Showing papers by "Hilary Koprowski published in 2005"

Uric acid protects against secondary damage after spinal cord injury.

Abstract: Peroxynitrite contributes to the pathogenesis of various neurodegenerative disorders through multiple mechanisms and is thought to mediate secondary neuronal cell death after spinal cord injury (SCI). Here we establish that physiologically relevant levels of uric acid (UA), a selective inhibitor of certain peroxynitrite-mediated reactions, block the toxic effects of peroxynitrite on primary spinal cord neurons in vitro. Furthermore, administration of UA at the onset of SCI in a mouse model inhibits several pathological changes in the spinal cord including general tissue damage, nitrotyrosine formation, lipid peroxidation, activation of poly(ADP-ribose) polymerase, and neutrophil invasion. More importantly, UA treatment improves functional recovery from the injury. Taken together, our findings support the concept that peroxynitrite contributes to the pathophysiology of secondary damage after SCI. They also raise the possibility that elevating UA levels may provide a therapeutic approach for the treatment of SCI as well as other neurological diseases with a peroxynitrite-mediated pathological component.

Pathogenesis of Rabies

Abstract: Rabies is a central nervous system (CNS) disease that is almost invariably fatal. The causative agent is rabies virus (RV), a negative-stranded RNA virus of the rhabdovirus family. RV pathogenesis, like that of other viruses, is a multigenic trait. Recent findings indicate that in addition to the RV G protein viral elements that regulate gene expression, especially expression of the L gene, are also likely to play a role in RV pathogenesis. In vivo, RV infects almost exclusively neurons, and neuroinvasiveness is the major defining characteristic of a classical RV infection. A key factor in the neuroinvasion of RV is transsynaptic neuronal spread. While the ability of RV to spread from the post-synaptic site to the pre-synaptic site is mediated by the RV G protein, the RV P protein might be an important determinant of retrograde transport of the virus within axons. Although the mechanism(s) by which an RV infection cause(s) a lethal neurological disease are still not well understood, the most significant factor underlying the lethal outcome of an RV infection appears to be the neuronal dysfunction due to drastically inhibited synthesis of proteins required in maintaining neuronal functions.

A single immunization with a rhabdovirus-based vector expressing severe acute respiratory syndrome coronavirus (SARS-CoV) S protein results in the production of high levels of SARS-CoV-neutralizing antibodies

Abstract: Foreign viral proteins expressed by rabies virus (RV) have been shown to induce potent humoral and cellular immune responses in immunized animals. In addition, highly attenuated and, therefore, very safe RV-based vectors have been constructed. Here, an RV-based vaccine vehicle was utilized as a novel vaccine against severe acute respiratory syndrome coronavirus (SARS-CoV). For this approach, the SARS-CoV nucleocapsid protein (N) or envelope spike protein (S) genes were cloned between the RV glycoprotein G and polymerase L genes. Recombinant vectors expressing SARS-CoV N or S protein were recovered and their immunogenicity was studied in mice. A single inoculation with the RV-based vaccine expressing SARS-CoV S protein induced a strong SARS-CoV-neutralizing antibody response. The ability of the RV-SARS-CoV S vector to confer immunity after a single inoculation makes this live vaccine a promising candidate for eradication of SARS-CoV in animal reservoirs, thereby reducing the risk of transmitting the infection to humans.

Orally Delivered, Plant-Produced Tat Protein Primes Mice For a Challenge DNA Vaccine Expressing Tat

Abstract: The Tat protein has been recently explored as a prospective vaccine candidate against HIV-1 with broad, subtype non-specific action. A truncated version of Tat()Tat) with the basic loop, involved in immunosuppression, removed has been previously demonstrated as efficacious as the full-size Tat protein. We produced both full-size Tat and truncated _Tat in plants, including one edible species – spinach, thus simultaneously addressing problems of an inexpensive Tat production and a direct delivery through the mucosal route. We tested this oral delivery route in a mouse model. Tat and )Tat genes were assembled from a set of synthetic overlapping oligonucleotides, and subsequently cloned into a plant virus-based expression vector. Codon optimization allows production of up to 300–500 mg of Tat or )Tat antigen per 1 g of leaf tissue in spinach. Spinach plants inoculated with the Tat-producing constructs were collected and fed to mice 7–14 days post inoculation with or without mucosal adjuvants. Mice were fed with the Tat-producing or control vector-inoculated spinach. After 3 voluntary feedings, 1 week apart, 1 g per mice, no differences were detected in the growth rate or behavior of the animals fed with these two types of spinach. None of the animals developed measurable Tat antibodies. Challenge DNA vaccination with a homologous Tatexpressing construct was performed using a gene gun. Following DNA vaccination, however, mice previously receiving oral Tat with cholera toxin as an adjuvant, developed higher antibody titers to Tat than did the controls, with the titers peaking at four weeks post-vaccination. Thus, our data suggested that oral Tat primed for the development of Tat antibodies when mice were challengevaccinated with plasmid DNA for expression of Tat. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005