scholarly journals DNA Immunization with Plasmids Encoding Fusion and Nucleocapsid Proteins of Bovine Respiratory Syncytial Virus Induces a Strong Cell-Mediated Immunity and Protects Calves against Challenge

2007 ◽  
Vol 81 (13) ◽  
pp. 6879-6889 ◽  
Author(s):  
Mathieu Boxus ◽  
Marylène Tignon ◽  
Stefan Roels ◽  
Jean-François Toussaint ◽  
Karl Walravens ◽  
...  
Keyword(s):  
Cellular Response ◽  
Clinical Signs ◽  
Effective Vaccine ◽  
Cell Mediated Immunity ◽  
Respiratory Pathogens ◽  
Lymphoproliferative Response ◽  
Promising Alternative ◽  
Young Infants ◽  
Syncytial Virus

ABSTRACT Respiratory syncytial viruses (RSV) are one of the most important respiratory pathogens of humans and cattle, and there is currently no safe and effective vaccine prophylaxis. In this study, we designed two codon-optimized plasmids encoding the bovine RSV fusion (F) and nucleocapsid (N) proteins and assessed their immunogenicity in young calves. Two administrations of both plasmids elicited low antibody levels but primed a strong cell-mediated immunity characterized by lymphoproliferative response and gamma interferon production in vitro and in vivo. Interestingly, this strong cellular response drastically reduced viral replication, clinical signs, and pulmonary lesions after a highly virulent challenge. Moreover, calves that were further vaccinated with a killed-virus vaccine developed high levels of neutralizing antibody and were fully protected following challenge. These results indicate that DNA vaccination could be a promising alternative to the classical vaccines against RSV in cattle and could therefore open perspectives for vaccinating young infants.

scholarly journals Florfenicol - pharmacodynamic, pharmacokinetics and clinical efficacy of oral formulations in domestic animals: A systematic review

2005 ◽  
Vol 59 (5-6) ◽  
pp. 635-654 ◽  
Author(s):  
Leon Scuka
Keyword(s):  
Systematic Review ◽  
Clinical Efficacy ◽  
Meta Analysis ◽  
Clinical Signs ◽  
Domestic Animals ◽  
Oral Solution ◽  
Favorable Effect ◽  
Respiratory Pathogens ◽  
Oral Formulations

Porcine respiratory disease complex (PRDC) is a major economic problem for swine producers world-wide. Pharmacodynamic, pharmacokinetics and clinical efficacy of florfenicol oral formulations in domestic animals were evaluated. For this purpose the systematic review and meta-analysis were done. In vitro efficacy of florfenicol showed that this drug is highly effective against most important respiratory pathogens. All these facts are shown in our survey. Three studies in pigs were relevant to include in the meta-analysis, which showed that results in the florfenicol group were better than in comparative control groups in all observed parameters: clinical signs, lung lesions and resolution of Actinobacillus pleuropneumoniae (P<0,001). A second meta-analysis with 7 studies showed that the usage of florfenicol reduces mortality in pig herds with PRDC (P<0.05). Other field trials in pigs using florfenicol oral forms where reviewed. After treatment with florfenicol oral solution there was a significant drop of mortality in both groups of pigs (P<0.01); eg. one using florfenicol oral solution in treating PRDC (n=85) and another mixed pneumoenteric infection (n=54). Analysis of data when using premix in pigs (n=118) also suggests that a medicated premix has a favorable anti-infectious effect on pigs, irrespective of the group of animals or the evolution stage of the disease. Finally, favorable effect of florfenicol in treating swine ileitis was also presented. Regarding their pharmacokinetics, in vitro and clinical efficacy of florfenicol oral forms, they should be considered as a powerful tool for combating complex infections that are frequently met in intensive animal production.

scholarly journals Enhanced Detection of Mycobacterium bovis-Specific T Cells in Experimentally-Infected Cattle

2021 ◽  
Vol 8 ◽  
Author(s):  
Paola M. Boggiatto ◽  
Carly R. Kanipe ◽  
Mitchell V. Palmer
Keyword(s):  
T Cells ◽  
Mycobacterium Bovis ◽  
Cellular Response ◽  
Γδ T Cells ◽  
T Cell Response ◽  
Health Concern ◽  
Diagnostic Tools ◽  
Infection Model ◽  
Cell Mediated Immunity

Bovine tuberculosis (bTB), caused by infection with Mycobacterium bovis, continues to be a major economic burden associated with production losses and a public health concern due to its zoonotic nature. As with other intracellular pathogens, cell-mediated immunity plays an important role in the control of infection. Characterization of such responses is important for understanding the immune status of the host, and to identify mechanisms of protective immunity or immunopathology. This type of information can be important in the development of vaccination strategies, diagnostic assays, and in predicting protection or disease progression. However, the frequency of circulating M. bovis-specific T cells are often low, making the analysis of such responses difficult. As previously demonstrated in a different cattle infection model, antigenic expansion allows us to increase the frequency of antigen-specific T cells. Moreover, the concurrent assessment of cytokine production and proliferation provides a deeper understanding of the functional nature of these cells. The work presented here, analyzes the T cell response following experimental M. bovis infection in cattle via in vitro antigenic expansion and re-stimulation to characterize antigen-specific CD4, CD8, and γδ T cells and their functional phenotype, shedding light on the variable functional ability of these cells. Data gathered from these studies can help us better understand the cellular response to M. bovis infection and develop improved vaccines and diagnostic tools.

Clinical and Immunological Characterisation of Coversin, a Novel Small Protein Inhibitor of Complement C5 with Potential As a Therapeutic Agent in PNH and Other Complement Mediated Disorders

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4280-4280 ◽  
Author(s):  
Wynne H Weston-Davies ◽  
Miles A Nunn ◽  
Fernando O Pinto ◽  
Ian J Mackie ◽  
Stephen John Richards ◽  
...  
Keyword(s):  
Clinical Stage ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Clinical Signs ◽  
Immunological Response ◽  
Leukotriene B4 ◽  
Response To Therapy ◽  
Red Cells ◽  
Cell Transplant ◽  
Promising Alternative

Abstract Coversin is a clinical stage recombinant protein molecule (16.7kDa) derived from a salivary molecule from the Ornithodros moubata tick where it assists the parasite to feed without provoking a host immunological response. It prevents activation of complement C5 and binds leukotriene B4 (LTB4) with high affinity. It is not an antibody and can therefore be manufactured in prokaryotic cells such as E. coli leading to potential savings in manufacturing costs. As its mode of action on C5 is similar to that of the monoclonal antibody eculizumab (Soliris®), it is considered to be a promising alternative therapeutic approach to thrombotic and hemolytic diseases mediated by complement activation including atypical hemolytic uremic syndrome (aHUS), catastrophic anti-phospholipid syndrome (APS) and paroxysmal nocturnal hemoglobinuria (PNH). In order to test this hypothesis, experiments were undertaken to determine whether Coversin could inhibit the hemolysis of PNH red cells in vitro using a modified Ham test combined with visualisation of the results by flow cytometric measurement of CD59 expression. Initial experiments showed maximum inhibition of hemolysis compared to control occurred at a concentration of approximately 10mcg/mL. Further experiments using PNH red blood cells also demonstrated the effectiveness of Coversin in blocking in vitro hemolysis of PNH red cells that had both type III (complete GPI-deficiency) and type II (partial GPI deficiency) red cells and also the deposition and accumulation of C3d on both types of PNH red cells. In a comparative experiment Coversin 10mcg/mL was found to be as effective as eculizumab 50mcg/mL, a molar equivalent dose. As Coversin is a non-humanised xenologous protein a mouse study was performed in order to assess immunogenicity and its potential to induce the formation of neutralising antibodies. Daily repeat subcutaneous doses of Coversin (0.57mg/kg) or vehicle were administered to 5 groups of 6 BALB/c mice and blood samples taken after 7, 14, and 28 days administration with an additional group where samples were taken 14 days following cessation of 28 days dosing. Immunoblots showed that by Day 14 33% of mice had developed low titre IgG antibodies to Coversin. By 28 days this had risen to 75% of mice receiving the active compound. Using CH50 lytic assays the antibodies were shown to be non-neutralising and no animals exhibited clinical signs of allergy or injection site reactions. The group of 6 mice that received vehicle showed no evidence of antibodies at 28 days. A heterozygous C5 mutation leading to a p.Arg885His polymorphism and interfering with the binding of eculizumab was recently reported in Japanese PNH patients and this was associated with a poor response to therapy. This was subsequently found to affect 3.5% of the general Japanese and Han Chinese population. A similar polymorphism has now been shown in a 4 year old Caucasian child with persistent thrombocytopenia following a stem cell transplant for chronic granulomatous disease. Prolonged eculizumab treatment was ineffective leading to discovery of the mutation. Serum from the patient was spiked with ascending concentrations of Coversin and CH50 activity was measured by ELISA. This produced a dose response curve corresponding to that found in serum from normal subjects. Coversin, which binds to a slightly different site on the C5 molecule, seems therefore to be unaffected by the polymorphism and to achieve superior inhibition of C5 activation compared to eculizumab. A Phase I, single ascending dose clinical trial was performed in 24 healthy volunteers. In the top dose cohort total blockade of complement C5 was achieved following subcutaneous injection at the predicted therapeutic loading dose of 0.57mg/kg. Activity remained below 50% for 48 hours suggesting that dosing once a day is feasible at steady state (see figure). The drug was well tolerated and no drug-related side effects were seen. Phase II clinical trials in PNH and other thrombotic micro-angiopathies (TMAs) are planned. Coversin appears to be a promising alternative to eculizumab for patients with PNH and other TMAs including those with polymorphisms which interfere with optimal binding of eculizumab to complement C5. Figure 1 Figure 1. Disclosures Weston-Davies: Volution Immuno Pharmaceuticals (VIP) SA: Consultancy. Nunn:Volution Immuno Pharm: Consultancy. Prudo:Volution Immuno Pharmaceuticals (VIP) SA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

scholarly journals RSV604, a Novel Inhibitor of Respiratory Syncytial Virus Replication

2007 ◽  
Vol 51 (9) ◽  
pp. 3346-3353 ◽  
Author(s):  
Joanna Chapman ◽  
Elizabeth Abbott ◽  
Dagmar G. Alber ◽  
Robert C. Baxter ◽  
Sian K. Bithell ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Virus Replication ◽  
Cell Model ◽  
Antiviral Treatment ◽  
Effective Vaccine ◽  
Initial Development ◽  
Basolateral Side ◽  
Syncytial Virus ◽  
Tract Infections

ABSTRACT Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.

scholarly journals Vitamin D Modulation of the Innate Immune Response to Paediatric Respiratory Pathogens Associated with Acute Lower Respiratory Infections

Nutrients ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 276
Author(s):  
Amy S. Bleakley ◽  
Paul V. Licciardi ◽  
Michael J. Binks
Keyword(s):  
Vitamin D ◽  
Immune Responses ◽  
Immune Cell ◽  
Respiratory Infections ◽  
Cell Types ◽  
Innate Immune ◽  
Respiratory Pathogens ◽  
Acute Lower Respiratory Infections ◽  
Syncytial Virus

Vitamin D is an essential component of immune function and childhood deficiency is associated with an increased risk of acute lower respiratory infections (ALRIs). Globally, the leading childhood respiratory pathogens are Streptococcus pneumoniae, respiratory syncytial virus and the influenza virus. There is a growing body of evidence describing the innate immunomodulatory properties of vitamin D during challenge with respiratory pathogens, but recent systematic and unbiased synthesis of data is lacking, and future research directions are unclear. We therefore conducted a systematic PubMed literature search using the terms “vitamin D” and “Streptococcus pneumoniae” or “Respiratory Syncytial Virus” or “Influenza”. A priori inclusion criteria restricted the review to in vitro studies investigating the effect of vitamin D metabolites on human innate immune cells (primary, differentiated or immortalised) in response to stimulation with the specified respiratory pathogens. Eleven studies met our criteria. Despite some heterogeneity across pathogens and innate cell types, vitamin D modulated pathogen recognition receptor (PRRs: Toll-like receptor 2 (TLR2), TLR4, TLR7 and nucleotide-binding oligomerisation domain-containing protein 2 (NOD2)) expression; increased antimicrobial peptide expression (LL-37, human neutrophil peptide (HNP) 1-3 and β-defensin); modulated autophagosome production reducing apoptosis; and modulated production of inflammatory cytokines (Interleukin (IL) -1β, tumour necrosis factor-α (TNF-α), interferon-ɣ (IFN-ɣ), IL-12p70, IFN-β, Regulated on Activation, Normal T cell Expressed (RANTES), IL-10) and chemokines (IL-8 and C-X-C motif chemokine ligand 10 (CXCL10)). Differential modulation of PRRs and IL-1β was reported across immune cell types; however, this may be due to the experimental design. None of the studies specifically focused on immune responses in cells derived from children. In summary, vitamin D promotes a balanced immune response, potentially enhancing pathogen sensing and clearance and restricting pathogen induced inflammatory dysregulation. This is likely to be important in controlling both ALRIs and the immunopathology associated with poorer outcomes and progression to chronic lung diseases. Many unknowns remain and further investigation is required to clarify the nuances in vitamin D mediated immune responses by pathogen and immune cell type and to determine whether these in vitro findings translate into enhanced immunity and reduced ALRI in the paediatric clinical setting.

scholarly journals Characterising Interactions between Influenza A Virus and Respiratory Syncytial Virus during In Vitro Coinfection

Proceedings ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 48
Author(s):  
Joanne Haney ◽  
Kieran Dee ◽  
Colin Loney ◽  
Swetha Vijayakrishnan ◽  
Pablo R. Murcia
Keyword(s):  
Respiratory Syncytial Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Lung Epithelial Cells ◽  
Respiratory Pathogens ◽  
Biological Interactions ◽  
Infection Dynamics ◽  
Syncytial Virus ◽  
Virus Interactions

Influenza A virus (IAV) and respiratory syncytial virus (RSV) are important respiratory pathogens that share common epidemiological features and cellular tropism within the respiratory tract. This gives rise to the potential for biological interactions between IAV and RSV during coinfection of hosts. Virus–virus interactions are increasingly recognised for their contribution to viral dynamics during infection, however, the molecular processes underpinning these interactions are unknown. Here, we developed an in vitro coinfection system to characterise the infection dynamics of IAV (A/Puerto Rico/8/34, H1N1) and RSV (A2) in single virus infection or coinfection in lung epithelial cells, with the aim to identify biological processes that drive virus–virus interactions during coinfection. We compared viral replication kinetics at different multiplicities of infection and observed that RSV replication was inhibited during coinfection with IAV, whilst IAV replication was facilitated by coinfection. To further characterise IAV/RSV interactions, we determined the relative proportions of single virus infected or coinfected cells during early and late timepoints post-infection and observed differences in expression of viral proteins between single and coinfected states. Additionally, cell viability was measured determine differences in viral-induced cytopathic effect. Compared with RSV infection, cell death is induced at earlier timepoints post IAV infection and coinfection, indicating that different cellular processes are initiated in response to infection. These studies highlight that both competitive and facilitative ecological interactions occur between IAV and RSV during coinfection and shed light on sources of potential interactions at the cellular and molecular level.

scholarly journals Regulation of Dendritic Cell Functions against Harmful Respiratory Pathogens by a Cysteinyl Leukotrienes Receptor Antagonist

2012 ◽  
Vol 3 (1) ◽  
pp. ar.2012.3.0021 ◽  
Author(s):  
Hiroto Matsuse ◽  
Hiroko Hirose ◽  
Susumu Fukahori ◽  
Tomoko Tsuchida ◽  
Shinya Tomari ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Receptor Antagonist ◽  
Mite Allergen ◽  
Respiratory Pathogens ◽  
Cysteinyl Leukotrienes ◽  
Cell Functions ◽  
Dc Function ◽  
Syncytial Virus ◽  
Antimicrobial Immunity

Cysteinyl leukotriene receptor antagonist (LTRA) is a widely used medicine for asthma. Cysteinyl leukotrienes (cysLTs) are involved in the regulation of dendritic cell (DC) function. However, the effects of LTRA on DC-related antimicrobial immunity against harmful respiratory pathogens remain unknown. The purpose of this study was to examine the effects of LTRA administered in vivo on DC function against representative respiratory pathogens in vitro. Pulmonary DCs were isolated from four groups of mice: control, mite allergen sensitized (AS), and AS mice treated with the corticosteroid dexamethasone (Dex) or with the LTRA pranlukast (Prl). These DCs were incubated with mite allergen, lipopolysaccharide (LPS), Aspergillus fumigatus, or respiratory syncytial virus (RSV). IL-10 and IL-12 production was then determined. Dex treatment significantly inhibited lipopolysaccharide (LPS)-induced IL-10 and IL-12 production as well as baseline IL-12 production in AS mice. The Prl did not significantly inhibit LPS-induced IL-10 and IL-12 production in AS mice. More importantly, Prl significantly increased IL-10 and IL-12 in AS mice after RSV infection. This study shows that LTRA that is used for asthma potentially up-regulates antimicrobial immunity through modulation of DC function against some respiratory infections without immunosuppression.

scholarly journals I267L Is Neither the Virulence- Nor the Replication-Related Gene of African Swine Fever Virus and Its Deletant Is an Ideal Fluorescent-Tagged Virulence Strain

Viruses ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 53
Author(s):  
Yanyan Zhang ◽  
Junnan Ke ◽  
Jingyuan Zhang ◽  
Huixian Yue ◽  
Teng Chen ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
African Swine Fever Virus ◽  
Clinical Signs ◽  
Case Fatality ◽  
African Swine Fever ◽  
Fever Virus ◽  
Economic Losses ◽  
Effective Vaccine ◽  
Domestic Pigs

African swine fever virus (ASFV) is the causative agent of African swine fever (ASF) which reaches up to 100% case fatality in domestic pigs and wild boar and causes significant economic losses in the swine industry. Lack of knowledge of the function of ASFV genes is a serious impediment to the development of the safe and effective vaccine. Herein, I267L was identified as a relative conserved gene and an early expressed gene. A recombinant virus (SY18ΔI267L) with I267L gene deletion was produced by replacing I267L of the virulent ASFV SY18 with enhanced green fluorescent protein (EGFP) cassette. The replication kinetics of SY18ΔI267L is similar to that of the parental isolate in vitro. Moreover, the doses of 102.0 TCID50 (n = 5) and 105.0 TCID50 (n = 5) SY18ΔI267L caused virulent phenotype, severe clinical signs, viremia, high viral load, and mortality in domestic pigs inoculated intramuscularly as the virulent parental virus strain. Therefore, the deletion of I267L does not affect the replication or the virulence of ASFV. Utilizing the fluorescent-tagged virulence deletant can be easy to gain a visual result in related research such as the inactivation effect of some drugs, disinfectants, extracts, etc. on ASFV.

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