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M C Zink

Publications and source records attributed to M C Zink.

At least 55 records · Page 3Linked to original sources
PubMed1992

Infection with Borna disease virus: molecular and immunobiological characterization of the agent.

Borna disease virus (BDV), which seems to be distinct from all other known viruses, exhibits a unique mechanism of pathogenesis. This review highlights several aspects of the biology of infection with this virus and summarizes the preliminary characterization of the agent. Studies on BDV may help to illuminate several important areas of neurobiology, including the mechanisms regulating the replication of a new type of RNA virus in the nuclei of neural cells, the neuroinvasiveness and neurotropism of such viruses, their T cell-mediated immunopathology, tolerance in newborn animals to persistent viral infection of the central nervous system, and behavioral diseases and eating disorders induced by such agents.

Animals↗
PubMed1992

Pathogenesis of acute infection in rhesus macaques with a lymphocyte-tropic strain of simian immunodeficiency virus.

The simian immunodeficiency virus, SIVmac, causes disease affecting multiple organ systems in macaques similar to human immunodeficiency virus infection in humans. Molecularly cloned SIVmac with a strong lymphocyte tropism was used in pathogenesis experiments to correlate viral cell tropism with disease. In 5 animals, exhaustive analyses on viruses from tissues and identification of infected precursor cells were done at multiple times during infection to ensure the virus had not mutated into a macrophage-tropic variant. Viral replication was measured by infectivity, infectious center assays, and in situ hybridization. Lymphocytes produced most virus in tissues, indicating the virus maintained its cell tropism in vivo. Lymphocytes in bone marrow were latently infected and those in the spleen and lymph nodes were productively infected. The virus failed to replicate in the brain after intracerebral inoculation. SIVmac that maintained a strong tropism for lymphocytes and a corresponding poor tropism for macrophages can cause persistent infection and AIDS but not other diseases such as primary pneumonia and encephalitis in rhesus macaques.

Acute Disease↗
PubMed1992

Neutralizing antibodies modulate replication of simian immunodeficiency virus SIVmac in primary macaque macrophages.

Cultured macaque macrophages are permissive for the replication of SIVmac251, and inoculation with virus is followed by the production of viral p27. Neutralizing macaque polyclonal and murine monoclonal antibodies preincubated with the virus prevented infection but did not prevent cytopathic virus replication when added more than 3 days after inoculation with virus. However, application of the neutralizing antibodies to macrophages 24 h after inoculation with virus resulted in sustained, low-level production of viral antigen. Cell lysates and individual macrophages from treated cultures contained less viral protein by Western blot (immunoblot) and immunocytochemistry than untreated controls. In situ hybridization and polymerase chain reaction procedures for detecting and estimating relative amounts of viral RNA and DNA showed that both viral nucleic acids failed to increase beyond the levels obtained before the addition of neutralizing antibodies. The data suggest that macrophages may need to be infected with a minimum threshold of virus particles in order to reach their full potential for virus replication and that their exposure to neutralizing antibodies prior to reaching this threshold resulted in limited virus replication.

Animals↗
PubMed1992

Derivation of neurotropic simian immunodeficiency virus from exclusively lymphocytetropic parental virus: pathogenesis of infection in macaques.

Neurological disease resulting from lentivirus (including human immunodeficiency virus) infections is usually caused by a strain of virus that replicates productively in microglia in vivo and in macrophage cultures in vitro. We undertook this study using the model of simian immunodeficiency virus in macaques (SIVmac) to test the hypothesis that macrophage tropism is a prerequisite for neurotropism of the virus. Using molecularly cloned SIVmac239, a virus which is lymphocyte- but not macrophagetropic, we showed that this virus failed to infect brain after intracerebral (i.c.) inoculation into two macaques. Rather, these inoculations resulted in disseminated infection in lymphoid organs and the bone marrow. Two sequential passages of infected bone marrow cells inoculated i.c. into new macaques resulted in severe neurological disease and classical neuropathological lesions. Virus obtained from affected brain answered the hypothetical question: it was neurotropic and macrophagetropic. New findings in the study were that both lymphocyte- and macrophage-tropic viruses were present in the animals, but the viruses localized in different tissues: the lymphotropic virus in the spleen, lymph nodes, and plasma and the macrophagetropic virus in the brain and lungs. To determine whether the brain virus was preferentially neurotropic and whether it had neuroinvasive properties, infectious brain homogenate was inoculated into one animal i.c. and into two others peripherally. The i.c. inoculated animal developed fatal encephalitis 5 months later, and examination of tissues showed cell-free virus only in brain homogenates. Only microglia were infected despite persistent viremia and infection in bone marrow cells. The two macaques inoculated peripherally remained healthy and were euthanized at 6 months. Virus replication was detected only in the bone marrow cells and peripheral blood mononuclear cells. No infection in any macrophage population in visceral organs was detected, and the virus did not invade the brain. The strictly microglial specificity of this virus suggested that different macrophage populations in the body may select specific phenotypes of lentivirus from the quasispecies of virus in the bone marrow. This could provide the basis for specific disease affecting different organ systems.

Adaptation, Biological↗
PubMed1992

Lentivirus induced arthritis in animals.

Retroviral arthritis in sheep and goats depends on persistent infection in the animals. Virus is latent in macrophage precursor cells and viral replication is initiated when these cells are induced to differentiate. Antiviral antibodies and cytokines modulate the efficiency of viral gene product expression. Specific cytokines induced during replication of the lentivirus in mononuclear cells are also responsible for directing infected cells from peripheral blood through the vascular endothelium to particular tissues. Cytokines induced by other infectious agents such as bacteria, mycoplasma or protozoa, may also contribute to this chemotactic process. Once in the tissue, macrophages interact with lymphocytes to induce an inflammatory cascade with further production of cytokines which enhances expression of class II major histocompatibility complex antigens and proliferation of B and CD8 lymphocytes. In addition, immune complexes between viral glycoproteins and immunoglobulins are produced locally and probably lead to further enhancement of pathological changes in the tissues.

Animal Diseases↗
PubMed1992

Serum amyloid A gene transcription in synovial cells during retroviral arthritis.

In situ hybridization was used to demonstrate serum amyloid A (SAA) gene expression in arthritic joint tissue from lentivirus-infected sheep and goats. SAA gene transcription occurs in isolated individual synovial cells and occasional giant cells but not in uninfected or uninflamed synovial tissue. These findings support the notion (derived from in vitro observations) that at least one member of the SAA gene/protein family may function as an autocrine collagenase inducer in inflammatory arthritis. Since we used heterologous DNA probes derived from human clones, our findings also support the growing evidence for interspecies conservation of SAA genes.

Animals↗
PubMed1991

Rhesus monkey macrophages infected with simian immunodeficiency virus cause rapid lysis of CD4-bearing lymphocytes.

Inoculation of simian immunodeficiency virus into cultures of primary rhesus monkey macrophages or CD4-bearing transformed T lymphocytes resulted in persistent infection, with minimal virus replication in the macrophages and extensive replication in the lymphocytes. However, uninfected T cells added to infected macrophages underwent rapid fusion and lysis and were almost completely eliminated without the production of virus particles. Lysis required direct contact between the T cells and the infected macrophages, which enabled binding between CD4 on the former and viral gp120 on the latter to occur. This process was blocked by soluble CD4 and dextran sulphate. Neutralizing antibodies in the serum of an infected macaque prevented cell fusion by preventing infection of the macrophages. However, these antibodies did not prevent fusion when added to previously infected macrophages. Infected macrophages were incorporated into the syncytia of lymphocytes and continued incorporation of new lymphocytes into the syncytia required infected macrophages to be metabolically active. One inference from these studies is that infected macrophages in vivo could help mediate the well known depletion of T4 cells in patients with AIDS.

Animals↗
PubMed1991

Analysis of Borna disease virus-specific RNAs in infected cells and tissues.

Borna disease virus (BDV) is an infectious agent that causes profound disturbances in motor function and behaviour in a wide range of animal species and possibly humans. The infectious nature of BDV has long been established, but the aetiological agent has not been isolated or classified. Recently, we have reported the isolation of BDV-specific cDNA clones using subtractive libraries constructed from mRNA from infected material. Here we describe studies on one of these cDNA clones, B8, and confirm its specificity by in situ hybridization on sections of BDV-infected brain. The complete nucleotide sequence of BDV-specific clone B8 was determined. Oligonucleotides of positive and negative polarity synthesized from sequences from the 5' and 3' ends, as well as the central part, of clone B8 identified both positive- and negative-strand BDV-specific RNAs in infected rat brain. All B8 sequences used as oligonucleotide probes were found to be contained in the larger positive- and negative-strand RNAs. Thus, the structure of the BDV-specific RNAs appears to be a nested set of multiple, overlapping subgenomic positive- and negative-strand RNA transcripts.

Amino Acid Sequence↗
PubMed1991

Molecular and immunopathological studies of borna disease virus infection in rats.

Borna disease virus is an agent distinct from all known viruses. Pathogenesis of its infection is also unique. This review highlights several aspects of the biology of this viral infection and the preliminary characterization of the agent. BDV can be used to answer important questions in neurobiology. These include neuroinvasiveness and neurotropism of viral agents, CD4+ T cell-mediated immunopathology and tolerance in newborn animals to a persistent viral infection in the CNS and behavioral diseases and eating disorders induced by neurotropic viruses. This review is dedicated to Prof. Dr. Rott on occasion of his 65th birthday in recognition of his immense contributions to studies on Borna disease and also for his success focusing the attention of the scientific community to this still evolving unique viral disease.

Animals↗
PubMed1990

A borna virus cDNA encoding a protein recognized by antibodies in humans with behavioral diseases.

Borna disease virus (BDV) causes a rare neurological disease in horses and sheep. The virus has not been classified because neither an infectious particle nor a specific nucleic acid had been identified. To identify the genome of BDV, a subtractive complementary DNA expression library was constructed with polyadenylate-selected RNA from a BDV-infected MDCK cell line. A clone (B8) was isolated that specifically hybridized to RNA isolated from BDV-infected brain tissue and BDV-infected cell lines. This clone hybridized to four BDV-specific positive strand RNAs (10.5, 3.6, 2.1, and 0.85 kilobases) and one negative strand RNA (10.5 kilobases) in BDV-infected rat brain. Nucleotide sequence analysis of the clone suggested that it represented a full-length messenger RNA which contained several open reading frames. In vitro transcription and translation of the clone resulted in the synthesis of the 14- and 24-kilodalton BDV-specific proteins. The 24-kilodalton protein, when translated in vitro from the clone, was recognized by antibodies in the sera of patients (three of seven) with behavioral disorders. This BDV-specific clone will provide the means to isolate the other BDV-specific nucleic acids and to identify the virus responsible for Borna disease. In addition, the significance of BDV or a BDV-related virus as a human pathogen can now be more directly examined.

Amino Acid Sequence↗
PubMed1990

Pathogenesis of caprine arthritis encephalitis virus. Cellular localization of viral transcripts in tissues of infected goats.

Pathologic specimens of 18 goats with classical lesions of caprine arthritis-encephalitis (CAE) virus infection were examined morphologically and by in situ hybridization using molecularly cloned CAEV deoxyribonucleic acid (DNA) to determine which tissues and cells of naturally infected goats supported virus replication. Large numbers of cells with viral transcripts were detected in inflamed brain, spinal cord, lung, joints, and mammary gland. These cells were morphologically compatible with macrophages. Fewer cells with viral transcripts were seen in noninflamed tissues. Viral RNA was identified in macrophagelike cells in lung, liver, spleen, and lymph nodes, in cells lining the vessels of brain and synovium, and in epithelial cells of intestinal crypts, renal tubules, and thyroid follicles. These data suggest that the cell tropism of lentiviruses may extend beyond the narrow boundaries of lymphocytes and macrophages.

Age Factors↗
PubMed1989

Lentivirus-induced interferon inhibits maturation and proliferation of monocytes and restricts the replication of caprine arthritis-encephalitis virus.

In this study, we investigated the effect of a lentivirus-induced interferon (LV-IFN) on the interaction of caprine arthritis-encephalitis virus and its host cell, the monocyte-macrophage. LV-IFN was produced in culture supernatant 48 h after adding fresh goat lymphocytes to caprine arthritis-encephalitis virus-infected goat macrophages. The culture supernatant contained IFN activity at a titer of 1:360 as assayed by inhibition of vesicular stomatitis virus-induced lysis of fibroblasts. LV-IFN inhibited in vitro monocyte proliferation and maturation of monocytes to macrophages. Nevertheless, treated monocytes produced prostaglandin E2, a cytokine generally produced by activated macrophages. By inhibiting the maturation of monocytes to the more permissive macrophage, LV-IFN indirectly downregulated virus replication. The cytokine also had a direct inhibitory effect on virus gene expression in already mature macrophages. In these cells, LV-IFN blocked the viral life cycle at the level of transcription. Finally, LV-IFN blocked fusion between infected macrophages and highly permissive goat synovial membrane cells. By restricting macrophage maturation, viral replication, and cell fusion, LV-IFN may downregulate the net rate of virus replication in vivo. These functions may contribute to the persistence of the virus in the host by reducing the expression of the viral genome.

Animals↗
PubMed1988

Lentivirus-host interactions: lessons from visna and caprine arthritis-encephalitis viruses.

The biological properties of the ruminant animal lentiviruses, visna and caprine arthritis-encephalitis viruses, closely resemble those of their human counterparts, the human immunodeficiency viruses (HIV). All of these viruses are morphologically identical and are disseminated from host to host in nature during exchange of body fluids. Artificial conditions that favor excess exchange of such fluids precipitate epidemics by these viruses. The strategy of replication of the animal viruses in tissue culture and in vivo are very similar to that of the human virus. Virus replication is highly productive in tissue culture and leads to cytopathic effects characterized by fusion. In vivo, the rate of virus replication is restricted and lesions, suggestive of an immunopathological origin, develop after prolonged periods of subclinical infection. Similar to the animal viruses, the human viruses have a tropism for macrophages in vivo, and this leads somehow to a loss of T helper lymphocytes and proliferation of cytotoxic lymphocytes. In addition, the viruses are highly neurotropic and this results in acute fulminating disease in neonatal hosts and chronic encephalopathy in adults. Both animal and human viruses cause persistent infections and have similar strategies for eluding host immune responses. These include sequestration of neutralizing epitopes, induction of low titers of neutralizing antibodies, and antigenic drift during persistent infection. Despite close homology between genetic sequences of HIV-I and -II, these two viruses seem to have as much biological disparity from each other as does visna virus from caprine arthritis-encephalitis virus. The latter two viruses induce neutralizing antibodies that are highly strain specific and show no cross protection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animal Diseases↗
PubMed1987

Pathogenesis of visna/maedi and caprine arthritis-encephalitis: new leads on the mechanism of restricted virus replication and persistent inflammation.

Lentiviruses are unique retroviruses which cause diseases with long incubation periods and prolonged clinical courses. The prototype lentiviruses, visna/maedi of sheep and arthritis-encephalitis virus of goats (CAEV), infect cells of the monocyte-macrophage system and replicate at a restricted level in these cells. The virus life cycle is closely associated with maturational factors in the cells; monocytes support the early stages of the replication cycle which goes to completion only when the cells mature to macrophages. Virus replication in the monocyte-macrophage results in lesions characterized by mononuclear cell infiltration of the central nervous system (CNS), lungs, synovium and mammary gland and their draining lymph nodes. Co-cultivation of sheep or goat lymphocytes with macrophages infected with visna or CAE viruses results in production of a unique interferon (LV-IFN). LV-IFN is a non-glycosylated protein of 54,000 to 64,000 daltons and has biological properties which have several implications for pathogenesis. Firstly, it retards the rate of maturation of monocytes and thus indirectly slows the rate of virus replication. Second, it restricts the rate of virus replication in mature macrophages by preventing virus maturation. Third, it induces expression of class II (Ia) antigens of the major histocompatibility complex on cells of macrophage lineage. Thus, by curtailing virus replication and enhancing expression of MHC class II antigens, LV-IFN may contribute to the induction and augmentation of the host's lymphoproliferative response to the virus.

Animals↗
PubMed1987

The interaction of Rhodococcus equi and foal neutrophils in vitro.

Polymorphonuclear neutrophil leukocytes (PMNL) from 8 healthy foals (2-14 weeks of age) and 2 foals with bacterial pneumonia were separated from whole blood using a 2 step Percoll gradient. Purified PMNL were tested for bactericidal function against Rhodococcus equi and Staphylococcus aureus in the presence of normal horse serum. The percentage uptake after a 15-min pre-incubation of PMNL and bacteria was also calculated. Ultrastructural examination of the interaction of R. equi and normal foal PMNL was performed after 15 min incubation. Results indicated that foal PMNL effectively phagocytose and destroy R. equi and S. aureus in the presence of normal horse serum. The mean percent uptake for R. equi was 99.3 +/- 0.4% and for S. aureus 99.9 +/- 0.1%. Further, 97.8 +/- 0.1% ingested R. equi and 98.4 +/- 0.1% ingested S. aureus were destroyed in the 15-min incubation period. Over the 3-h incubation, 91.9% of remaining R. equi were killed, but only 49.2 +/- 31.9% of S. aureus (P less than 0.01). Total bactericidal effect of foal PMNL, however, was 99.3 +/- 0.4% against R. equi and 99.9 +/- 0.1% against S. aureus. The percentage uptake and total bactericidal efficacy of neutrophils from sick foals was greater than 95%. Ultrastructural examination of the PMNL-R. equi interaction after 15 min incubation revealed phagocytosis of the bacteria and morphologic changes consistent with neutrophil degranulation. This study suggests that a defect in PMNL bactericidal capability is not likely to be a contributing factor in the pathogenesis of R. equi pneumonia in foals.

Actinomycetales Infections↗