Suppression Of Immune Response Research Articles

The segmented flavivirus Alongshan virus reduces mitochondrial mass by degrading STAT2 to suppress the innate immune response.

Alongshan virus (ALSV) is a newly discovered pathogen in the Flaviviridae family, characterized by a unique multi-segmented genome that is distantly related to the canonical flaviviruses. Understanding the pathogenic mechanism of this emerging segmented flavivirus is crucial for the development of effective intervention strategies. In this study, we demonstrate that ALSV can infect various mammalian cells and induce the expression of antiviral genes. Furthermore, ALSV is sensitive to IFN-β, but it has developed strategies to counteract the host's type I IFN response. Mechanistically, ALSV's nonstructural protein NSP1 interacts with and degrades human STAT2 through an autophagy pathway, with species-dependent effects. This degradation directly inhibits the expression of interferon-stimulated genes (ISGs). Additionally, NSP1-mediated degradation of STAT2 disrupts mitochondrial dynamics, leading to mitophagy and inhibition of mitochondrial biogenesis. This, in turn, suppresses the host's innate immune response. Interestingly, we found that inhibiting mitophagy using 3-methyladenine and enhancing mitochondrial biogenesis with the PPARγ agonist pioglitazone can reverse NSP1-mediated inhibition of ISGs, suggesting that promoting mitochondrial mass could serve as an effective antiviral strategy. Specifically, the NSP1 methyltransferase domain binds to the key sites of F175/R176 located in the coiled-coil domain of STAT2. Our findings provide valuable insights into the intricate regulatory cross talk between ALSV and the host's innate immune response, shedding light on the pathogenesis of this emerging segmented flavivirus and offering potential intervention strategies.IMPORTANCEAlongshan virus (ALSV), a segmented flavivirus belonging to the Flaviviridae family, was first identified in individuals who had been bitten by ticks in Northeastern China. ALSV infection is responsible for causing Alongshan fever, a condition characterized by various clinical symptoms, including fever, headache, skin rash, myalgia, arthralgia, depression, and coma. There is an urgent need for effective antiviral therapies. Here, we demonstrate that ALSV is susceptible to IFN-β but has developed mechanisms to counteract the host's innate immune response. Specifically, the ALSV nonstructural protein NSP1 interacts with STAT2, leading to its degradation via an autophagy pathway that exhibits species-dependent effects. Additionally, NSP1 disrupts mitochondrial dynamics and suppresses mitochondrial biogenesis, resulting in a reduction in mitochondrial mass, which ultimately contributes to the inhibition of the host's innate immune response. Interestingly, we found that inhibiting mitophagy and promoting mitochondrial biogenesis can reverse NSP1-mediated suppression of innate immune response by increasing mitochondrial mass. These findings provide valuable insights into the molecular mechanisms of ALSV pathogenesis and suggest potential therapeutic targets against ALSV infection.

Immunohaemostasis and the significance of immune reactions in the regulation of blood coagulation.

This study was conducted to determine the specific features of the mutual influence of the immune and haemostatic systems in immunohaemostasis, the role of immune reactions in the regulationof blood coagulation, and the efficacy of modern methods of treating thrombosis andbleeding. The study analysed relevant scientific sources on immunology and haematology and identified the specific features of the blood clotting process and the role of immune reactions in it. The study found that the immune system influences the haematological system through the interaction of blood clotting factors, platelets, plasminogen, endothelial cells with immune cells. Thehaemostatic system influences the immune system through mechanisms to maintain immune tolerance and immune memory and the properties of clotting factors to activate the stimulation and migration of immune cells to the site of infection. Immune reactions regulate blood coagulation by activating platelets, regulating blood coagulation factors, affecting fibrinolysis, and immune tolerance. The process of platelet activation involves immune cells, immune complexes, and microbial components.The regulation of blood coagulation factors is influenced by the ability of immune cells to produce activators and inhibitors of these factors and to stimulate or slow down fibrinolysis. The immune system's maintenance of immune tolerance to blood components is regulated by mechanisms of immune response suppression, partial immune ignoring of certain blood elements, inhibition of activation of certain immune cells, apoptosis, and selection of immature T-lymphocytes. Treatment methods for patients at risk of thrombosis and bleeding include anticoagulation, antiplatelet, dual antiplatelet therapy, thrombectomy, endovascular methods, medical prophylaxis of bleeding, and coagulation monitoring. The findings of this study suggest the significance of immune responses in the regulation of blood coagulation processes, and therefore they can be used in the development of immunotherapy methods for the treatment of thrombosis and bleeding.

Coronavirus nucleocapsid protein enhances the binding of p-PKCα to RACK1: Implications for inhibition of nucleocytoplasmic trafficking and suppression of the innate immune response.

The hallmark of coronavirus infection lies in its ability to evade host immune defenses, a process intricately linked to the nuclear entry of transcription factors crucial for initiating the expression of antiviral genes. Central to this evasion strategy is the manipulation of the nucleocytoplasmic trafficking system, which serves as an effective target for the virus to modulate the expression of immune response-related genes. In this investigation, we discovered that infection with the infectious bronchitis virus (IBV) dynamically impedes the nuclear translocation of several transcription factors such as IRF3, STAT1, STAT2, NF-κB p65, and the p38 MAPK, leading to compromised transcriptional induction of key antiviral genes such as IFNβ, IFITM3, and IL-8. Further examination revealed that during the infection process, components of the nuclear pore complex (NPC), particularly FG-Nups (such as NUP62, NUP153, NUP42, and TPR), undergo cytosolic dispersion from the nuclear envelope; NUP62 undergoes phosphorylation, and NUP42 exhibits a mobility shift in size. These observations suggest a disruption in nucleocytoplasmic trafficking. Screening efforts identified the IBV nucleocapsid (N) protein as the agent responsible for the cytoplasmic distribution of FG-Nups, subsequently hindering the nuclear entry of transcription factors and suppressing the expression of antiviral genes. Interactome analysis further revealed that the IBV N protein interacts with the scaffold protein RACK1, facilitating the recruitment of activated protein kinase C alpha (p-PKCα) to RACK1 and relocating the p-PKCα-RACK1 complex to the cytoplasm. These observations are conserved across diverse coronaviruses N proteins. Concurrently, the presence of both RACK1 and PKCα/β proved essential for the phosphorylation and cytoplasmic dispersion of NUP62, the suppression of antiviral cytokine expression, and efficient virus replication. These findings unveil a novel, highly effective, and evolutionarily conserved mechanism.

Downy mildew effector HaRxL106 interacts with the transcription factor BIM1 altering plant growth, BR signaling and susceptibility to pathogens.

Hyaloperonospora arabidopsidis (Hpa) is an oomycete pathogen that causes downy mildew disease on Arabidopsis. This obligate biotroph manipulates the homeostasis of its host plant by secreting numerous effector proteins, among which are the RxLR effectors. Identifying the host targets of effectors and understanding how their manipulation facilitates colonization of plants are key to improve plant resistance to pathogens. Here we characterize the interaction between the RxLR effector HaRxL106 and BIM1, an Arabidopsis transcription factor (TF) involved in Brassinosteroid (BR) signaling. We report that HaRxL106 interacts with BIM1 in vitro and in planta. BIM1 is required by the effector to increase the host plant susceptibility to (hemi)biotrophic pathogens, and thus can be regarded as a susceptibility factor. Mechanistically, HaRxL106 requires BIM1 to induce the transcriptional activation of BR-responsive genes and cause alterations in plant growth patterns that phenocopy the shade avoidance syndrome. Our results support previous observations of antagonistic interactions between activation of BR signaling and suppression of plant immune responses and reveal that BIM1, a new player in this crosstalk, is manipulated by the pathogenic effector HaRxL106.

The SARS-CoV-2 ORF6 protein inhibits nuclear export of mRNA and spliceosomal U snRNA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 19 (COVID-19). SARS-CoV-2 infection suppresses host innate immunity and impairs cell viability. Among the viral proteins, ORF6 exhibits potent interferon (IFN) antagonistic activity and cellular toxicity. It also interacts with the RNA export factor RAE1, which bridges the nuclear pore complex and nuclear export receptors, suggesting an effect on RNA export. Using the Xenopus oocyte microinjection system, I found that ORF6 blocked the export of not only mRNA but also spliceosomal U snRNA. I further demonstrated that ORF6 affects the interaction between RAE1 and nuclear export receptors and inhibits the RNA binding of RAE1. These effects of ORF6 may cumulatively block the export of several classes of RNA. I also found that ORF6 binds RNA and forms oligomers. These findings provide insights into the suppression of innate immune responses and the reduction in cell viability caused by SARS-CoV-2 infection, contributing to the development of antiviral drugs targeting ORF6.

Stress Can Induce Bovine Alpha-Herpesvirus 1 (BoHV-1) Reactivation from Latency.

Bovine alpha-herpesvirus 1 (BoHV-1) is a significant problem for the cattle industry, in part because the virus establishes latency, and stressful stimuli increase the incidence of reactivation from latency. Sensory neurons in trigeminal ganglia and unknown cells in pharyngeal tonsils are importantsites for latency. Reactivation from latency can lead to reproductive problems in pregnant cows, virus transmission to young calves, suppression of immune responses, and bacterial pneumonia. BoHV-1 is also a significant cofactor in bovine respiratory disease (BRD). Stress, as mimicked by the synthetic corticosteroid dexamethasone, reproducibly initiates reactivation from latency. Stress-mediated activation of the glucocorticoid receptor (GR) stimulates viral replication and transactivation of viral promoters that drive the expression of infected cell protein 0 (bICP0) and bICP4. Notably, GR and Krüppel-like factor 15 (KLF15) form a feed-forward transcription loop that cooperatively transactivates immediate early transcription unit 1 (IEtu1 promoter). Two pioneer transcription factors, GR and KLF4, cooperatively transactivate the bICP0 early promoter. Pioneer transcription factors bind silent viral heterochromatin, remodel chromatin, and activate gene expression. Thus, wepredict that these novel transcription factors mediate early stages of BoHV-1 reactivation from latency.

Dynamics of clinical and immunological parameters in retinal pigment epithelium transplantation in the context of combined immunosuppressive therapy in the rabbit model of retinal degeneration

Progressive damage of the retinal pigment epithelium (RPE) underlies the pathogenesis of degenerative retinal diseases such as: age-related macular degeneration (AMD), Stargardt’s disease, retinitis pigmentosa, Best’s disease and others. This group of diseases led by AMD leads to irreversible loss of visual functions, blindness and disability. The possibilities of therapy of late stages of AMD are extremely limited. The most promising approach to replace the damaged retinal pigment epithelium appears to be transplantation of RPE cells derived from induced pluripotent stem cells (iPSC-RPE) into the subretinal space (SRS). Despite immune privilege in the SRS, transplantation of xenogeneic cellular material causes severe inflammation in the posterior segment of the eye and leads to graft rejection in an in vivo experiment in the absence of immunosuppression. The solution to the problem of tissue incompatibility in this case can be the use of combined immunosuppressive therapy (CIT), aimed, on the one hand, at suppression of local inflammation (in the eye) and, on the other hand, at suppression of the systemic transplantation immune response. The aim of the study: clinical and immunological analysis of the results of transplantation of IPSC-RPE suspension on the background of CIT, including single intravitreal intraoperative administration of kenalog and further systemic application of mycophenolate mofetil (MMF), in the model of RPE atrophy in rabbits. Standard and specialized ophthalmological examination was performed at early and distant terms after the intervention in order to clinically assess the posttransplantation process. To analyze the immune status, vitreous humor (VH) and blood serum (BS) of rabbits of the experimental groups were collected. The concentrations of TGF-β1, TGF-β2, and IL-2 were determined in the biomaterial using solid-phase enzyme immunoassay. According to the results of the study, subretinal transplantation of IPSC-RPE, performed against the background of combination of single intravitreal intraoperative administration of kenalog and systemic application of MMF, is a safe method, which provides preservation of the retina and other adjacent structures of the eye and allows to prevent rejection of xenogenic material during its transplantation both in a healthy eye and with pre-formed RPE atrophy, which opens perspectives for full testing of biological effects realized by IPSC-RPE.

Some parameters of the immune system in women with hyperandrogenism

The article is dedicated to studying certain parameters of the immune system, which holds great significance in obstetrics and gynecology. Examining immune system parameters allows for identifying disruptions in reproductive-aged women with hyperandrogenism, which holds crucial practical implications. The authors conducted an immunological study of women with hyperandrogenism and women without this pathology. The aim of the study was to investigate the immune system status in women suffering from hyperandrogenism. Materials and methods of the study: 58 reproductive-aged women diagnosed with hyperandrogenism, under observation at the Women’s Health Center “AyolCare” in Tashkent, were examined. Comprehensive clinical and laboratory examinations were conducted for all women. The control group comprised 35 practically healthy reproductive-aged women. The obtained results indicate that women with altered hormonal balance, including those with hyperandrogenism, experience specific changes in the immune system. The conducted research revealed that the levels of T lymphocytes and T helper/inducer cells decrease, while the number of T killer cells, CD25+ cells (carrying IL-2 receptor), and CD95+ cells (carrying apoptosis signaling receptor) increases. The elevated levels of CD95+ cells indicate increased activation of apoptosis processes, which serve as a protective function of T killer cells. This increase in lymphocyte activation is likely associated with elevated levels of mature activated macrophages and a range of cytokines they produce, which directly stimulate lymphocytes. The detected imbalance in immunological parameters likely indicates that in hyperandrogenism, either the elimination of activated clones of T helper cells is absent or disrupted, which usually leads to the formation of immune response suppression. The increase in the number of activated clones of T lymphocytes is observed in the decreased process of their apoptosis, which is likely intensified by the influence of androgens.

TRIP13: A promising cancer immunotherapy target.

The tumor microenvironment (TME) facilitates tumor development through intricate intercellular signaling, thereby supporting tumor growth and suppressing the immune response. Thyroid hormone receptor interactor 13 (TRIP13), an AAA+ ATPase, modulates the conformation of client macromolecules, consequently influencing cellular signaling pathways. TRIP13 has been implicated in processes such as proliferation, invasion, migration, and metastasis during tumor progression. Recent studies have revealed that TRIP13 also plays a role in immune response suppression within the TME. Thus, inhibiting these functions of TRIP13 could potentially enhance immune responses and improve the efficacy of immune checkpoint inhibition. This review summarizes the recent research progress of TRIP13 and discusses the potential of targeting TRIP13 to improve immune-based therapies for patients with cancer.

Peripheral Blood Mononuclear Cell Transcriptome of Dairy Cows Naturally Infected with Bovine Leukemia Virus.

The current literature has identified many abnormalities in the immune expression of cows infected with the bovine leukemia virus (BLV). These studies have focused on individual cell, gene, or protein expression, failing to provide a comprehensive understanding of the changes in immune expression in animals with BLV. To identify the overall alterations in immune expression during BLV infection, the transcriptomes of the peripheral blood mononuclear cells (PBMCs) of cows seropositive or seronegative for BLV antibodies were sequenced. Whole blood samples were collected from 20 dairy cows and screened for BLV antibodies and PCR was used to quantify the proviral load of the samples. PBMCs were separated from whole blood using density gradient centrifugation from which RNA was isolated and sequenced. Three seropositive samples (BLV+; n = 3), including one of each PVL category, low (n = 1), moderate (n = 1), and high (n = 1), and three seronegative samples (BLV-; n = 3) were sequenced for differential gene expression analysis. The results showed major differences in the transcriptome profiles of the BLV+ and BLV- PBMCs and revealed a wide variety of immunological pathways affected by BLV infection. Our results suggest that disease state and PBMC gene expression vary depending on BLV proviral load levels and that BLV causes the suppression of normal immune responses and influences B and T cell gene expression, resulting in immune dysfunction.

Aspartyl proteases target host actin nucleator complex protein to limit epithelial innate immunity

Epithelial-immune cell communication is pivotal to control microbial infections. We show that glycosylphosphatidylinositol-linked aspartyl proteases (Yapsins) of the human opportunistic pathogenic yeast Candida glabrata (Cg) thwart epithelial cell (EC)-neutrophil signalling by targeting the EC protein, Arpc1B (actin nucleator Arp2/3 complex subunit), which leads to actin disassembly and impeded IL-8 secretion by ECs. Further, the diminished IL-8 secretion inhibits neutrophil migration, and protects Cg from the neutrophil-mediated killing. CgYapsin-dependent Arpc1B degradation requires Arginine-142 in Arpc1B, and leads to reduced Arpc1B-p38 MAPK interaction and downregulated p38 signalling. Consistently, Arpc1B or p38 deletion promotes survival of the Cg aspartyl protease-deficient mutant in ECs. Importantly, kidneys of the protease-deficient mutant-infected mice display elevated immune cell infiltration and cytokine secretion, implicating CgYapsins in immune response suppression in vivo. Besides delineating Cg-EC interplay, our results uncover a novel target, Arpc1B, that pathogens attack to constrain the host signalling networks, and link Arpc1B mechanistically with p38 activation.

Fibrinogen induces inflammatory responses via the immune activating receptor LILRA2.

The leukocyte immunoglobulin-like receptor (LILR) family, a group of primate-specific immunoreceptors, is widely expressed on most immune cells and regulates immune responses through interactions with various ligands. The inhibitory type, LILRB, has been extensively studied, and many ligands, such as HLA class I, have been identified. However, the activating type, LILRA, is less understood. We have previously identified microbially cleaved immunoglobulin as a non-self-ligand for LILRA2. In this study, we identified fibrinogen as an endogenous ligand for LILRA2 using mass spectrometry. Although human plasma contains fibrinogen in abundance in its soluble form, LILRA2 only recognizes solid-phase fibrinogen. In addition to the activating LILRA2, fibrinogen was also recognized by the inhibitory LILRB2 and by soluble LILRA3. In contrast, fibrin was recognized by LILRB2 and LILRA3, but not by LILRA2. Moreover, LILRA3 bound more strongly to fibrin than to fibrinogen and blocked the LILRB2-fibrinogen/fibrin interaction. These results suggest that morphological changes in fibrinogen determine whether activating or inhibitory immune responses are induced. Upon recognizing solid-phase fibrinogen, LILRA2 activated human primary monocytes and promoted the expression of various inflammation-related genes, such as chemokines, as revealed by RNA-seq analysis. A blocking antibody against LILRA2 inhibited the fibrinogen-induced inflammatory responses, indicating that LILRA2 is the primary receptor of fibrinogen. Taken together, our findings suggest that solid-phase fibrinogen is an inflammation-inducing endogenous ligand for LILRA2, and this interaction may represent a novel therapeutic target for inflammatory diseases.

Aspergillus fumigatus-derived gliotoxin impacts innate immune cell activation through modulating lipid mediator production in macrophages.

Gliotoxin (GT), a secondary metabolite and virulence factor of the fungal pathogen Aspergillus fumigatus, suppresses innate immunity and supports the suppression of host immune responses. Recently, we revealed that GT blocks the formation of the chemotactic lipid mediator leukotriene (LT)B4 in activated human neutrophils and monocytes, and in rodents in vivo, by directly inhibiting LTA4 hydrolase. Here, we elucidated the impact of GT on LTB4 biosynthesis and the entire lipid mediator networks in human M1- and M2-like monocyte-derived macrophages (MDMs) and in human tissue-resident alveolar macrophages. In activated M1-MDMs with high capacities to generate LTs, the formation of LTB4 was effectively suppressed by GT, connected to attenuated macrophage phagocytic activity as well as human neutrophil movement and migration. In resting macrophages, especially in M1-MDMs, GT elicited strong formation of prostaglandins, while bacterial exotoxins from Staphylococcus aureus evoked a broad spectrum of lipid mediator biosynthesis in both MDM phenotypes. We conclude that GT impairs functions of activated innate immune cells through selective suppression of LTB4 biosynthesis, while GT may also prime the immune system by provoking prostaglandin formation in macrophages.

SARS-COV-2 CORONAVIRUS ANTIGENS MODULATE THE ACTIVITY OF HUMAN T-REGULATORY CELLS

Regulatory T cells (Treg cells) play a crucial role in regulation of immune response. It is believed that excessive activity of Treg cells in the early stages of infectious diseases reduces the pro-inflammatory activity of cells in the innate and adaptive immune response, thereby contributing to the development of chronic inflammation or excessive inflammation. Additionally, it is known that aging leads to changes in the quantity of Treg cells and disrupts their activity. It is established that infection with the SARS-CoV-2 virus leads to fatal and severe cases of the disease, primarily among the elderly population. However, the underlying cause of the development of severe forms in elderly individuals remains incompletely understood. Thus, we hypothesized that the dysregulation of the Treg cell activity in elderly individuals may contribute to the development of severe forms and lethality from SARS-CoV-2, leading to the emergence of hyper inflammation in this population. To investigate the impact of SARS-CoV-2 on the immunosuppressive properties of Treg cells, venous blood samples were obtained from young healthy volunteers and elderly individuals. Dendritic cells were obtained by PBMC adhesion on plastic. Adherent monocytes were cultured in cytokine medium with interleukin 4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-SCF), with addition of lipopolysaccharide (LPS) after 48 hours and incubated for an additional 24 hours with S1 or N antigens of SARS-CoV-2 virus. The obtained dendritic cells presenting SARS-CoV-2 antigens were then co-cultured with autologous CD4+-T lymphocytes ex vivo. The expression level of immunosuppressive membrane-associated and soluble molecules expressed by Treg cells was assessed using flow cytometry. Our results indicate that the immunosuppressive activity of Treg cells exhibits contrasting patterns in the two donor groups studied in response to the presentation of SARS-CoV-2 antigens. The proportion of Treg cells, as well as the expression levels of the immunosuppressive molecules, including tumor growth factor beta (TGF-b), CD39, glucocorticoid-induced tumor necrosis factor receptor-related (GITR) protein, and the levels of the intracellular immunosuppressive cytokines, including IL-10 and IL-35, in Treg cells obtained from peripheral blood of elderly donors, significantly increased in response to the presentation of SARS-CoV-2 antigens ex vivo, when compared to the group of young donors. Conversely, in the group of young donors were observed a decrease in the expression of these markers and an increase in the concentration of extracellular pro-inflammatory cytokines IL-2 and IFN-γ ex vivo, which activate the effector immune cells and contribute to virus elimination. In summary, the presented results suggest that Treg cells derived from elderly individuals exhibit elevated immunosuppressive activity in response to SARS-CoV-2 antigens ex vivo. Obtained results may indicate that in elderly individuals on the early stages of SARS-CoV-2 infection Treg cells may also possess enhanced immunosuppressive activity, which may contribute to the overall suppression of anti-viral immune responses, thereby potentially leading to the delayed SARS-CoV-2 virus clearance and development of severe forms of the disease.

The right educational environment: Oral tolerance in early life.

Oral tolerance promotes the suppression of immune responses to innocuous antigen and is primarily mediated by regulatory T cell (Tregs). The development of oral tolerance begins in early life during a "window of tolerance," which occurs around weaning and is mediated by components in breastmilk. Herein, we review the factors dictating this window and how Tregs are uniquely educated in early life. In early life, the translocation of luminal antigen for Treg induction is primarily dictated by goblet cell-associated antigen passages (GAPs). GAPs in the colon are negatively regulated by maternally-derived epidermal growth factor and the microbiota, restricting GAP formation to the "periweaning" period (postnatal day 11-21 in mice, 4-6 months in humans). The induction of solid food also promotes the diversification of the bacteria such that bacterially-derived metabolites known to promote Tregs-short-chain fatty acids, tryptophan metabolites, and bile acids-peak during the periweaning phase. Further, breastmilk immunoglobulins-IgA and IgG-regulate both microbial diversity and the interaction of microbes with the epithelium, further controlling which antigens are presented to T cells. Overall, these elements work in conjunction to induce a long-lived population of Tregs, around weaning, that are crucial for maintaining homeostasis in adults.

Plantago asiatica seed as a protective agent for mitigating metals toxicity on Penaeusvannamei

Plantago asiatica seeds (PS) are commonly used as a medicinal plant. This study investigates the efficacy of PS against heavy metal toxicity in white shrimp (Penaeus vannamei). After feeding PS diet (5 g/kg) or basal diet (control group) for 7 days, shrimps were exposed to sublethal concentrations of heavy metals in seawater (As: 12 mg/L, Pb: 250 mg/L, Hg: 0.4 mg/L). The 7-day survival observation showed that the survival in groups fed with PS were significantly higher than that in the control group, revealing that dietary PS had the efficacy to mitigate heavy metal toxicity in white shrimp. Under the same feeding condition, white shrimps were exposed to safety dose of heavy metals (1/10 of sublethal concentrations) to understand the mechanism of mitigation. The metal accumulations in haemolymph, gills, hepatopancreas, and muscle tissues as well as the immune, anti-oxidative, stress related gene expressions in haemocytes, gills and hepatopancreas were measured for 14 days. The As accumulation in gills and hepatopancreas of groups fed with PS were significantly lower than those of control group on day 7 and 14, respectively; The Pb concentration in haemolymph of group fed with PS was significantly lower than that of control group on day 7 and 14; The Hg concentration in hepatopancreas of the group fed with PS was significantly lower than that of control group on day 7. Dietary PS could mitigate heavy metal-induced immune suppression, oxidative stress, and stress response by positively regulating immune (proPO I, Toll, IMD), antioxidant (SOD, GST, Trx), and negatively regulating stress response genes (HSP70, MT). The present study demonstrated that dietary PS could protect white shrimp against metal toxicity by reducing metal accumulations and regulating the immune, antioxidant, and stress response gene expressions in specific tissue. Therefore, PS may serve as a beneficial feed additive in the aquaculture.

The immun function of dendritic cells in SFTS patients

ObjectivesSevere fever with thrombocytopenia syndrome (SFTS) is a newly emerging infectious disease caused by a novel bunyavirus in which host immune system suppression is thought to be crucial in disease development. Dendritic cells (DCs) are professional antigen-presenting cells (APCs) critical for initiation and orchestration of the immune response. And it have been suggested that functionally impaired DCs may mediate the suppression of host-specific T-cell immune responses and thus facilitate viral persistence and disease progression.This study was designed to improve the in vitro culture method for DCs and investigate the different immunologic functions of DCs between SFTS patients and healthy people. MethodsAll confirmed SFTS patients (N = 10) were recruited from the Jinan Infectious Diseases Hospital in 2019; routine laboratory parameters were collected. The frequencies, phenotypes were analyzed by flow cytometry. And the levels of 8 cytokines in the cell culture supernatant were detected by flow cytometry. ResultsOn day 8 of the incubation period, cells were harvested and analyzed by flow cytometry. There were significant differences in the rates of CD1a-, CD83-positive cells between SFTS patients and healthy people (all P < 0.05). The detection of 8 cytokines in the culture supernatant showed that the expressions of IFN-α and IFN-γ in the culture supernatant of DC cells in SFTS patients were lower than those in normal people (P < 0.05, P < 0.01). ConclusionsThe present results indicate that DCs may be functionally impaired in SFTS. A decreased level of circulating mDCs was closely correlated with SFTS progression.

Monocyte-to-platelets ratio (MPR) at diagnosis is associated with inferior progression-free survival in patients with mantle cell lymphoma: a multi-center real-life survey.

Mantle cell lymphoma (MCL) pathogenesis is strongly related to the role of the tumor immune microenvironment (TIME) in which MCL cells proliferate. TIME cells can produce growth signals influencing MCL cells' survival and exert an antitumoral immune response suppression. The activity of TIME cells might be mirrored by some ratios of peripheral blood cell subpopulations, such as the monocyte-to-platelet ratio (MPR). We reviewed the clinical features of 165 consecutive MCL patients newly diagnosed and not eligible for autologous stem cell transplantation (both for age or comorbidities) who accessed two Italian Centers between 2006 and 2020. MPR was calculated using data obtained from the complete blood cell count at diagnosis before any cytotoxic treatment and correlated with PFS. Univariate analysis showed that MPR ≥ 3 was associated with inferior PFS (p = 0.02). Multivariate analysis confirmed that MPR ≥ 3, LDH > 2.5 ULN, and bone marrow involvement were significant independent variables in predicting PFS. For these reasons, MPR ≥ 3 seems the most promising prognostic factor in patients with MCL, and it could be considered a variable in new predictive models.

Pyroptotic-Spatiotemporally Selective Delivery of siRNA against Pyroptosis and Autoimmune Diseases.

Small-interfering RNAs (siRNAs) offer promising prospects for treating pyroptosis-related autoimmune diseases. However, poor stability and off-target effects during in vivo transportation hinder their practical clinical applications. Precision delivery and adaptive release of siRNAs into inflamed tissues and immune cells could unleash their full therapeutic potential. This study establishes a pyroptotic-spatiotemporally selective siRNA delivery system (PMRC@siGSDME) that selectively targets inflammatory tissues, responds to pyroptosis, and exhibits remarkable therapeutic efficacy against various autoimmune diseases. Novel hybrid nanovesicles (NVs) are designed as a combination of pyroptotic macrophage membranes (PMs) and R8-cardiolipin-containing nanovesicles (RC-NVs). Evidence provides that PM-derived proteins involved in cell-cell interactions and membrane trafficking may contribute to the specificity of NVs to inflammatory tissue. In addition, cardiolipin anchored in the hybrid NVs increases its affinity for activated gasdermin E (GSDME) and achieves pyroptosis-adaptive release of siGSDME for the spatiotemporally selective suppression of immune responses. More importantly, PMRC@siGSDME displays significant anti-inflammatory and therapeutic effects in multiple mouse autoimmune disease models, including arthritis and inflammatory bowel disease (IBD). Collectively, an innovative siRNA delivery strategy precisely tailored for pyroptotic cells has been developed, paving the way for new treatments for autoimmune inflammatory diseases with minimal side effects and wide clinical applicability.

Proteomes of native and non-native symbionts reveal responses underpinning host-symbiont specificity in the cnidarian-dinoflagellate symbiosis.

Cellular mechanisms responsible for the regulation of nutrient exchange, immune responses, and symbiont population growth in the cnidarian-dinoflagellate symbiosis are poorly resolved, particularly with respect to the dinoflagellate symbiont. Here, we characterized proteomic changes in the native symbiont Breviolum minutum during colonization of its host sea anemone Exaiptasia diaphana ("Aiptasia"). We also compared the proteome of this native symbiont in the established symbiotic state with that of a non-native symbiont, Durusdinium trenchii. The onset of symbiosis between Aiptasia and Breviolum minutum increased the accumulation of symbiont proteins associated with the acquisition of inorganic carbon and photosynthesis, nitrogen metabolism, micro- and macronutrient starvation, suppression of host immune responses, tolerance to low pH, and management of oxidative stress. Such responses are consistent with a functional, persistent symbiosis. In contrast, D. trenchii predominantly showed elevated levels of immunosuppressive proteins, consistent with the view that this symbiont is an opportunist that forms a less beneficial, less well-integrated symbiosis with this model anemone. By adding symbiont analysis to the already known responses of the host proteome, our results provide a more holistic view of cellular processes that determine host-symbiont specificity and how differences in symbiont partners (i.e. native versus non-native symbionts) may impact the fitness of the cnidarian-dinoflagellate symbiosis.