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Biomedical subjects

K L Tyler

Publications and source records attributed to K L Tyler.

At least 73 records · Page 4Linked to original sources
PubMed1989

Immediate-early regulatory gene mutants define different stages in the establishment and reactivation of herpes simplex virus latency.

Using nonsense and deletion mutants of herpes simplex virus type 1, we investigated the roles of three immediate-early proteins (ICP4, ICP27 and ICP0) in the establishment and reactivation of ganglionic latency in a mouse ocular model. DNA hybridization, superinfection-rescue, and cocultivation techniques provided quantitative data that distinguished between the failure of a virus to establish latency in the ganglion and its failure to reactivate. Null mutants with lesions in the genes for ICP4 and ICP27 did not replicate in the eye or in ganglia and failed to establish reactivatable latent infections. Three ICP0 deletion mutants which could replicate in the eye and ganglia varied in their ability to establish and reactivate from the latent state, demonstrating that ICP0 plays a role both in the establishment and the reactivation of latency. The use of viral mutants and a variety of stage-specific assays allowed us to better define the stages in the establishment and reactivation of herpes simplex virus type 1 latency.

Animals↗
PubMed1988

Antibody protects against lethal infection with the neurally spreading reovirus type 3 (Dearing).

The mammalian reoviruses have provided a valuable model for studying the pathogenesis of viral infections of the central nervous system (CNS). We have used this model to study the effect of antibody on disease produced by the neurally spreading reovirus type 3 (Dearing) (T3). Polyclonal and monoclonal antibodies protect mice from fatal infection with T3 after either footpad or intracerebral virus challenge. Protection occurs with monoclonal antibodies directed against the viral cell attachment protein sigma 1, and with polyclonal antisera without T3 sigma 1 binding activity. In vivo protection occurs with both neutralizing and nonneutralizing monoclonal antibodies. Antibody-mediated protection does not require serum complement and, under specific circumstances, can occur via Fc-independent mechanisms. Antibody can protect mice when transferred up to 5 days after intracerebral challenge and up to 7 days after footpad challenge, times when high titers of virus are present in the CNS. Thus, antibody mediated protection against this neurally spreading virus does not require neutralizing antibody or serum complement and occurs even in the face of established CNS infection.

Animals↗
PubMed1987

Molecular pathogenesis of neurotropic viral infections.

Classical virologists defined a number of viruses that affect the nervous system and identified tissue tropism, extraneural replication, and viremia as important parameters that determine whether viral infections will affect the central nervous system. Molecular techniques are expanding this knowledge by permitting us to relate specific genes and gene products to two defined phenotypes: neuroinvasion and neurovirulence. Two converging situations make this knowledge particularly useful: (1) the development of antiviral drugs and subunit vaccines, which mandate that pathogenesis be related to specific regions of the viral genome; and (2) the expanding problem of central nervous system infections in immunodeficient states.

Cell Survival↗
PubMed1987

Molecular and genetic aspects of the pathogenesis of viral infections of the central nervous system.

Viral pathogenesis can be defined in terms of a series of successive interactions between a virus and its target host. In order for a virus to injure a target organ such as the central nervous system (CNS), it must first enter the host animal, replicate in some primary site near its place of entry, spread from this site to the CNS and infect and injure specific populations of cells within the CNS. At each of these steps, the virus must avoid or overcome a variety of immunological and nonimmunological host defenses. It has recently become possible to begin to identify the role of specific viral genes and the proteins they encode at specific steps in the pathogenesis cycle. This review focuses on current knowledge concerning the molecular and genetic basis for the pathogenesis of viral infections of the CNS. Emphasis is placed on recent research with a wide variety of neurotropic viruses including reoviruses, bunyaviruses, lymphocytic choriomeningitis virus, rabies virus, polio virus, herpes viruses, lentiviruses, and the unconventional agents responsible for disease such as scrapie.

Humans↗
PubMed1986

Distinct pathways of viral spread in the host determined by reovirus S1 gene segment.

The genetic and molecular mechanisms that determine the capacity of a virus to utilize distinct pathways of spread in an infected host were examined by using reoviruses. Both reovirus type 1 and reovirus type 3 spread to the spinal cord following inoculation into the hindlimb or forelimb footpad of newborn mice. For type 3 this spread is through nerves and occurs via the microtubule-associated system of fast axonal transport. By contrast, type 1 spreads to the spinal cord through the bloodstream. With the use of reassortant viruses containing various combinations of double-stranded RNA segments (genes) derived from type 1 and type 3, the viral S1 double-stranded RNA segment was shown to be responsible for determining the capacity of reoviruses to spread to the central nervous system through these distinct pathways.

Animals↗
PubMed1986

Genetic basis for altered pathogenesis of an immune-selected antigenic variant of reovirus type 3 (Dearing).

In this paper we provide a step by step comparison of the pathogenesis of murine infection caused by reovirus type 3 (Dearing) and an antigenic variant (K) selected by its resistance to neutralization with a monoclonal antibody (G5) directed against the T3 hemagglutinin. To show that specific changes in the biologic properties of variant K were due to mutation in the S1 double-stranded RNA segment (gene), which encodes the viral hemagglutinin, we generated a reassortant virus ("1 HA K") containing the variant K S1 gene and compared its properties to variant K and to a reassortant ("1 HA 3") containing the T3 (Dearing) S1 gene. These studies, in conjunction with our previous nucleotide sequence analysis of the S1 genes of variant K and T3 (Dearing) [R. Bassel-Duby, A. Jayasuriya, D. Chatterjee, N. Sonenberg, J. V. Maizel, Jr., and B. N. Fields, Nature (London) 315:421-423, 1985; R. Bassel-Duby, D. R. Spriggs, K. L. Tyler, and B. N. Fields, submitted for publication], indicate that a single amino acid change in the T3 hemagglutinin can alter viral growth and tropism within the central nervous system without affecting either its primary replication in the intestine or its pattern of spread to or within the central nervous system.

Animals↗
PubMed1986

Identification of attenuating mutations on the reovirus type 3 S1 double-stranded RNA segment with a rapid sequencing technique.

Reovirus type 3 variants with mutations in the major neutralization domain of the sigma 1 protein have attenuated neurovirulence and restricted neurotropism. We devised a variation of the rapid RNA sequencing technique to facilitate the analysis of double-stranded RNA. We sequenced the S1 double-stranded RNA segment, which encodes the sigma 1 protein, of five attenuated reovirus type 3 variants. Four of the variants have changes in codon 419, and a fifth variant has a change at codon 340, all of which resulted in amino acid substitutions in the sigma 1 protein. We identified two sites on the reovirus type 3 sigma 1 protein that play a critical role in neurovirulence.

Amino Acid Sequence↗
PubMed1986

Unusual viral causes of transverse myelitis: hepatitis A virus and cytomegalovirus.

Twenty to 40% of cases of acute transverse myelitis are attributed to viral infections, although the specific viral etiology is only rarely identified. We studied two patients with transverse myelitis in association with acute hepatitis A virus (HAV) infection and acute primary cytomegalovirus (CMV) infection. This is the first well-documented report of an association between HAV infection and transverse myelitis, and only the fourth documented case of transverse myelitis in association with CMV infection in an immunocompetent adult. Both viruses should be considered as rare causes of transverse myelitis in immunologically normal adults.

Adult↗
PubMed1984

Charles Edouard Brown-Séquard: professor of physiology and pathology of the nervous system at Harvard Medical School.

Brown-Séquard's career as Harvard's first professor of the physiology and pathology of the nervous system is chronicled in a unique and previously unpublished series of his private letters and university archival material. At Harvard, Brown-Séquard tried to modernize the curriculum by adding laboratory exercises and animal experiments in the teaching of physiology. He dreamed of constructing a great physiologic institute to study fundamental problems in neurology, including epilepsy, paralysis, muscular atrophy, nerve injuries, and a wide variety of other problems. His letters reveal Brown-Séquard as a disarmingly "modern" professor who avoided faculty meetings, complained constantly about lecture schedules, his salary, and the improper care of his animals--and threatened to resign regularly!

History, 19th Century↗