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Frontiers in Veterinary Science 2024Infectious bursal disease (IBD) is one of the dangerous diseases of poultry that affects the bursa of Fabricius, which is an important organ of the bird's immune system.... (Review)
Review
Infectious bursal disease (IBD) is one of the dangerous diseases of poultry that affects the bursa of Fabricius, which is an important organ of the bird's immune system. IBD virus is resistant to many drugs, making its control difficult. Vaccination of IBD is in practice for a long time worldwide to control IBD, but secondary issues like vaccine failure and lower efficacy lead to their reduced use in the field. Multiple medicines are currently used, but the phytochemicals have emerged as promising agents for controlling IBD. The drugs to be developed should possess direct antiviral properties by targeting viral entry mechanisms, enhancing the host immune response, and inhibiting viral protein synthesis. Phytochemicals have potential to contribute to food security by minimizing the possibility of disease outbreaks and ensuring that consumers worldwide obtain healthy poultry products. It has been now claimed that direct and indirect activities of phytochemicals can be effective in the control of IBDV. Although available evidence suggest that the phytochemicals can contribute in controlling occurrence IBDV, there is a definite need of focused studies to gain more insight and develop rational strategies for their practical use. This review highlights the disease caused by IBDV, inhibition of viral replication, boosting the immune system, disruption of viral membrane, and important phytochemicals showing antiviral activities against IBDV.
PubMed: 38919155
DOI: 10.3389/fvets.2024.1421668 -
Addiction Science & Clinical Practice Jun 2024Clinic-based interventions are needed to promote successful direct acting antiviral (DAA) treatment for chronic hepatitis C virus (HCV) infection in patients with...
BACKGROUND
Clinic-based interventions are needed to promote successful direct acting antiviral (DAA) treatment for chronic hepatitis C virus (HCV) infection in patients with substance use disorders (SUDs) among rural Veterans.
METHODS
We implemented a clinic-based intervention which used motivational interviewing (MI) techniques to promote medication adherence and treatment completion with 12 weeks of DAA treatment among rural Veterans with chronic HCV and SUDs. Patients received an MI session with a licensed psychologist at baseline and at each two-week follow-up visit during DAA treatment. Patients received $25 per study visit completed. Patients were to attend a laboratory visit 12 weeks after treatment completion to assess for sustained virologic response (SVR).
RESULTS
Of the 20 participants who enrolled, 75% (n = 15) completed the planned 12-week course of treatment. Average adherence by pill count was 92% (SD = 3%). Overall SVR was 95% (19/20).
CONCLUSIONS
We demonstrated that a clinic-based intervention which incorporated frequent follow up visits and MI techniques was feasible and acceptable to a sample of predominantly rural Veterans with chronic HCV and SUDs.
CLINICAL TRIAL REGISTRATION
Registered at ClinicalTrials.gov (NCT02823457) on July 1, 2016. https://clinicaltrials.gov .
Topics: Humans; Veterans; Male; Antiviral Agents; Substance-Related Disorders; Hepatitis C, Chronic; Middle Aged; Rural Population; Female; Medication Adherence; Motivational Interviewing; Adult; Sustained Virologic Response; Aged
PubMed: 38918869
DOI: 10.1186/s13722-024-00480-8 -
BMC Pediatrics Jun 2024Hypereosinophilia is a rare presentation in all age groups, particularly when it is severe, persistent, and progressive. We describe the clinical characteristics and...
Hypereosinophilia is a rare presentation in all age groups, particularly when it is severe, persistent, and progressive. We describe the clinical characteristics and course of severe hypereosinophilia in a full-term Saudi female neonate. A febrile respiratory illness evolved with a progressive increase in peripheral blood leukocyte and eosinophil counts, reaching 44.9% of leukocytes and an absolute value of 57,000 cells/µl. Different etiological examinations (for viral, bacterial, immunodeficiency, hyper IgE syndrome, gene mutations) revealed extremely high CMV antigenemia and a homozygous mutation in the STAT1 gene. Anhelation was relieved by oxygen and anti-viral treatment. Steroids brought a dramatic response in peripheral blood counts within 24 h. After a 6-week course of antiviral and steroid treatment at home, she had an excellent general condition. Conclusion: Although a rare pathology, it is important to consider genetic disorders when there is an atypical immune response to viral infections.
Topics: Humans; Female; STAT1 Transcription Factor; Infant, Newborn; Cytomegalovirus Infections; Mutation; Eosinophilia
PubMed: 38918745
DOI: 10.1186/s12887-024-04846-4 -
BioRxiv : the Preprint Server For... Jun 2024The abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor that can trigger dysregulated immune activation is...
The abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor that can trigger dysregulated immune activation is cytosolic mitochondrial double-stranded RNAs (mt-dsRNAs). However, the mechanism by which mt-dsRNAs stimulate immune responses remains poorly understood. Here, we discover SRA stem-loop interacting RNA binding protein (SLIRP) as a key amplifier of mt-dsRNA-triggered antiviral signals. In autoimmune diseases, SLIRP is commonly upregulated, and targeted knockdown of SLIRP dampens the interferon response. We find that the activation of melanoma differentiation-associated gene 5 (MDA5) by exogenous dsRNAs upregulates SLIRP, which then stabilizes mt-dsRNAs and promotes their cytosolic release to activate MDA5 further, augmenting the interferon response. Furthermore, the downregulation of SLIRP partially rescues the abnormal interferon-stimulated gene expression in autoimmune patients' primary cells and makes cells vulnerable to certain viral infections. Our study unveils SLIRP as a pivotal mediator of interferon response through positive feedback amplification of antiviral signaling.
PubMed: 38915695
DOI: 10.1101/2024.03.28.587146 -
Frontiers in Immunology 2024Cytomegalovirus (CMV) reactivation is a significant concern following allogeneic stem cell transplantation. While previous research has highlighted the anti-CMV...
BACKGROUND
Cytomegalovirus (CMV) reactivation is a significant concern following allogeneic stem cell transplantation. While previous research has highlighted the anti-CMV reactivation effect of γδ T cells in immunocompromised transplant patients, their characterization in recipients at high risk of CMV reactivation remains limited.
METHODS
This study focused on D+/R+ recipients (where both donor and recipient are CMV seropositive) at high risk of CMV reactivation. We analyzed 28 patients who experienced CMV recurrence within 100 days post-allogeneic hematopoietic stem cell transplantation, along with 36 matched recipients who did not experience CMV recurrence. Clinical data from both groups were compared, and risk factors for CMV reactivation were identified. Additionally, CMV viral load was measured, and flow cytometric analysis was conducted to assess changes in peripheral blood γδ T cell proportions, subpopulation distribution, and differentiation status. We also analyzed the CDR3 repertoire of the TCR δ chain in different γδ T cell subsets. Functional analysis was performed by measuring the lysis of CMV-infected cells upon stimulation.
RESULTS
CMV reactivation post-transplantation was associated with acute graft-versus-host disease (aGvHD) and reactivation of non-CMV herpesviruses. Notably, CMV reactivation led to sustained expansion of γδ T cells, primarily within the Vδ2 γδ T cell subpopulation, with a trend toward differentiation from Naive to effector memory cells. Analysis of the δ chain CDR3 repertoire revealed a delay in the reconstitution of clonal diversity in Vδ2 γδ T cells following CMV reactivation, while Vδ2 T cells remained unaffected. Upon stimulation with CMV-infected MRC5 cells, the Vδ2 γδ T cell subpopulation emerged as the primary effector cell group producing IFN-γ and capable of lysing CMV-infected cells. Moreover, our findings suggest that NKG2D is not necessary involved in Vδ2 γδ T cell-mediated anti-CMV cytotoxicity.
CONCLUSION
This study provides novel insights into the role of γδ T cells in the immune response to CMV reactivation in transplantation recipients at high risk of CMV infection. Specifically, the Vδ2 γδ T cell subpopulation appears to be closely associated with CMV reactivation, underscoring their potential role in controlling infection and reflecting CMV reactivation in HSCT patients.
Topics: Humans; Cytomegalovirus Infections; Male; Cytomegalovirus; Virus Activation; Female; Adult; Middle Aged; Hematopoietic Stem Cell Transplantation; Receptors, Antigen, T-Cell, gamma-delta; Transplantation, Homologous; Graft vs Host Disease; Young Adult; Memory T Cells; Aged
PubMed: 38915409
DOI: 10.3389/fimmu.2024.1397483 -
JCI Insight May 2024Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators...
Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.
Topics: Animals; Membrane Proteins; Mice; Female; Signal Transduction; T-Lymphocytes, Cytotoxic; Triple Negative Breast Neoplasms; Indomethacin; Cell Line, Tumor; Humans; Lung Neoplasms; Cyclooxygenase Inhibitors; Nucleotidyltransferases; Interferon Type I; Cyclooxygenase 2; Lymphocytes, Tumor-Infiltrating; Mice, Inbred BALB C
PubMed: 38912586
DOI: 10.1172/jci.insight.165356 -
Frontiers in Cellular and Infection... 2024is an intracellular parasite of importance to human and veterinary health. The structure and diversity of the genotype population of varies considerably with respect...
INTRODUCTION
is an intracellular parasite of importance to human and veterinary health. The structure and diversity of the genotype population of varies considerably with respect to geography, but three lineages, type I, II and III, are distributed globally. Lineage III genotypes are the least well characterized in terms of biology, host immunity and virulence. Once a host is infected with , innate immune mechanisms are engaged to reduce the parasite burden in tissues and create a pro-inflammatory environment in which the T1 response develops to ensure survival. This study investigated the early cellular immune response of Swiss-Webster mice post intraperitoneal infection with 10 tachyzoites of four distinct non-clonal genotypes of lineage III and a local isolate of ToxoDB#1. The virulence phenotype, cumulative mortality (CM) and allele profiles of ROP5, ROP16, ROP18 and GRA15 were published previously.
METHODS
Parasite dissemination in different tissues was analyzed by real-time PCR and relative expression levels of IFNγ, IL12-p40, IL-10 and TBX21 in the cervical lymph nodes (CLN), brain and spleen were calculated using the ΔΔCt method. Stage conversion was determined by detection of the BAG1 transcript in the brain.
RESULTS
Tissue dissemination depends on the virulence phenotype but not CM, while the TBX21 and cytokine levels and kinetics correlate better with CM than virulence phenotype. The earliest detection of BAG1 was seven days post infection. Only infection with the genotype of high CM (69.4%) was associated with high T-bet levels in the CLN 24 h and high systemic IFNγ expression which was sustained over the first week, while infection with genotypes of lower CM (38.8%, 10.7% and 6.8%) is characterized by down-regulation and/or low systemic levels of IFNγ. The response intensity, as assessed by cytokine levels, to the genotype of high CM wanes over time, while it increases gradually to genotypes of lower CM.
DISCUSSION
The results point to the conclusion that the immune response is not correlated with the virulence phenotype and/or allele profile, but an early onset, intense pro-inflammatory response is characteristic of genotypes with high CM. Additionally, high IFNγ level in the brain may hamper stage conversion.
Topics: Toxoplasma; Animals; Mice; Virulence; Genotype; Cytokines; Toxoplasmosis, Animal; Phenotype; Female; Spleen; Brain; Protozoan Proteins; Disease Models, Animal; Lymph Nodes; Interferon-gamma; T-Box Domain Proteins; Immunity, Cellular
PubMed: 38912206
DOI: 10.3389/fcimb.2024.1414067 -
Frontiers in Immunology 2024Advanced age is associated with an increased susceptibility to Coronavirus Disease (COVID)-19 and more severe outcomes, although the underlying mechanisms are...
Advanced age is associated with an increased susceptibility to Coronavirus Disease (COVID)-19 and more severe outcomes, although the underlying mechanisms are understudied. The lung endothelium is located next to infected epithelial cells and bystander inflammation may contribute to thromboinflammation and COVID-19-associated coagulopathy. Here, we investigated age-associated SARS-CoV-2 pathogenesis and endothelial inflammatory responses using humanized K18-hACE2 mice. Survival was reduced to 20% in aged mice (85-112 weeks) versus 50% in young mice (12-15 weeks) at 10 days post infection (dpi). Bulk RNA-sequencing of endothelial cells from mock and infected mice at 2dpi of both age groups (aged: 72-85 weeks; young: 15 weeks) showed substantially lower significant differentially regulated genes in infected aged mice than in young mice (712 versus 2294 genes). Viral recognition and anti-viral pathways such as RIG-I-like receptor signaling, NOD-like receptor signaling and interferon signaling were regulated in response to SARS-CoV-2. Young mice showed several fold higher interferon responses (, , ) and interferon-induced chemokines ( and ) than aged mice. Endothelial cells from infected young mice displayed elevated expression of chemokines (, ) and leukocyte adhesion markers () underscoring that inflammation of lung endothelium during infection could facilitate leukocyte adhesion and thromboinflammation. TREM1 and acute phase response signaling were particularly prominent in endothelial cells from infected young mice. Immunohistochemistry was unable to detect viral protein in pulmonary endothelium. In conclusion, our data demonstrate that the early host response of the endothelium to SARS-CoV-2 infection declines with aging, which could be a potential contributor to disease severity.
Topics: Animals; COVID-19; SARS-CoV-2; Endothelial Cells; Mice; Lung; Humans; Aging; Disease Models, Animal; Inflammation; Angiotensin-Converting Enzyme 2; Mice, Transgenic
PubMed: 38911865
DOI: 10.3389/fimmu.2024.1397990 -
Frontiers in Immunology 2024Complement activation is considered to contribute to the pathogenesis of severe SARS-CoV-2 infection, mainly by generating potent immune effector mechanisms including a...
Complement activation is considered to contribute to the pathogenesis of severe SARS-CoV-2 infection, mainly by generating potent immune effector mechanisms including a strong inflammatory response. Involvement of the lectin complement pathway, a major actor of the innate immune anti-viral defense, has been reported previously. It is initiated by recognition of the viral surface Spike glycoprotein by mannose-binding lectin (MBL), which induces activation of the MBL-associated protease MASP-2 and triggers the proteolytic complement cascade. A role for the viral nucleoprotein (N) has also been reported, through binding to MASP-2, leading to protease overactivation and potentiation of the lectin pathway. In the present study, we reinvestigated the interactions of the SARS-CoV-2 N protein, produced either in bacteria or secreted by mammalian cells, with full-length MASP-2 or its catalytic domain, in either active or proenzyme form. We could not confirm the interaction of the N protein with the catalytic domain of MASP-2 but observed N protein binding to proenzyme MASP-2. We did not find a role of the N protein in MBL-mediated activation of the lectin pathway. Finally, we showed that incubation of the N protein with MASP-2 results in proteolysis of the viral protein, an observation that requires further investigation to understand a potential functional significance in infected patients.
Topics: Mannose-Binding Protein-Associated Serine Proteases; Humans; SARS-CoV-2; Complement Pathway, Mannose-Binding Lectin; COVID-19; Protein Binding; Coronavirus Nucleocapsid Proteins; Complement Activation; Mannose-Binding Lectin; Phosphoproteins
PubMed: 38911852
DOI: 10.3389/fimmu.2024.1419165 -
ACS Omega Jun 2024The suppression of the host's innate antiviral immune response by SARS-CoV-2, a contributing factor to the severity of disease, has been considerably studied in recent...
The suppression of the host's innate antiviral immune response by SARS-CoV-2, a contributing factor to the severity of disease, has been considerably studied in recent years. Many of these studies have focused on the actions of the structural proteins of the virus because of their accessibility to host immunological components. However, less is known about SARS-CoV-2 nonstructural and accessory proteins in relation to viral evasion. Herein, we study SARS-CoV-2 nonstructural proteins Orf3a, Orf6, and Nsp9 in a mimicked virus-infected state using poly(I:C), a synthetic analog of viral dsRNA, that elicits the antiviral immune response. Through genome-wide expression profiling, we determined that Orf3a, Orf6, and Nsp9 all modulate the host antiviral signaling transcriptome to varying extents, uniquely suppressing aspects of innate immune signaling. Our data suggest that SARS-CoV-2 Nsp9 hinders viral detection through suppression of RIG-I expression and antagonizes the interferon antiviral cascade by downregulating NF-kB and TBK1. Our data point to unique molecular mechanisms through which the different SARS-CoV-2 proteins suppress immune signaling and promote viral evasion. Nsp9 in particular acts on major elements of the host antiviral pathways to impair the antiviral immune response.
PubMed: 38911767
DOI: 10.1021/acsomega.4c02631