Manipulation of the MHC-I presentation pathway, and thus limiting MHC-I cell surface expression, is used by many viruses to evade immune recognition. In particular, downregulation of MHC-I molecules ...at the cell surface can reduce the ability of CD8
T cells to recognize viral peptides presented by MHC-I molecules and thereby delay viral clearance by CD8
T cells. To date, MHC-I downregulation by influenza viruses has not been reported. Given that influenza virus infections are a global health concern and that CD8
T cells play an important role in promoting influenza virus clearance and recovery from influenza disease, we investigated whether influenza A and B viruses (IAV, IBV) downregulated MHC-I as a novel mechanism to evade cellular immunity. Here, we showed that infection of several cell types, including epithelial A549 cells, with a panel of IAV and IBV viruses downregulated the surface MHC-I expression on IAV/IBV-infected cells during the late stages of influenza virus infection
. This observation was consistent across a panel of class I-reduced (C1R) cell lines expressing 14 different HLA-A or -B alleles and a panel of 721.221 cell lines expressing 11 HLA-C alleles. Interestingly, IBV infection caused more pronounced reduction in surface MHC-I expression compared to IAV. Importantly, the two viruses utilized two distinct mechanisms for MHC-I downregulation. Our data demonstrated that while IAV caused a global loss of MHC-I within influenza-infected cells, IBV infection resulted in the preferential loss of MHC-I molecules from the cell surface, consequent of delayed MHC-I trafficking to the cell surface, resulting from retaining MHC-I intracellularly during IBV infection. Overall, our study suggests that influenza viruses across both IAV and IBV subtypes have the potential to downregulate MHC-I surface expression levels. Our findings provide new insights into the host-pathogen interaction of influenza A and B viruses and inform the design of novel vaccine strategies against influenza viruses.
Infection triggers large-scale changes in the phenotype and function of T cells that are critical for immune clearance, yet the gene regulatory mechanisms that control these changes are largely ...unknown. Using ChIP-seq for specific histone post-translational modifications (PTMs), we mapped the dynamics of ∼25,000 putative CD8+ T cell transcriptional enhancers (TEs) differentially utilized during virus-specific T cell differentiation. Interestingly, we identified a subset of dynamically regulated TEs that exhibited acquisition of a non-canonical (H3K4me3+) chromatin signature upon differentiation. This unique TE subset exhibited characteristics of poised enhancers in the naive CD8+ T cell subset and demonstrated enrichment for transcription factor binding motifs known to be important for virus-specific CD8+ T cell differentiation. These data provide insights into the establishment and maintenance of the gene transcription profiles that define each stage of virus-specific T cell differentiation.
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•Virus-specific CTLs exhibit specific changes in enhancer activity upon activation•H3K4me3 is acquired at lineage-specific enhancers in activated CTL•H3K4me3 is deposited predominantly at TEs initially poised in the naive state•H3K4me3+ enhancers are specific targets for T cell-specific transcription factors
Russ et al. demonstrate that a subset of poised transcriptional enhancers found in naive virus-specific CD8+ T cells acquire a non-canonical chromatin signature upon differentiation. These data provide the genomic location for T cell lineage-specific transcription factor binding that is necessary for virus-specific T cell differentiation.
Knowns and unknowns of influenza B viruses Koutsakos, Marios; Nguyen, Thi HO; Barclay, Wendy S ...
Future microbiology,
2016-January-01, 2016-00-00, 2016-01-00, 20160101, Volume:
11, Issue:
1
Journal Article
Peer reviewed
Open access
Influenza B viruses (IBVs) circulate annually along with influenza A (IAV) strains during seasonal epidemics. IBV can dominate influenza seasons and cause severe disease, particularly in children and ...adolescents. Research has revealed interesting aspects of IBV and highlighted the importance of these viruses in clinical settings. Yet, many important questions remain unanswered. In this review, the clinical relevance of IBV is emphasized, unique features in epidemiology, host range and virology are highlighted and gaps in knowledge pinpointed. Multiple aspects of IBV epidemiology, evolution, virology and immunology are discussed. Future research into IBV is needed to understand how we can prevent severe disease in high-risk groups, especially children and elderly.
Seasonal influenza virus infections cause 290,000–650,000 deaths annually and severe morbidity in 3–5 million people. CD8+ T-cell responses towards virus-derived peptide/human leukocyte antigen (HLA) ...complexes provide the broadest cross-reactive immunity against human influenza viruses. Several universally-conserved CD8+ T-cell specificities that elicit prominent responses against human influenza A viruses (IAVs) have been identified. These include HLA-A*02:01-M158-66 (A2/M158), HLA-A*03:01-NP265-273, HLA-B*08:01-NP225-233, HLA-B*18:01-NP219-226, HLA-B*27:05-NP383-391 and HLA-B*57:01-NP199-207. The immunodominance hierarchies across these universal CD8+ T-cell epitopes were however unknown. Here, we probed immunodominance status of influenza-specific universal CD8+ T-cells in HLA-I heterozygote individuals expressing two or more universal HLAs for IAV. We found that while CD8+ T-cell responses directed towards A2/M158 were generally immunodominant, A2/M158+CD8+ T-cells were markedly diminished (subdominant) in HLA-A*02:01/B*27:05-expressing donors following ex vivo and in vitro analyses. A2/M158+CD8+ T-cells in non-HLA-B*27:05 individuals were immunodominant, contained optimal public TRBV19/TRAV27 TCRαβ clonotypes and displayed highly polyfunctional and proliferative capacity, while A2/M158+CD8+ T cells in HLA-B*27:05-expressing donors were subdominant, with largely distinct TCRαβ clonotypes and consequently markedly reduced avidity, proliferative and polyfunctional efficacy. Our data illustrate altered immunodominance patterns and immunodomination within human influenza-specific CD8+ T-cells. Accordingly, our work highlights the importance of understanding immunodominance hierarchies within individual donors across a spectrum of prominent virus-specific CD8+ T-cell specificities prior to designing T cell-directed vaccines and immunotherapies, for influenza and other infectious diseases.
Parthenogenesis is an activation process of oocytes that occur without the participation of sperm. Evidence suggests that normal development of embryos requires proper expression of several imprinted ...genes inherited from both the paternal and maternal genomes. Compared to gene expression, histone modifications and chromatin remodeling are not well-documented. In this research, by using immunofluorescence staining for several developmental-associated histone modifications, we investigated whether epigenetic impairments in parthenogenetic embryos act as constraints for proper development. At early stages, fertilized embryos exhibited high methylation of histone H3 at lysine 9 (Me-H3-K9) and Heterochromatin Protein 1 (HP1) present in the maternal chromatin, while paternal chromatin showed weaker HP1 signals. We found that at the two-cell stage in fertilized embryos, HP1, initially detected around the nucleolus, colocalized with chromocenters at one pole of the blastomere, while parthenotes showed a diffused distribution pattern of HP1 throughout the entire nucleoplasm. At the four-cell stage, methylation of histone H3 at arginine 26 (Me-H3-R26) increased at nascent RNA repression sites in fertilized embryos, while parthenotes recorded weaker signals throughout the nucleoplasm, suggesting differences in pluripotency of the ICM cells between the two types of embryos. Moreover, at the blastocyst stage, we observed that the acetylation level of histone H4 at lysine 12 (Ac-H4-K12) was significantly decreased in parthenogenetic ICM compared to that in its fertilized counterpart. To summarize, differences in epigenetic modifications correlating with paternal chromatin’s capacity to regulate nascent RNA repression may contribute to aberrant development and lineage allocation in mouse parthenogenetic embryos.
Indigenous people worldwide are at high risk of developing severe influenza disease. HLA-A*24:02 allele, highly prevalent in Indigenous populations, is associated with influenza-induced mortality, ...although the basis for this association is unclear. Here, we define CD8
T-cell immune landscapes against influenza A (IAV) and B (IBV) viruses in HLA-A*24:02-expressing Indigenous and non-Indigenous individuals, human tissues, influenza-infected patients and HLA-A*24:02-transgenic mice. We identify immunodominant protective CD8
T-cell epitopes, one towards IAV and six towards IBV, with A24/PB2
-specific CD8
T cells being cross-reactive between IAV and IBV. Memory CD8
T cells towards these specificities are present in blood (CD27
CD45RA
phenotype) and tissues (CD103
CD69
phenotype) of healthy individuals, and effector CD27
CD45RA
PD-1
CD38
CD8
T cells in IAV/IBV patients. Our data show influenza-specific CD8
T-cell responses in Indigenous Australians, and advocate for T-cell-mediated vaccines that target and boost the breadth of IAV/IBV-specific CD8
T cells to protect high-risk HLA-A*24:02-expressing Indigenous and non-Indigenous populations from severe influenza disease.
CD8+ T cells play an important role in vaccination and immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although numerous SARS-CoV-2 CD8+ T cell epitopes have ...been identified, the molecular basis underpinning T cell receptor (TCR) recognition of SARS-CoV-2-specific T cells remains unknown. The T cell response directed toward SARS-CoV-2 spike protein–derived S269–277 peptide presented by the human leukocyte antigen (HLA)-A∗02:01 allomorph (hereafter the HLA-A2S269–277 epitope) is, to date, the most immunodominant SARS-CoV-2 epitope found in individuals bearing this allele. As HLA-A2S269–277-specific CD8+ T cells utilize biased TRAV12 gene usage within the TCR α-chain, we sought to understand the molecular basis underpinning this TRAV12 dominance. We expressed four TRAV12+ TCRs which bound the HLA-A2S269–277 complex with low micromolar affinity and determined the crystal structure of the HLA-A2S269–277 binary complex, and subsequently a ternary structure of the TRAV12+ TCR complexed to HLA-A2S269–277. We found that the TCR made extensive contacts along the entire length of the S269–277 peptide, suggesting that the TRAV12+ TCRs would be sensitive to sequence variation within this epitope. To examine this, we investigated cross-reactivity toward analogous peptides from existing SARS-CoV-2 variants and closely related coronaviruses. We show via surface plasmon resonance and tetramer studies that the TRAV12+ T cell repertoire cross-reacts poorly with these analogous epitopes. Overall, we defined the structural basis underpinning biased TCR recognition of CD8+ T cells directed at an immunodominant epitope and provide a framework for understanding TCR cross-reactivity toward viral variants within the S269–277 peptide.
Arsenic (As) contamination in soil, water and air is an alarming issue worldwide and has serious effects on human health and environment. Arsenic is a naturally occurring element found in rocks, ...soil, and water, and exposure to high levels of arsenic can lead to a range of health problems. The effects of arsenic contamination can also be felt in the environment, as it can harm plants and animals and disrupt ecological systems. The major purpose of this study was to produce transgenic plants with improved tolerance to and accumulation of arsenic via transformation of arsenate reductase gene (ArsC) into tobacco genome. Transgenic plants were screen by PCR and southern blot. Further, their tolerance and accumulation to arsenic were evaluated. In the result, we have cloned, characterized, and transformed the ArsC gene from Pityrogramma calomelanos L. (PcArsC). Its phylogenetic analysis revealed 99% homology to ArsC gene in GenBank (accession number X80057.1). Moreover, Southern blot analysis showed that ArsC gene was integrated into the tobacco genome as a single-copy. These single-copy transgenic lines showed much higher tolerance to and accumulation of As than wild type, with no other phenotypes observed. These results demonstrated that Pityrogramma calomelanos ArsC gene can improve arsenic tolerance and accumulation in transgenic tobacco lines. Thus, using Pityrogramma calomelanos L. ArsC gene for genetic engineering has potential implications in the decontamination of arsenic-containing soil.
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