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Frontiers in Immunology 2024is a bacterial pathogen that causes a variety of infections across diverse animal species, with one of the most devastating associated diseases being hemorrhagic...
BACKGROUND
is a bacterial pathogen that causes a variety of infections across diverse animal species, with one of the most devastating associated diseases being hemorrhagic septicemia. Outbreaks of hemorrhagic septicemia in cattle and buffaloes are marked by rapid progression and high mortality. These infections have particularly harmful socio-economic impacts on small holder farmers in Africa and Asia who are heavily reliant on a small number of animals kept as a means of subsistence for milk and draft power purposes. A novel vaccine target, PmSLP-3, has been identified on the surface of hemorrhagic septicemia-associated strains of and was previously shown to elicit robust protection in cattle against lethal challenge with a serogroup B strain.
METHODS
Here, we further investigate the protective efficacy of this surface lipoprotein, including evaluating the immunogenicity and protection upon formulation with a variety of adjuvants in both mice and cattle.
RESULTS
PmSLP-3 formulated with Montanide ISA 61 elicited the highest level of serum and mucosal IgG, elicited long-lasting serum antibodies, and was fully protective against serogroup B challenge. Studies were then performed to identify the minimum number of doses required and the needed protein quantity to maintain protection. Duration studies were performed in cattle, demonstrating sustained serum IgG titres for 3 years after two doses of vaccine and full protection against lethal serogroup B challenge at 7 months after a single vaccine dose. Finally, a serogroup E challenge study was performed, demonstrating that PmSLP-3 vaccine can provide protection against challenge by the two serogroups responsible for hemorrhagic septicemia.
CONCLUSION
Together, these data indicate that PmSLP-3 formulated with Montanide ISA 61 is an immunogenic and protective vaccine against hemorrhagic septicemia-causing strains in cattle.
Topics: Animals; Cattle; Pasteurella multocida; Hemorrhagic Septicemia; Bacterial Vaccines; Cattle Diseases; Mice; Antibodies, Bacterial; Female; Serogroup; Pasteurella Infections; Adjuvants, Immunologic; Immunoglobulin G; Mice, Inbred BALB C; Vaccination
PubMed: 38835751
DOI: 10.3389/fimmu.2024.1392681 -
Nature Communications Jun 2024Given the absence of approved treatments for pathogenic variants in Peripherin-2 (PRPH2), it is imperative to identify a universally effective therapeutic target for...
Given the absence of approved treatments for pathogenic variants in Peripherin-2 (PRPH2), it is imperative to identify a universally effective therapeutic target for PRPH2 pathogenic variants. To test the hypothesis that formation of the elongated discs in presence of PRPH2 pathogenic variants is due to the presence of the full complement of rhodopsin in absence of the required amounts of functional PRPH2. Here we demonstrate the therapeutic potential of reducing rhodopsin levels in ameliorating disease phenotype in knockin models for p.Lys154del (c.458-460del) and p.Tyr141Cys (c.422 A > G) in PRPH2. Reducing rhodopsin levels improves physiological function, mitigates the severity of disc abnormalities, and decreases retinal gliosis. Additionally, intravitreal injections of a rhodopsin-specific antisense oligonucleotide successfully enhance the physiological function of photoreceptors and improves the ultrastructure of discs in mutant mice. Presented findings shows that reducing rhodopsin levels is an effective therapeutic strategy for the treatment of inherited retinal degeneration associated with PRPH2 pathogenic variants.
Topics: Peripherins; Animals; Rhodopsin; Mice; Humans; Disease Models, Animal; Down-Regulation; Retinal Degeneration; Oligonucleotides, Antisense; Retina; Retinal Diseases; Mice, Inbred C57BL; Mutation; Female; Gene Knock-In Techniques; Male
PubMed: 38834544
DOI: 10.1038/s41467-024-48846-5 -
Frontiers in Immunology 2024Recently, OTULIN haploinsufficiency was linked to enhanced susceptibility to infections accompanied by local necrosis and systemic inflammation. The pathogenesis...
Recently, OTULIN haploinsufficiency was linked to enhanced susceptibility to infections accompanied by local necrosis and systemic inflammation. The pathogenesis observed in haploinsufficient patients differs from the hyperinflammation seen in classical OTULIN-related autoinflammatory syndrome (ORAS) patients and is characterized by increased susceptibility of dermal fibroblasts to alpha toxin-inflicted cytotoxic damage. Immunological abnormalities were not observed in OTULIN haploinsufficient patients, suggesting a non-hematopoietic basis. In this research report, we investigated an mouse model after provocation with lipopolysaccharide (LPS) to explore the potential role of hematopoietic-driven inflammation in OTULIN haploinsufficiency. We observed a hyperinflammatory signature in LPS-provoked mice, which was driven by CD64 monocytes and macrophages. Bone marrow-derived macrophages (BMDMs) of mice demonstrated higher proinflammatory cytokine secretion after stimulation with LPS or polyinosinic:polycytidylic acid (Poly(I:C)). Our experiments in full and mixed bone marrow chimeric mice suggest that, in contrast to humans, the observed inflammation was mainly driven by the hematopoietic compartment with cell-extrinsic effects likely contributing to inflammatory outcomes. Using an OTULIN haploinsufficient mouse model, we validated the role of OTULIN in the regulation of environmentally directed inflammation.
Topics: Animals; Haploinsufficiency; Mice; Inflammation; Lipopolysaccharides; Macrophages; Disease Models, Animal; Cytokines; Poly I-C; Mice, Inbred C57BL; Mice, Knockout; Humans
PubMed: 38827742
DOI: 10.3389/fimmu.2024.983686 -
BMC Ecology and Evolution May 2024Monitoring mollusk biodiversity is a great challenge due to their large diversity and broad distribution. Environmental DNA (eDNA) technology is increasingly applied for... (Comparative Study)
Comparative Study
Monitoring mollusk biodiversity is a great challenge due to their large diversity and broad distribution. Environmental DNA (eDNA) technology is increasingly applied for biodiversity monitoring, but relevant studies on marine mollusks are still limited. Although previous studies have developed several pairs of primers for mollusk eDNA analyses, most of them targeted only a small group of mollusks. In this study, seven primers were designed for the mollusk community and validated and compared with eight pairs of published primers to select the best candidates. After in silico test, MollCOI154 and MollCOI255 primers showed non-specific amplification, and same results were also obtained in published primers (COI204, Sepi, and veneroida). Moll12S100, Moll12S195 and Moll16S primers failed to amplify across all genomic DNA from selected mollusk. Except Moll16S, all developed and two published (unionoida and veneroida) primers were successfully amplified on four eDNA samples from Yangtze River estuary. After annotation of the amplified sequences, MollCOI253 showed higher annotation of the amplification results than the other primers. In conclusion, MollCOI253 had better performance in terms of amplification success and specificity, and can provide technical support for eDNA-based research, which will be beneficial for molluscan biodiversity investigation and conservation.
Topics: Mollusca; Animals; DNA Barcoding, Taxonomic; DNA, Environmental; DNA Primers; Biodiversity
PubMed: 38822255
DOI: 10.1186/s12862-024-02265-8 -
Frontiers in Cellular and Infection... 2024While astrocytes participate in the CNS innate immunity against herpes simplex virus type 1 (HSV-1) infection, they are the major target for the virus. Therefore, it is...
INTRODUCTION
While astrocytes participate in the CNS innate immunity against herpes simplex virus type 1 (HSV-1) infection, they are the major target for the virus. Therefore, it is of importance to understand the interplay between the astrocyte-mediated immunity and HSV-1 infection.
METHODS
Both primary human astrocytes and the astrocyte line (U373) were used in this study. RT-qPCR and Western blot assay were used to measure IFNs, the antiviral IFN-stimulated genes (ISGs), IFN regulatory factors (IRFs) and HSV-1 DNA. IRF1 knockout or knockdown was performed with CRISPR/Cas9 and siRNA transfection techniques.
RESULTS
Poly(dA:dT) could inhibit HSV-1 replication and induce IFN-β/IFN-λs production in human astrocytes. Poly(dA:dT) treatment of astrocytes also induced the expression of the antiviral ISGs (Viperin, ISG56 and MxA). Among IRFs members examined, poly(dA:dT) selectively unregulated IRF1 and IRF9, particularly IRF1 in human astrocytes. The inductive effects of poly(dA:dT) on IFNs and ISGs were diminished in the IRF1 knockout cells. In addition, IRF1 knockout attenuated poly(dA:dT)-mediated HSV-1 inhibition in the cells.
CONCLUSION
The DNA sensors activation induces astrocyte intracellular innate immunity against HSV-1. Therefore, targeting the DNA sensors has potential for immune activation-based HSV-1 therapy.
Topics: Humans; Astrocytes; Interferon Regulatory Factor-1; Herpesvirus 1, Human; Virus Replication; Immunity, Innate; Poly dA-dT; Herpes Simplex; Cytosol; Cell Line; Cells, Cultured; DNA, Viral; Gene Knockout Techniques
PubMed: 38808062
DOI: 10.3389/fcimb.2024.1383811 -
Frontiers in Immunology 2024The coronavirus disease 2019 (COVID-19) spread rapidly and claimed millions of lives worldwide. Acute respiratory distress syndrome (ARDS) is the major cause of...
OBJECTIVE
The coronavirus disease 2019 (COVID-19) spread rapidly and claimed millions of lives worldwide. Acute respiratory distress syndrome (ARDS) is the major cause of COVID-19-associated deaths. Due to the limitations of current drugs, developing effective therapeutic options that can be used rapidly and safely in clinics for treating severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections is necessary. This study aims to investigate the effects of two food-extracted immunomodulatory agents, ajoene-enriched garlic extract (AGE) and cruciferous vegetables-extracted sulforaphane (SFN), on anti-inflammatory and immune responses in a SARS-CoV-2 acute lung injury mouse model.
METHODS
In this study, we established a mouse model to mimic the SARS-CoV-2 infection acute lung injury model via intratracheal injection of polyinosinic:polycytidylic acid (poly[I:C]) and SARS-CoV-2 recombinant spike protein (SP). After the different agents treatment, lung sections, bronchoalveolar lavage fluid (BALF) and fresh faeces were harvested. Then, H&E staining was used to examine symptoms of interstitial pneumonia. Flow cytometry was used to examine the change of immune cell populations. Multiplex cytokines assay was used to examine the inflammatory cytokines.16S rDNA high-throughput sequencing was used to examine the change of gut microbiome.
RESULTS
Our results showed that AGE and SFN significantly suppressed the symptoms of interstitial pneumonia, effectively inhibited the production of inflammatory cytokines, decreased the percentage of inflammatory cell populations, and elevated T cell populations in the mouse model. Furthermore, we also observed that the gut microbiome of genus were enriched in the AGE-treated group.
CONCLUSION
Here, for the first time, we observed that these two novel, safe, and relatively inexpensive immunomodulatory agents exhibited the same effects on anti-inflammatory and immune responses as neutralizing monoclonal antibodies (mAbs) against interleukin 6 receptor (IL-6R), which have been suggested for treating COVID-19 patients. Our results revealed the therapeutic ability of these two immunomodulatory agents in a mouse model of SARS-CoV-2 acute lung injury by promoting anti-inflammatory and immune responses. These results suggest that AGE and SFN are promising candidates for the COVID-19 treatment.
Topics: Animals; Mice; Acute Lung Injury; Disease Models, Animal; COVID-19; SARS-CoV-2; Immunomodulating Agents; Anti-Inflammatory Agents; Angiotensin-Converting Enzyme 2; COVID-19 Drug Treatment; Isothiocyanates; Sulfoxides; Humans; Cytokines; Spike Glycoprotein, Coronavirus; Lung; Male; Poly I-C; Plant Extracts
PubMed: 38807598
DOI: 10.3389/fimmu.2024.1374541 -
Nature Communications May 2024The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part...
The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12 endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.
Topics: Humans; Glioblastoma; Aptamers, Nucleotide; Chemokine CXCL12; Male; Female; Middle Aged; Aged; Brain Neoplasms; Adult; Maximum Tolerated Dose; Quality of Life; Neoplasm Recurrence, Local
PubMed: 38806504
DOI: 10.1038/s41467-024-48416-9 -
PloS One 2024Studies of the interplay between metabolism and immunity, known as immunometabolism, is steadily transforming immunological research into new understandings of how...
Studies of the interplay between metabolism and immunity, known as immunometabolism, is steadily transforming immunological research into new understandings of how environmental cues like diet are affecting innate and adaptive immune responses. The aim of this study was to explore antiviral transcriptomic responses under various levels of polyunsaturated fatty acid. Atlantic salmon kidney cells (ASK cell line) were incubated for one week in different levels of the unsaturated n-3 eicosapentaneoic acid (EPA) resulting in cellular levels ranging from 2-20% of total fatty acid. These cells were then stimulated with the viral mimic and interferon inducer poly I:C (30 ug/ml) for 24 hours before total RNA was isolated and sequenced for transcriptomic analyses. Up to 200 uM EPA had no detrimental effects on cell viability and induced very few transcriptional changes in these cells. However, in combination with poly I:C, our results shows that the level of EPA in the cellular membranes exert profound dose dependent effects of the transcriptional profiles induced by this treatment. Metabolic pathways like autophagy, apelin and VEGF signaling were attenuated by EPA whereas transcripts related to fatty acid metabolism, ferroptosis and the PPAR signaling pathways were upregulated. These results suggests that innate antiviral responses are heavily influenced by the fatty acid profile of salmonid cells and constitute another example of the strong linkage between general metabolic pathways and inflammatory responses.
Topics: Animals; Salmo salar; Immunity, Innate; Eicosapentaenoic Acid; Cell Line; Poly I-C; Kidney; Transcriptome; Signal Transduction; Cell Survival; Gene Expression Profiling
PubMed: 38805503
DOI: 10.1371/journal.pone.0302286 -
Fish & Shellfish Immunology Jul 2024Land-based recirculating aquaculture systems (RAS) have risen in prevalence in recent years for Atlantic salmon production, enabling intensive production which allows...
Land-based recirculating aquaculture systems (RAS) have risen in prevalence in recent years for Atlantic salmon production, enabling intensive production which allows increased growth and environmental control, but also having the potential for reducing water use and eutrophication. The Atlantic salmon has an anadromous life history with juvenile stages in freshwater (FW) and on-growing in seawater (SW), enabled by a transformational process known as smoltification. The timing of smoltification and transfer of smolts from FW to SW is critical under commercial production with high mortalities during this period. The impact of FW rearing system on immune function following seawater transfer (SWT) is not well understood. In this study parr were raised in either RAS or a traditional open-LOCH system until smolting and then transferred to a common marine environment. Two-weeks post-SWT fish were immune stimulated with a viral mimic (poly I:C) for 24 h to assess the ability to mount an antiviral immune response, assessed by whole transcriptome analysis of gill tissue, an important immune organ in fish. We show that unstimulated smolts reared in the LOCH had higher immune gene expression than those reared in RAS as determined by functional analysis. However, following stimulation, smolts reared in the RAS mounted a greater magnitude of response with a suite of immune genes displaying higher fold induction of transcription compared to LOCH reared smolts. We suggest RAS smolts have a lower steady state immune-associated transcriptome likely due to an unvarying environment, in terms of environmental factors and lack of exposure to pathogens, which shows a compensatory mechanism following stimulation allowing immune 'catch-up' with those reared in the LOCH. Alternatively, the RAS fish are experiencing an excessive response to the immune stimulation.
Topics: Animals; Seawater; Salmo salar; Gills; Fresh Water; Aquaculture; Poly I-C; Fish Diseases; Immunity, Innate
PubMed: 38801843
DOI: 10.1016/j.fsi.2024.109653 -
Cancer Control : Journal of the Moffitt... 2024CpG ODN is a Toll-like receptor 9 agonist with immunotherapeutic potential for many cancer types, including aggressive breast cancers. There is strong interest in...
OBJECTIVES
CpG ODN is a Toll-like receptor 9 agonist with immunotherapeutic potential for many cancer types, including aggressive breast cancers. There is strong interest in utilizing CpG ODN as an adjuvant to improve clinical efficacy of current treatments and immunogenicity of breast cancers not traditionally responsive to active immunotherapy, such as those that are human epidermal growth factor receptor 2 (HER2)-positive. This study aimed to study the efficacy and safety of combination CpG ODN plus anti-HER2 antibody trastuzumab treatment in patients with advanced/metastatic breast cancer.
METHODS
This single-arm, open-label phase II clinical trial treated patients (n = 6) with advanced/metastatic HER2-positive breast cancer with weekly subcutaneous CpG ODN and trastuzumab. Patients may have received any number of prior therapies to be enrolled (most enrolled at median 1 prior line of chemotherapy). Peripheral blood was collected at baseline and weeks 2, 6, 12, and 18 for immune analyses. Six patients were enrolled and 50% achieved stable disease (SD) response.
RESULTS
Median PFS was 8.3 months. Three of the six patients enrolled opted to stop treatment due to tolerability issues. Multiplex assay for cytokine measurements revealed significantly higher VEGF-D levels at week 2 compared to baseline. Peripheral blood mononuclear cells analyzed by flow cytometry showed a significant increase in monocytic MDSC between weeks 6 and 12. Patients with progressive disease tended to have higher levels of week 6 monocytic MDSC and PD-1+ T cells than patients with SD. NK cell populations did not significantly change throughout treatment.
CONCLUSIONS
CpG ODN and trastuzumab treatment of metastatic HER2 + breast cancer was safe but was not tolerable for all patients. This combination did induce potentially predictive immune profile changes in treated patients with metastatic HER2 + breast cancer, the significance of which needs to be further explored.
Topics: Humans; Female; Breast Neoplasms; Oligodeoxyribonucleotides; Trastuzumab; Receptor, ErbB-2; Middle Aged; Adult; Antineoplastic Combined Chemotherapy Protocols; Aged
PubMed: 38797949
DOI: 10.1177/10732748241250189