The biology and development of vaccines for bovine alphaherpesvirus 1.

Bovine alphaherpesvirus type 1 (BoAHV-1) infections lead to compromised herd health and significantly reduced productivity of affected cattle. While BoAHV-1 may cause rhinotracheitis, conjunctivitis, genital infections, and abortions, respiratory tract infections constitute the predominant clinical disease. Immune suppression induced by BoAHV-1 may contribute to co-infections initiating the bovine respiratory disease complex.

Comprehensive Analysis of the Tegument Proteins Involved in Capsid Transport and Virion Morphogenesis of Alpha, Beta and Gamma Herpesviruses.

Herpesviruses are enveloped and have an amorphous protein layer surrounding the capsid, which is termed the tegument. Tegument proteins perform critical functions throughout the viral life cycle. This review provides a comprehensive and comparative analysis of the roles of specific tegument proteins in capsid transport and virion morphogenesis of selected, well-studied prototypes of each of the three subfamilies of i.

Bovine Herpesvirus-1 Glycoprotein M Mediates the Translocation to the Golgi Apparatus and Packaging of VP8.

VP8, the most abundant tegument protein of bovine herpesvirus-1 (BoHV-1), plays an important role in viral replication. According to our previous studies, VP8 localizes to the Golgi apparatus of BoHV-1-infected cells where it can be packaged into the virus; however, Golgi localization of VP8 does not occur outside of the context of infection. The goal of this study was to identify the viral factor(s) involved in the tropism of VP8 towards the Golgi.

VP8, the Major Tegument Protein of Bovine Herpesvirus-1, Is Partially Packaged during Early Tegument Formation in a VP22-Dependent Manner.

Bovine herpesvirus-1 (BoHV-1) is a major cause of rhinotracheitis and vulvovaginitis in cattle. VP8, the major tegument protein of BoHV-1, is essential for viral replication in the host. VP8 is phosphorylated by the viral kinase US3, mediating its translocation to the cytoplasm.

Chitosan nanoparticles fabricated through host-guest interaction for enhancing the immunostimulatory effect of CpG oligodeoxynucleotide.

CpG oligodeoxynucleotides (CpG ODNs) which can induce innate immune responses and promote adaptive immune responses, are powerful tools in defeating diseases. Here, a novel chitosan nanoparticle (CS-NPs) based on host-guest interaction has been designed for encapsulation and delivery of CpG ODNs for the first time. The CS-NPs exhibited high encapsulation efficiency (98.

Comprehensive Lipidomic and Metabolomic Analysis for Studying Metabolic Changes in Lung Tissue Induced by a Vaccine against Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections in young children. Although the disease may be severe in immunocompromised, young, and elderly people, there is currently no approved vaccine. We previously reported the development and immunological assessment of a novel intranasal vaccine formulation consisting of a truncated version of the RSV fusion protein (ΔF) combined with a three-component adjuvant (TriAdj).

Low molecular weight chitosan nanoparticles for CpG oligodeoxynucleotides delivery: Impact of molecular weight, degree of deacetylation, and mannosylation on intracellular uptake and cytokine induction.

Although synthetic CpG oligodeoxynucleotides (ODNs) have shown substantial potential as immunotherapeutic agents, their effective intracellular delivery remains challenging. In this work, nanoparticles prepared from low-molecular weight (LMW) chitosans were investigated as CpG ODN delivery systems. Chitosan samples with a molecular weight (M) of 5 and 15 kDa and degree of deacetylation (DDA) of 50 and 80% were prepared.

Innate immunemodulator containing adjuvant formulated HA based vaccine protects mice from lethal infection of highly pathogenic avian influenza H5N1 virus.

The highly pathogenic avian influenza (HPAI) H5N1 viruses and their spillover into the human population pose substantial economic and public health threats. Although antiviral drugs have some effect in treating influenza infection, vaccination is still the most effective intervention to prevent possible pandemic outbreaks. We have developed a novel H5 influenza vaccine to improve the world's pandemic preparedness.

Innate immune protection from pneumonia virus of mice induced by a novel immunomodulator is prolonged by dual treatment and mediated by macrophages.

Respiratory syncytial virus (RSV) is responsible for a large proportion of acute lower respiratory tract infections, specifically in children. Pneumonia virus of mice (PVM) causes similar lung pathology and clinical disease in rodents, and is therefore an appropriate model of RSV infection. Previously, we demonstrated that a single intranasal dose of P-I-P, a novel immunomodulator composed of the toll-like receptor 3 agonist poly(I:C), an innate defense regulator peptide and a polyphosphazene, confers protection in Balb/c mice for up to 3 days from lethal PVM-15 infection.

Selection of adjuvants for vaccines targeting specific pathogens.

Adjuvants form an integral component in most of the inactivated and subunit vaccine formulations. Careful and proper selection of adjuvants helps in promoting appropriate immune responses against target pathogens at both innate and adaptive levels such that protective immunity can be elicited. Areas covered: Herein, we describe the recent progress in our understanding of the mode of action of adjuvants that are licensed for use in human vaccines or in clinical or pre-clinical stages at both innate and adaptive levels.

Metabolomic and Immunological Profiling of Respiratory Syncytial Virus Infection after Intranasal Immunization with a Subunit Vaccine Candidate.

Respiratory syncytial virus (RSV) is a significant cause of mortality and morbidity in infants, the elderly, immunocompromised individuals, and patients with congenital heart diseases. Despite extensive efforts, a vaccine against RSV is still not available. We have previously reported the development of a subunit vaccine (ΔF/TriAdj) composed of a truncated version of the fusion protein (ΔF) and a polymer-based combination adjuvant (TriAdj).

US3 Kinase-Mediated Phosphorylation of Tegument Protein VP8 Plays a Critical Role in the Cellular Localization of VP8 and Its Effect on the Lipid Metabolism of Bovine Herpesvirus 1-Infected Cells.

Bovine herpesvirus 1 (BoHV-1) infects bovine species, causing respiratory infections, genital disorders and abortions. VP8 is the most abundant tegument protein of BoHV-1 and is critical for virus replication in cattle. In this study, the cellular transport of VP8 in BoHV-1-infected cells and its ability to alter the cellular lipid metabolism were investigated.

The bovine herpesvirus-1 major tegument protein, VP8, interacts with host HSP60 concomitant with deregulation of mitochondrial function.

The U47 gene product, VP8, is a major tegument protein of BoHV-1. While VP8 is not essential for virus replication in cell culture, a U47-deleted virus exhibits a smaller tegument structure and is avirulent in cattle. To obtain pure VP8 protein for structural analysis, we expressed a N-terminally truncated version of VP8 in Eschericia coli.

The Major Tegument Protein of Bovine Herpesvirus 1, VP8, Interacts with DNA Damage Response Proteins and Induces Apoptosis.

VP8, the gene product in bovine herpesvirus-1 (BoHV-1), is a major tegument protein that is essential for virus replication The major DNA damage response protein, ataxia telangiectasia mutated (ATM), phosphorylates Nijmegen breakage syndrome (NBS1) and structural maintenance of chromosome-1 (SMC1) proteins during the DNA damage response. VP8 was found to interact with ATM and NBS1 during transfection and BoHV-1 infection. However, VP8 did not interfere with phosphorylation of ATM in transfected or BoHV-1-infected cells.

The respiratory syncytial virus fusion protein formulated with a polymer-based adjuvant induces multiple signaling pathways in macrophages.

Respiratory syncytial virus (RSV) causes acute respiratory tract infections in infants, the elderly and immunocompromised individuals. No licensed vaccine is available against RSV. We previously reported that intranasal immunization of rodents and lambs with a RSV vaccine candidate (ΔF/TriAdj) induces protective immunity with a good safety profile.

Defining a standard and weighted mathematical index for maturation of dendritic cells.

The concept of dendritic cell (DC) maturation generally refers to the changes in morphology and function of DCs. Conventionally, DC maturity is based on three criteria: loss of endocytic ability, gain of high-level capacity to present antigens and induce proliferation of T cells, and mobility of DCs toward high concentrations of CCL19. Impairment of DC maturation has been suggested as the main reason for infectivity or chronicity of several infectious agents.

A novel combination adjuvant platform for human and animal vaccines.

Adjuvants are crucial components of many vaccines. They are used to improve the immunogenicity of vaccines with the aim of conferring long-term protection, to enhance the efficacy of vaccines in newborns, elderly or immunocompromised persons, and to reduce the amount of antigen or the number of doses required to elicit effective immunity. Novel combination adjuvants have been tested in both candidate animals and humans vaccines and have generated encouraging results.

Herpesvirus tegument and immediate early proteins are pioneers in the battle between viral infection and nuclear domain 10-related host defense.

The sophisticated anti-viral functions of nuclear domain 10 (ND10) are revealed by identifying the role of each component and the countermeasures applied by viruses. Several ND10 proteins suppress herpesviruses at initial and early phases of infection. Herpesviruses need to antagonize these anti-viral proteins to start a productive infection.

Local innate responses and protective immunity after intradermal immunization with bovine viral diarrhea virus E2 protein formulated with a combination adjuvant in cattle.

Bovine viral diarrhea virus (BVDV) is one of the most serious pathogens in cattle. Recently, we developed a novel adjuvant platform (TriAdj) that includes a toll-like receptor 3 agonist, poly (I:C); an innate defense regulatory peptide; and water-soluble polymer, poly[di(sodiumcarboxylatoethylphenoxy)]-phosphazene (PCEP). To develop a needle-free intradermal (ID) subunit vaccine, the BVDV type-2 E2 protein was formulated with TriAdj, and immune protection was evaluated in calves against a BVDV-2 strain.

Us3 and Us9 proteins contribute to the stromal invasion of bovine herpesvirus 1 in the respiratory mucosa.

Bovine herpesvirus 1 (BHV-1) infection may lead to conjunctivitis, upper respiratory tract problems, pneumonia, genital disorders and abortion. BHV-1 is able to spread quickly in a plaque-wise manner and invade by breaching the basement membrane (BM) barrier in the respiratory mucosa. BHV-1 Us3, a serine/threonine kinase, induces a dramatic cytoskeletal reorganization and BHV-1 Us9, a tail-anchored membrane protein, is required for axonal transport of viruses in neurons.

Intranasal treatment with a novel immunomodulator mediates innate immune protection against lethal pneumonia virus of mice.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in infants and young children. There are no licensed RSV vaccines available, and the few treatment options for high-risk individuals are either extremely costly or cause severe side effects and toxicity. Immunomodulation mediated by a novel formulation consisting of the toll-like receptor 3 agonist poly(I:C), an innate defense regulator peptide and a polyphosphazene (P-I-P) was evaluated in the context of lethal infection with pneumonia virus of mice (PVM).

Induction of functional interferon alpha and gamma responses during acute infection of cattle with non-cytopathic bovine viral diarrhea virus.

As a part of their pathogenic mechanism, many pathogens causing persistent infections, including bovine viral diarrhea virus (BVDV), immunosuppress their hosts, often by limiting the ability to either produce, or respond to, interferon. The objective of this study was to quantify the extent to which an acute infection of cattle with a non-cytopathic strain of BVDV induces interferon responses and to establish the functionality of these responses. Functionality of responses was investigated using a bovine specific peptide array to monitor kinase-mediated signal transduction activity within peripheral blood mononuclear cells (PBMCs) at time points corresponding to the interferon gamma (IFN-γ) and alpha (IFN-α) responsive phases of acute BVDV infection.

A single intranasal immunization with a subunit vaccine formulation induces higher mucosal IgA production than live respiratory syncytial virus.

Respiratory syncytial virus (RSV) causes serious respiratory illness in infants and elderly. RSV infection induces short-lived immunity, which leaves people prone to re-infection. In contrast, the RSV fusion (F) protein formulated with a novel adjuvant (∆F/TriAdj) elicits long term protective immunity.

Formulation of the respiratory syncytial virus fusion protein with a polymer-based combination adjuvant promotes transient and local innate immune responses and leads to improved adaptive immunity.

Respiratory syncytial virus (RSV) causes serious upper and lower respiratory tract infections in newborns and infants. Presently, there is no licensed vaccine against RSV. We previously reported the safety and efficacy of a novel vaccine candidate (ΔF/TriAdj) in rodent and lamb models following intranasal immunization.

IL-12p40 gene-deficient BALB/c mice exhibit lower weight loss, reduced lung pathology and decreased sensitization to allergen in response to infection with pneumonia virus of mice.

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and pneumonia in infants and pneumonia virus of mice (PVM) causes similar disease. BALB/c mice are highly susceptible, while C57BL/6 mice are more resistant to PVM. IL-12 was significantly more up-regulated in response to PVM infection in BALB/c than in C57BL/6 mice.