set of SNPs associated with body weight, gain, and birth weight in Iranian dromedaries. Next, 0.5 kb upstream and downstream of each candidate SNP were selected from NCBI (assembly accession: GCA_000803125.3). The annotation of fragments with candidate SNPs regarding the reference genome was retrieved using the Blast2GO tool. Candidate SNPs associated with growth were mapped to 22 genes, and 25 significant biological themes were identified to be related to growth in dromedaries. The main biological functions included calcium ion binding, protein binding, DNA-binding transcription factor activity, protein kinase activity, tropomyosin binding, myosin complex, actin-binding, ATP binding, receptor signaling pathway via JAK-STAT, and cytokine activity. EFCAB5, MTIF2, MYO3A, TBX15, IFNL3, PREX1, and TMOD3 genes are candidates for improving growth in camel breeding programs. Full article

Congenital Zika syndrome (CZS) is characterized by a diverse group of congenital malformations induced by ZIKV infection during pregnancy. Type III interferons have been associated with placental immunity against ZIKV and restriction of vertical transmission in mice, and non-coding single-nucleotide polymorphisms (SNPs) on these genes are well known to influence susceptibility to other viral infections. However, their effect on ZIKV pathogenesis has not yet been explored. To investigate whether maternal non-coding SNPs at IFNL genes are associated with CZS, 52 women infected with ZIKV during pregnancy were enrolled in a case–control association study. A total of 28 women were classified as cases and 24 as controls based on the presence or absence of CZS in their infants, and seven Interferon-λ non-coding SNPs (rs12980275, rs8099917, rs4803217, rs4803219, rs8119886, rs368234815, rs12979860) were genotyped. The results of logistic regression analyses show an association between the G allele at rs8099917 and increased susceptibility to CZS under a log-additive model (_adjustedOR = 2.80; _95%CI = 1.14–6.91; p = 0.02), after adjustment for trimester of infection and genetic ancestry. These results provide evidence of an association between Interferon-λ SNPs and CZS, suggesting rs8099917 as a promising candidate for further studies on larger cohorts. Full article