ABSTRACT
A better understanding of the regulatory mechanisms governing the development of memory CD8+ T cells could provide instructive insights into vaccination strategies and T cell-based immunotherapies. In this article, we showed that CD160 surface protein is required for CD8+ T cell memory formation. In the response to acute lymphocytic choriomeningitis virus infection in a mouse model, CD160 ablation resulted in the failure of the development of all three memory CD8+ T cell subsets (central, effective, and tissue-resident memory), concomitant with a skewed differentiation into short-lived effector T cells. Such memory-related defect was manifested by a diminished protection from viral rechallenge. Mechanistically, CD160 deficiency led to downregulation of 4-1BB in activated CD8+ T cells, which contributes to the impaired cell survival and decreased respiratory capacity. The nexus between CD160 and 4-1BB was substantiated by the observation that ectopic introduction of 4-1BB was able to largely complement the loss of CD160 in memory CD8+ T cell development. Collectively, our studies discovered that CD160, once thought to be a coinhibitor of T cell signaling, is an essential promoter of memory CD8+ T cell development via activation of the costimulatory molecule 4-1BB.
ABSTRACT
OBJECTIVES: To investigate the efficacy and safety of nusinersen sodium in the treatment of children with spinal muscular atrophy (SMA). METHODS: A retrospective analysis was conducted on the clinical data of 50 children with 5q SMA who received nusinersen sodium treatment and multidisciplinary treatment management in Shanxi Children's Hospital from February 2022 to February 2024. RESULTS: Compared with the baseline data, 67% (8/12), 74% (35/47), and 74% (35/47) of the SMA children had a clinically significant improvement in the scores of Philadelphia Infant Test of Neuromuscular Disorders, Hammersmith Functional Motor Scale Expanded, and Revised Upper Limb Module, respectively, and the distance of 6-minute walking test increased from 207.00 (179.00, 281.50) meters to 233.00 (205.25, 287.50) meters (P<0.05) after nusinersen sodium treatment. Of all 50 children with SMA, 24 (48%) showed good tolerability after administration, with no significant or persistent abnormalities observed in 2 034 laboratory test results, and furthermore, there were no serious or immunological adverse events related to the treatment. After treatment, there was a significant change in forced vital capacity as a percentage of the predicted value in 27 children with restrictive ventilatory dysfunction, as well as a significant change in the level of 25-(OH) vitamin D in 15 children with vitamin D deficiency (P<0.05). CONCLUSIONS: For children with SMA, treatment with nusinersen sodium can continuously improve the response rates of motor function scales, with good tolerability and safety.
Subject(s)
Oligonucleotides , Humans , Male , Female , Retrospective Studies , Oligonucleotides/therapeutic use , Oligonucleotides/adverse effects , Infant , Child, Preschool , Muscular Atrophy, Spinal/drug therapy , Child , Treatment Outcome , Spinal Muscular Atrophies of Childhood/drug therapyABSTRACT
In temporal compressive imaging (TCI), high-speed object frames are reconstructed from measurements collected by a low-speed detector array to improve the system imaging speed. Compared with iterative algorithms, deep learning approaches utilize a trained network to reconstruct high-quality images in a short time. In this work, we study a 3D convolutional neural network for TCI reconstruction to make full use of the temporal and spatial correlation among consecutive object frames. Both simulated and experimental results demonstrate that our network can achieve better reconstruction quality with fewer number of layers.
ABSTRACT
BACKGROUND: The immune protective mechanisms during severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection remain to be deciphered for the development of an effective intervention approach. METHODS: We examined early responses of interleukin 37 (IL-37), a powerful anti-inflammatory cytokine, in 254 SARS-CoV-2-infected patients before any clinical intervention and determined its correlation with clinical prognosis. RESULTS: Our results demonstrated that SARS-CoV-2 infection causes elevation of plasma IL-37. Higher early IL-37 responses were correlated with earlier viral RNA negative conversion, chest computed tomographic improvement, and cough relief, consequently resulted in earlier hospital discharge. Further assays showed that higher IL-37 was associated with lower interleukin 6 and interleukin 8 (IL-8) and higher interferon α responses and facilitated biochemical homeostasis. Low IL-37 responses predicted severe clinical prognosis in combination with IL-8 and C-reactive protein. In addition, we observed that IL-37 administration was able to attenuate lung inflammation and alleviate respiratory tissue damage in human angiotensin-converting enzyme 2-transgenic mice infected with SARS-CoV-2. CONCLUSIONS: Overall, we found that IL-37 plays a protective role by antagonizing inflammatory responses while retaining type I interferon, thereby maintaining the functionalities of vital organs. IL-37, IL-8, and C-reactive protein might be formulated as a precise prediction model for screening severe clinical cases and have good value in clinical practice.
Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/virology , Interleukin-1/blood , Adult , Animals , C-Reactive Protein/metabolism , COVID-19/blood , Female , Humans , Inflammation/immunology , Inflammation/virology , Interleukin-8/blood , Male , Mice , Mice, Transgenic , Middle AgedABSTRACT
For applications such as remote sensing and bio-imaging, images from multiple bands can provide much richer information compared to a single band. However, most multispectral imaging systems have difficulty in acquiring images for high-speed moving objects. In this paper, we use a DMD-based temporal compressive imaging (TCI) system to obtain high-speed images of moving objects over a broad dual-band spectral range, in the visible and the near-infrared (NIR) bands simultaneously. To deal with the degraded reconstruction caused by the optics, four nonuniform calibration strategies are studied, which can also be implemented into other compressive imaging systems. Moving objects covered by paint or through a diffuser are reconstructed to demonstrate the superior performance of the calibrated broad dual-band TCI system.
ABSTRACT
In the mid-wave infrared (MIR) band, large detector arrays are extremely costly and technically difficult to be manufactured. Thus, it is difficult to obtain high-resolution images for a conventional MIR camera. Spatial compressive imaging can improve resolution. However, system errors due to misalignment or optical aberrations degrade reconstruction quality significantly. Another common issue for compressive imaging is the slow imaging speed, which is caused by slow measurement collection and reconstruction processes. To deal with the two issues, we use an imaging calibration method to improve reconstruction quality and a sliding window measurement collection strategy plus a reconstruction algorithm accelerated by parallel computing to fasten the speed. We build a prototype of a compressive imaging camera with an angular resolution 1.17 lp/mrad. A four-bar target is used as an object. We reconstruct a moving scene of size $1280 \times 1024$ with a frame rate 20 frames per second.
ABSTRACT
Progesterone (P4) are aquatic contaminants that can impair fish reproduction even in low concentrations. The aim of this study was to investigate the effects of P4 on the sex differentiation, by quantitative determination of transcriptional changes of a candidate target gene (dax1, has a function in the sex determination and gonadal differentiation of several vertebrate species) in Misgurnus anguillicaudatus. We first cloned and characterized the full-length cDNAs for the dax1 in M. anguillicaudatus (designated as Ma-dax1). Sequence analysis reveals that Ma-dax1 shares high homology with dax1 in other species. Quantitative real-time PCR (qRT-PCR) and in situ hybridization showed that Ma-dax1 gene was highly conserved during vertebrate evolution and involved in a wide range of developmental processes including embryogenesis, central nervous system development and gonad development. For the P4 administration assay, groups of mature fish were exposed for 1, 7, 14, 21 and 28 days to nominal concentrations of 10, 100, and 1000 ng/L P4 in a flow-through system. Quantification of Ma-dax1 transcripts revealed the expression of Ma-dax1 mRNA is altered after P4 treatment in mature gonads. Those showed that P4 could influence the sexual development and sex differentiation in M. anguillicaudatus by disturbing sex differentiation-associated gene expression, and dax1 can be used as a sensitive molecular biomarker for early warning to monitor the environmental progestins chemicals in fresh water environment.
Subject(s)
Cloning, Molecular/drug effects , DAX-1 Orphan Nuclear Receptor/genetics , Progesterone/toxicity , Sex Differentiation/drug effects , Animals , Cypriniformes/genetics , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/drug effects , Male , Progesterone/administration & dosage , RNA, Messenger/metabolism , Sexual Development/drug effects , Time FactorsABSTRACT
A number of studies have established that in vertebrates, Sox3 is involved in a wide range of developmental processes, including sex differentiation and neurogenesis. However, the exact functions of the Sox3 gene have not been documented so far in teleosts. Here, we cloned the full length cDNA of Sox3 from the teleost fish, Paramisgurnus dabryanus, which we designated PdSox3. Sequence analysis revealed that PdSox3 encodes a hydrophilic protein, and shares high homology with Sox3 in other species, ranging from mammals to fishes. Quantitative real-time reverse transcription PCR, and in situ hybridization showed that PdSox3 is consistently expressed during embryogenesis, mainly localized in the developing central nervous system. Tissue distribution analyses revealed that PdSox3 is abundant in the adult brain, especially in particle cell layer. Furthermore, PdSox3 expression was higher in gonads, in primary spermatocyte cells, primary oocytes, and previtellogenic oocyte cells. All of these results suggest that PdSox3 plays an important role in early embryonic development, in particular the formation and development of the nervous system, and gonad development, similarly to other vertebrates. This is the first report describing Sox3 gene expression from this species, and the results are necessary to provide fundamental information on both the functional and evolutionary role of Sox3 across different species.
Subject(s)
Cypriniformes/embryology , Cypriniformes/genetics , Fish Proteins/genetics , SOXB1 Transcription Factors/genetics , Animals , Cloning, Molecular , Fish Proteins/chemistry , Phylogeny , SOXB1 Transcription Factors/chemistry , Sequence Homology, Amino Acid , TranscriptomeABSTRACT
Persistent immune activation during chronic human immunodeficiency virus type 1 (HIV-1) infection facilitates immune dysfunction and thereby fuels disease progression. The translocation of bacterial derivatives into blood and the hyperinflammatory responsiveness of monocytes have been considered important causative factors for persistent immune activation. Whether microRNAs (miRNAs) are involved in regulating monocyte-mediated inflammatory responses during chronic HIV-1 infection remains elusive. In this study, we show that miR-126-5p functions as a positive regulator of monocyte-mediated inflammatory responses. Significantly increased miRNA miR-126-5p and decreased cylindromatosis (CYLD) were observed in primary monocytes from chronic HIV-1 patients. Inhibition of miR-126-5p in monocytes from chronic HIV-1 patients attenuated the responsiveness of these cells to lipopolysaccharide (LPS) stimulation. Gain-of-function assays confirmed that miR-126-5p could downregulate CYLD, which in turn caused an upregulation of phosphorylation of JNK protein (pJNK) and enhanced inflammatory responses of monocytes to LPS stimulation. Overall, miR-126-5p upregulates the responsiveness of monocytes to LPS stimulation in chronic HIV-1 infection, and the suppression of miR-126-5p and the promotion of CYLD expression in primary monocytes may represent a practical immune intervention strategy to contain persistent inflammation in chronic HIV-1 infection.IMPORTANCE Monocyte-mediated hyperinflammatory responses during chronic HIV-1 infection are important causative factors driving AIDS progression; however, the underlying mechanism has not been fully addressed. We demonstrated that miR-126-5p, one of the most upregulated miRNAs during chronic HIV-1 infection, could enhance the inflammatory responses of monocytes to LPS by suppressing the inhibitory protein CYLD and thereby unleashing the expression of pJNK in the LPS/Toll-like receptor 4/mitogen-activated protein kinase pathway. This observation reveals a new mechanism for HIV-1 pathogenesis, which could be targeted by immune intervention.
Subject(s)
Gene Expression Regulation , HIV Infections/immunology , Lipopolysaccharides/immunology , MicroRNAs/genetics , MicroRNAs/immunology , Monocytes/immunology , Tumor Suppressor Proteins/genetics , Chronic Disease , Deubiquitinating Enzyme CYLD , Down-Regulation , Humans , Inflammation , MAP Kinase Signaling System , Tumor Suppressor Proteins/metabolism , Up-RegulationABSTRACT
Owing to ongoing recognition of pathogen-associated molecular patterns, immune activation and upregulation of IFN-stimulated genes (ISGs) are sustained in the chronically infected host. Albeit most ISGs are important effectors for containing viral replication, some might exert compensatory immune suppression to limit pathological dysfunctions, although the mechanisms are not fully understood. In this study, we report that the ISG lymphocyte Ag 6 complex, locus E (LY6E) is a negative immune regulator of monocytes. LY6E in monocytes negatively modulated CD14 expression and subsequently dampened the responsiveness to LPS stimulation in vitro. In the setting of chronic HIV infection, the upregulation of LY6E was correlated with reduced CD14 level on monocytes; however, the immunosuppressive effect of LY6E was not adequate to remedy the hyperresponsiveness of activated monocytes. Taken together, the regulatory LY6E pathway in monocytes represents one of negative feedback mechanisms that counterbalance monocyte activation, which might be caused by LPS translocation through the compromised gastrointestinal tract during persistent HIV-1 infection and may serve as a potential target for immune intervention.
Subject(s)
Antigens, Surface/immunology , HIV Infections/immunology , HIV-1/immunology , Interferon-alpha/immunology , Lipopolysaccharide Receptors/immunology , Monocytes/immunology , Toll-Like Receptor 4/immunology , Adult , Antigens, Surface/genetics , Cell Line, Tumor , Female , GPI-Linked Proteins/genetics , GPI-Linked Proteins/immunology , Gastrointestinal Tract/immunology , HIV Infections/virology , HeLa Cells , Humans , Immune Tolerance , Interferon Regulatory Factors/genetics , Interferon-alpha/pharmacology , Lipopolysaccharide Receptors/biosynthesis , Lipopolysaccharides/immunology , Male , Middle Aged , RNA Interference , RNA, Small Interfering , Signal Transduction/immunology , Tumor Necrosis Factor-alpha/biosynthesis , Up-Regulation , Virus Replication/immunologyABSTRACT
HIV-1 primarily infects activated CD4+ T cells and macrophages. Quiescent CD4+ T cells, however, possess cellular factors that limit HIV-1 infection at different postentry steps of the viral life cycle. Here, we show that the previously reported immune regulator monocyte chemotactic protein-induced protein 1 (MCPIP1) restricts HIV-1 production in CD4+ T cells. While the ectopic expression of MCPIP1 in cell lines abolished the production of HIV-1, silencing of MCPIP1 enhanced HIV-1 production. Subsequent analysis indicated that MCPIP1 imposes its restriction by decreasing the steady levels of viral mRNA species through its RNase domain. Remarkably, common T-cell stimuli induced the rapid degradation of MCPIP1 in both T-cell lines and quiescent human CD4+ T cells. Lastly, blocking the proteosomal degradation of MCPIP1 by MG132 abrogated HIV-1 production in phorbol 12-myristate 13-acetate/ionomycin-stimulated human CD4+ T cells isolated from healthy donors. Overall, MCPIP1 poses a potent barrier against HIV-1 infection at a posttranscriptional stage. Although the observed HIV restriction conferred by MCPIP1 does not seem to be overcome by any viral protein, it is removed during cellular stimulation. These findings provide insights into the mechanisms of cellular activation-mediated HIV-1 production in CD4+ T cells.
Subject(s)
CD4-Positive T-Lymphocytes/metabolism , HIV Infections/prevention & control , Ribonucleases/metabolism , Transcription Factors/metabolism , Blotting, Northern , HEK293 Cells , Humans , Immunoblotting , Leupeptins/pharmacology , Lymphocyte Activation/immunology , Proteolysis/drug effects , RNA, Small Interfering/genetics , Real-Time Polymerase Chain ReactionABSTRACT
MISA (MicroSAtelite) software was employed to screen SSRs in 68 787 contigs of Swertia mussotii transcriptome sequences. 5 610 SSRs were distributed in 5 099 contigs which accounted for 7.41% of 68 787 contigs. There are 220 kinds of SSR motifs existing in S. mussotii transcriptome. On average, SSRs occurred every 12.60 kb in length. In the SSRs, the tri-nucleotide repeat motif was the most abundant (45.99%), followed by the di-nucleotide (41.62%). AT/TA and AAT/TTA were the main types of motif in di-, tri-nucleotide repeats. The repeat numbers of SSRs which from S. mussotii transcriptome SSRs were mainly from 5 to 10 and motif length of them mostly ranged from 12 bp to 30 bp. A total of 30 651 contigs were annotated, and only 1 447 SSRs were occurred in protein-coding regions. In the six repeat motifs, tri-nucleotide repeats were the most abundant in coding regions (928). There are abundant SSRs in S. mussotii transcriptome with high frequency and various types, indicating their usefulness in theory. This research may lay the foundation for designing the targeted SSR primers and developing SSR molecular markers by mining the information of SSRs loci in S. mussotii transcriptome sequences data.
Subject(s)
Data Mining , Medicine, Tibetan Traditional , Microsatellite Repeats , Swertia/genetics , Transcriptome , Plants, Medicinal/geneticsABSTRACT
Oxidative stress is generated in several peripheral nerve injury models. In response to oxidative stress, the transcription factor Nrf2 is activated to induce expression of antioxidant responsive element (ARE) genes. The role of Nrf2 in peripheral nerve injury has not been studied to date. In this study, we used a sciatic nerve crush model to examine how deletion of Nrf2 affects peripheral nerve degeneration and regeneration. Our study demonstrated that functional recovery in the Nrf2(-/-) mice were impaired compared to the wild type mice after sciatic nerve crush. Larger myelin debris were present in the distal nerve stump of the Nrf2(-/-) mice than in the wild type mice. The presence of larger myelin debris in the Nrf2(-/-) mice coincides with less macrophages accumulation in the distal nerve stump. Less accumulation of macrophages may have contributed to slower clearance of myelin and thus resulted in the presence of larger myelin debris. Meanwhile, axonal regeneration is comparatively lower in the Nrf2(-/-) mice than in the wild type mice. Even after 3months post the injury, more thinly myelinated axon fibers were present in the Nrf2(-/-) mice than in the wild type mice. Taken collectively, these data support the concept of therapeutic intervention with Nrf2 activators following nerve injury.
Subject(s)
NF-E2-Related Factor 2/metabolism , Nerve Degeneration/metabolism , Nerve Regeneration/physiology , Peripheral Nerve Injuries/pathology , Recovery of Function/physiology , Animals , Axons/metabolism , Axons/physiology , Blotting, Western , Immunohistochemistry , Mice , Mice, Knockout , Myelin Sheath/pathology , Nerve Crush , Nerve Degeneration/pathology , Peripheral Nerve Injuries/complications , Sciatic Nerve/injuriesABSTRACT
A number of genetic studies have established that Sox10 involved in a wide range of developmental processes including sex differentiation and neurogenesis in vertebrates. A Sox10 homologue was cloned from brain of Paramisgurnus dabryanus by using homologous cloning and RACE method, designated as PdSox10. The full-length cDNA of PdSox10 contains a 312 bp 5' UTR, a 1,476 bp open reading frame (ORF) encoding 492 amino acids and a 262 bp 3' UTR (Accession no.: JQ217143). The overall topology of the phylogenetic tree shows that the PdSox10 fits within the Sox10 clade. During embryogenesis, PdSox10 gene seemed to be de novo synthesized in the embryos from gastrulae stage. From the somitogenesis stage and thereafter, distinct expression of PdSox10 was observed in the medial neural tube, extending from the hindbrain through the posterior trunk. In adult, PdSox10 mRNA was detected primarily in the gonads, as well as in brain and heart by RT-PCR. In situ hybridization on gonadal sections further demonstrated that PdSox10 is expressed especially in premature germ cells, in early perinucleolus stage oocytes and cortical-alveolar stage oocytes in ovaries and in spermatogonia and spermatocytes in testes. These preliminary findings suggested that PdSox10 is highly conserved during vertebrate evolution and involved in a wide range of developmental processes including neurogenesis and sex differentiation in vertebrates.
Subject(s)
Cypriniformes/genetics , Embryonic Development , SOXE Transcription Factors/genetics , Animals , Brain/metabolism , Cloning, Molecular , Gene Expression Regulation, Developmental , RNA, Messenger/geneticsABSTRACT
A number of genetic studies have established that Sox10 is a transcription factor associated with neurogenesis in vertebrates. We have isolated a homologue of Sox10 gene from the brain of Misgurnus anguillicaudatus by using homologous cloning and RACE method, designated as MaSox10b. The full-length cDNA of MaSox10b contained a 311 bp 5'UTR, a 312 bp 3'UTR and an ORF encoding a putative protein of 490 amino acids with a characteristic HMG-box DNA-binding domain of 79 amino acids (aa: 105-183). Phylogenetic tree shows that the MaSOX10b fits within the Sox10 clade and clusters firmly into Sox10b branches. During embryogenesis, MaSox10b was first detected in gastrulae stage. From somitogenesis stage and thereafter, distinct expression was observed in the medial neural tube, extending from the hindbrain through the posterior trunk. Taken together, these preliminary findings suggested that MaSox10b is highly conserved during vertebrate evolution and involved in a wide range of developmental processes including embryogenesis and neurogenesis.
Subject(s)
Brain/metabolism , Cypriniformes/embryology , Cypriniformes/genetics , Gene Expression Regulation, Developmental/physiology , Neurogenesis/physiology , SOXE Transcription Factors/genetics , SOXE Transcription Factors/metabolism , Animals , Base Sequence , Cloning, Molecular , Computational Biology , DNA Primers/genetics , DNA, Complementary/genetics , Gene Expression Regulation, Developmental/genetics , In Situ Hybridization/veterinary , Molecular Sequence Data , Neural Tube/metabolism , Neurogenesis/genetics , Phylogeny , Polymerase Chain Reaction , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNA/veterinaryABSTRACT
A major theme of host against invading pathogens lies in multiple regulatory nodes that ensure sufficient signals for protection while avoiding excessive signals toward over-inflammation. The TLR4/MD-2/CD14 complex receptor-mediated response to bacterial lipopolysaccharide (LPS) represents a paradigm for understanding the proper control of anti-pathogen innate immunity. In this study, we studied the mechanism by which the glycosylphosphatidylinositol (GPI)-linked LY6E protein constrains LPS response via downregulating CD14. We first showed that LY6E downregulated CD14 via ubiquitin-dependent proteasomal degradation. The subsequent profiling of LY6E protein interactome led to the revelation that the degradation of CD14 by LY6E requires PHB1, which interacts with CD14 in a LY6E-dependent manner. Finally, we identified the PHB1-interacting TRIM21 as the major ubiquitin E3 ligase for the LY6E-mediated ubiquitination of CD14. Together, our study elucidated the molecular basis of LY6E-mediated governance of LPS response, alongside providing new insights to regulatory mechanisms controlling the homeostasis of membrane proteins.
ABSTRACT
The intracellular second messenger cAMP is frequently used in induction media to induce mesenchymal stem cells (MSCs) into neural lineage cells. To date, an understanding of the role cAMP exerts on MSCs and whether cAMP can induce MSCs into functional neurons is still lacking. We found cAMP initiated neuron-like morphology changes early and neural differentiation much later. The early phase changes in morphology were due to cell shrinkage, which subsequently rendered some cells apoptotic. While the morphology changes occurred prior to the expression of neural markers, it is not required for neural marker expression and the two processes are differentially regulated downstream of cAMP-activated protein kinase A. cAMP enabled MSCs to gain neural marker expressions with neuronal function, such as, calcium rise in response to neuronal activators, dopamine, glutamate, and potassium chloride. However, only some of the cells induced by cAMP responded to the three neuronal activators and further lack the neuronal morphology, suggesting that although cAMP is able to direct MSCs towards neural differentiation, they do not achieve terminal differentiation.
Subject(s)
Cell Differentiation , Cyclic AMP/physiology , Mesenchymal Stem Cells/cytology , Neurons/cytology , Animals , Apoptosis , Biomarkers , Calcium/metabolism , Cells, Cultured , Female , Mesenchymal Stem Cells/metabolism , Rats , Rats, Sprague-DawleyABSTRACT
Growing lines of evidence supported the importance of CD8+ lung tissue resident memory T (TRM) cells in protection against respiratory viruses, exemplified by influenza A virus. However, the underlying in vivo mechanism remains largely undetermined. Here, we used mouse infection models to dissect in vivo cross-protective activity of lung CD8+ TRM cells. By simultaneously interrogating transcriptional dynamics in lung CD8+ TRM cells and surrounding tissues during the early course of infection, we demonstrated that lung CD8+ TRM cells react to antigen re-exposure within hours, manifested by IFN-γ upregulation, and a tissue-wide interferon-stimulated gene (ISG) program is subsequently elicited. Using antibody-mediated IFN-γ neutralization and IFN-γ receptor knockout mice, we could show that the induction of several important antiviral ISGs required IFN-γ signaling, so did the suppression of key inflammatory cytokines. Interestingly, there were also examples of ISGs unaffected in the absence of IFN-γ activity. Collectively, focusing on in situ characterization of lung CD8+ TRM cells during very early stage of infection, a critical period of host antiviral defense that has been poorly investigated, our studies highlight that these cells, once triggered by antigen re-exposure, are programmed to produce IFN-γ expeditiously to promote a lung-wide antiviral response for effective virus control.
Subject(s)
CD8-Positive T-Lymphocytes , Immunologic Memory , Animals , Antigens , Antiviral Agents , Interferon-gamma , Lung , MiceABSTRACT
The outcome of infection with influenza A virus is determined by a complex virus-host interaction. A new H7N9 virus of avian origin crossed the species barrier to infect humans, causing high mortality and emerged as a potential pandemic threat. The mechanisms underlying the virulence and pathogenicity of H7N9 virus remains elusive. H7N9 virus originated from a genetic assortment that involved the avian H9N2 virus, which was the donor of the six internal genes. Unlike the H7N9 virus, the H9N2 virus caused only mild phenotype in infected mice. In this study, we used the mouse infection model to dissect the difference in the host response between the H7N9 and H9N2 viruses. Through analyzing transcriptomics of infected lungs, we surprisingly found that the H9N2 infection elicited an earlier induction of innate immunity than H7N9 infection. This finding was further corroborated by an immunohistochemical study demonstrating earlier recruitment of macrophage to the H9N2-infected lung than the H7N9-infected lung, which could occur as early as 6 hours post infection. In contrast, H7N9 infection was characterized by a late, strong lung CD8+ T cell response that is more robust than H9N2 infection. The different pattern of immune response may underlie more severe lung pathology caused by H7N9 infection compared to H9N2 infection. Finally, we could show that co-infection of the H9N2 virus protected mice from the challenge of both H7N9 and PR8 viruses, thereby strengthening the importance of the induction of an early innate immunity in the host's defense against influenza infection. Collectively, our study unraveled a previously unidentified difference in host response between H7N9 and H9N2 infection and shed new insight on how virus-host interaction shapes the in vivo outcome of influenza infection.
Subject(s)
Influenza A Virus, H7N9 Subtype , Influenza A Virus, H9N2 Subtype , Influenza in Birds , Influenza, Human , Animals , Disease Models, Animal , Humans , Immunity, Innate , MiceABSTRACT
Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) results in high susceptibility to infection. Although granulocytic myeloid-derived suppressor cells (gMDSC) are elevated in patients with HBV-ACLF, their role in HBV-ACLF pathogenesis is unknown. To elucidate the mechanism of gMDSC expansion and susceptibility to infection in HBV-ACLF patients, we analyzed the proportion of gMDSC in the peripheral blood and organ tissues of patients with HBV-ACLF and an ACLF mouse model established by continuous injection (eight times) of Concanavalin by flow cytometry and immunohistochemistry. We found that the proportion of gMDSC increased significantly in the blood and liver of patients with HBV-ACLF. This increase was positively correlated with disease severity, prognosis, and infection. gMDSC percentages were higher in peripheral blood, liver, spleen, and bone marrow than control levels in the ACLF mouse model. Immunofluorescence revealed that the gMDSC count increased in the liver of patients with HBV-ACLF as well as in the liver and spleen of ACLF mice. We further exposed peripheral blood monocyte cells from healthy donors to plasma from HBV-ACLF patients, recombinant cytokines, or their inhibitor, and found that TNF-α led to gMDSC expansion and significant upregulation of indoleamine 2, 3-dioxygenase (IDO), while blocking TNF-α signaling decreased gMDSC. Moreover, we detected proliferation and cytokine secretion of T lymphocytes when purified gMDSC was co-cultured with Pan T cells or IDO inhibitor and found that TNF-α-induced gMDSC inhibited T cell proliferation and interferon-γ production through the IDO signaling pathway. Lastly, the ability of gMDSC to phagocytose bacteria was low in patients with HBV-ACLF. Our findings elucidate HBV-ACLF pathogenesis and provide potential therapeutic targets.