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Biomedical subjects

Michael B A Oldstone

Publications and source records attributed to Michael B A Oldstone.

At least 19 recordsLinked to original sources
PubMed2006

Measles virus-dendritic cell interaction via SLAM inhibits innate immunity: selective signaling through TLR4 but not other TLRs mediates suppression of IL-12 synthesis.

Two hallmarks of measles virus (MV) infection are the ability of the virus to cause immunosuppression and the resultant enhanced susceptibility of the infected host to microbial insults. We investigated the effect of MV infection on the ability of dendritic cells (DCs) to induce IL-12 via toll-like receptor (TLR) signaling. When infected with MV, transgenic mice which expressed human SLAM receptor on their DCs were defective in the selective synthesis of IL-12 in DCs in response to stimulation of TLR4 signaling, but not to engagements of TLR2, 3, 7 or 9. MV suppressed TLR4-mediated IL-12 induction in DCs even in the presence of co-stimulation with another ligand for TLR2, 3, 7, or 9. While MV V and C proteins were not responsible for IL-12 inhibition, interaction of MV hemagglutinin with human SLAM facilitated the suppression. These results suggest that MV, by altering DC function, renders them unresponsive to secondary pathogens via TLR4.

Animals↗
PubMed2006

Interleukin-10 determines viral clearance or persistence in vivo.

Persistent viral infections are a major health concern. One obstacle inhibiting the clearance of persistent infections is functional inactivation of antiviral T cells. Although such immunosuppression occurs rapidly after infection, the mechanisms that induce the loss of T-cell activity and promote viral persistence are unknown. Herein we document that persistent viral infection in mice results in a significant upregulation of interleukin (IL)-10 by antigen-presenting cells, leading to impaired T-cell responses. Genetic removal of Il10 resulted in the maintenance of robust effector T-cell responses, the rapid elimination of virus and the development of antiviral memory T-cell responses. Therapeutic administration of an antibody that blocks the IL-10 receptor restored T-cell function and eliminated viral infection. Thus, we identify a single molecule that directly induces immunosuppression leading to viral persistence and demonstrate that a therapy to neutralize IL-10 results in T-cell recovery and the prevention of viral persistence.

Animals↗
PubMed2006

Adoptive immunotherapy induces CNS dendritic cell recruitment and antigen presentation during clearance of a persistent viral infection.

Given the global impact of persistent infections on the human population, it is of the utmost importance to devise strategies to noncytopathically purge tissues of infectious agents. The central nervous system (CNS) poses a unique challenge when considering such strategies, as it is an immunologically specialized compartment that contains a nonreplicative cell population. Administration of exogenously derived pathogen-specific memory T cells (referred to as adoptive immunotherapy) to mice burdened with a persistent lymphocytic choriomeningitis virus (LCMV) infection from birth results in eradication of the pathogen from all tissues, including the CNS. In this study, we sought mechanistic insights into this highly successful therapeutic approach. By monitoring the migration of traceable LCMV-specific memory CD8+ T cells after immunotherapy, it was revealed that cytotoxic T lymphocytes (CTLs) distributed widely throughout the CNS compartment early after immunotherapy, which resulted in a dramatic elevation in the activity of CNS antigen-presenting cells (APCs). Immunotherapy induced microglia activation as well as the recruitment of macrophages and dendritic cells (DCs) into the brain parenchyma. However, DCs emerged as the only CNS APC population capable of inducing memory CTLs to preferentially produce the antiviral cytokine tumor necrosis factor-alpha, a cytokine demonstrated to be required for successful immunotherapeutic clearance. DCs were also found to be an essential element of the immunotherapeutic process because in their absence, memory T cells failed to undergo secondary expansion, and viral clearance was not attained in the CNS. These experiments underscore the importance of DCs in the immunotherapeutic clearance of a persistent viral infection and suggest that strategies to elevate the activation/migration of DCs (especially within the CNS) may facilitate pathogen clearance.

Animals↗
PubMed2006

Prion-induced amyloid heart disease with high blood infectivity in transgenic mice.

We investigated extraneural manifestations in scrapie-infected transgenic mice expressing prion protein lacking the glycophosphatydylinositol membrane anchor. In the brain, blood, and heart, both abnormal protease-resistant prion protein (PrPres) and prion infectivity were readily detected by immunoblot and by inoculation into nontransgenic recipients. The titer of infectious scrapie in blood plasma exceeded 10(7) 50% infectious doses per milliliter. The hearts of these transgenic mice contained PrPres-positive amyloid deposits that led to myocardial stiffness and cardiac disease.

Amyloid↗
PubMed2006

Reprogramming of antiviral T cells prevents inactivation and restores T cell activity during persistent viral infection.

Failure to clear persistent viral infections results from the early loss of T cell activity. A pertinent question is whether the immune response is programmed to fail or if nonresponsive T cells can specifically be fixed to eliminate infection. Although evidence indicates that T cell expansion is permanently programmed during the initial priming events, the mechanisms that determine the acquisition of T cell function are less clear. Herein we show that in contrast to expansion, the functional programming of T cell effector and memory responses in vivo in mice is not hardwired during priming but is alterable and responsive to continuous instruction from the antigenic environment. As a direct consequence, dysfunctional T cells can be functionally reactivated during persistent infection even after an initial program of inactivation has been instituted. We also show that early therapeutic reductions in viral replication facilitate the preservation of antiviral CD4+ T cell activity, enabling the long-term control of viral replication. Thus, dysfunctional antiviral T cells can regain activity, providing a basis for future therapeutic strategies to treat persistent viral infections.

Adoptive Transfer↗
PubMed2006

CD4 T cell control primary measles virus infection of the CNS: regulation is dependent on combined activity with either CD8 T cells or with B cells: CD4, CD8 or B cells alone are ineffective.

Measles virus (MV), one of the most infectious of human pathogens, still infects over 30 million humans and causes over 500,000 deaths each year [Griffin, D., 2001. Measles virus. In: Fields, B., Knipe, D., Howley, P. (Eds.), Fields Virology. Lippincott-Raven, Philadelphia, pp. 1401-1442; ]. Death is primarily due to secondary microbial infections associated with the immunosuppression caused by MV. Studies of humans with genetic or acquired deficiencies of either the humoral or cellular arm of the immune system, and rodent models have implicated T cells in the control of the ongoing MV infection but the precise role and activities of the specific T cell subset or the molecules they produce is not clear. Using a transgenic mouse model in conjunction with depletion and reconstitution of individual B and T cell subsets alone or in combination, we show that neither CD4, CD8 nor B cells per se control acute MV infection. However, combinations of either CD4 T cells and B cells, or of CD4 and CD8 T cells are essential but CD8 T with B cells are ineffective. Interferon-gamma and neutralizing antibodies, but neither perforin nor TNF-alpha alone are associated with clearance of MV infection. TNF-alpha combined with interferon-gamma is more effective in protection than interferon alone. Further, the lack of an interferon-gamma response leads to persistence of MV.

Adoptive Transfer↗
PubMed2006

Viral persistence: parameters, mechanisms and future predictions.

For a virus to persist, it must actively curtail the host's antiviral immune response. Here, we review the conceptual basis by which this can occur and discuss the subsequent fate of differentiated cells infected over long periods of time. We also consider how the compromised antiviral immune response can be revigorated or replaced with a potent response that purges the virus and thereby terminates persistent infection.

Animals↗
PubMed2006

Altered central nervous system gene expression caused by congenitally acquired persistent infection with lymphocytic choriomeningitis virus.

Neonatal infection of most mouse strains with lymphocytic choriomeningitis virus (LCMV) leads to a life-long persistent infection characterized by high virus loads in the central nervous system (CNS) in the absence of inflammation and tissue destruction. These mice, however, exhibit impaired learning and memory. The occurrence of cognitive defects in the absence of overt CNS pathology led us to the hypothesis that chronic virus infection may contribute to neuronal dysfunction by altering the host's gene expression profile. To test this hypothesis, we examined the impact of LCMV persistence on host gene expression in the CNS. To model the natural route of human congenital CNS infection observed with a variety of viruses, we established a persistently infected mouse colony where the virus was maintained via vertical transmission from infected mothers to offspring (LCMV-cgPi). LCMV-cgPi mice exhibited a lifelong persistent infection involving the CNS; the infection was associated with impaired spatial-temporal learning. Despite high viral loads in neurons of the brains of adult LCMV-cgPi mice, we detected changes in the host's CNS gene expression for only 75 genes, 56 and 19 being significantly induced and reduced, respectively. The majority of the genes induced in the brain of LCMV-cgPi mice were interferon (IFN)-stimulated genes (ISGs) and included the transcription factors STAT1 and IRF9, the ISG15 protease UBP43, and the glucocorticoid attenuated-response genes GARG16 and GARG49. Based on their crucial role in antiviral defense, these ISGs may play an important role in limiting viral spread and replication. However, since IFNs have also been implicated in adverse effects on neuronal function, the chronic induction of some ISGs may also contribute to the observed cognitive impairment.

Animals↗
PubMed2006

Lack of intrinsic CTLA-4 expression has minimal effect on regulation of antiviral T-cell immunity.

CTLA-4 is considered one of the most potent negative regulators of T-cell activation. To circumvent experimental limitations due to fatal lymphoproliferative disease associated with genetic ablation of CTLA-4, we have used radiation chimeras reconstituted with a mixture of CTLA-4+/+ and CTLA-4-/- bone marrow that retain a normal phenotype and allow the evaluation of long-term T-cell immunity under conditions of intrinsic CTLA-4 deficiency. Following virus infection, we profiled primary, memory, and secondary CD8+ and CD4+ T-cell responses directed against eight different viral epitopes. Our data demonstrate unaltered antigen-driven proliferation, acquisition of effector functions, distribution of epitope hierarchies, T-cell receptor repertoire selection, functional avidities, and long-term memory maintenance in the absence of CTLA-4. Moreover, regulation of memory T-cell survival and homeostatic proliferation, as well as secondary responses, was equivalent in virus-specific CTLA4+/+ and CTL-A-4-/- T-cell populations. Thus, lack of CTLA-4 expression by antigen-specific T cells can be compensated for by extrinsic factors in the presence of CTLA-4 expression by other cells. These findings have implications for the physiologic, pathological, and therapeutic regulation of costimulation.

Animals↗
PubMed2005

A role for dual viral hits in causation of subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a progressive fatal neurodegenerative disease associated with persistent infection of the central nervous system (CNS) by measles virus (MV), biased hypermutations of the viral genome affecting primarily the matrix (M) gene with the conversion of U to C and A to G bases, high titers of antibodies to MV, and infiltration of B cells and T cells into the CNS. Neither the precipitating event nor biology underlying the MV infection is understood, nor is their any satisfactory treatment. We report the creation of a transgenic mouse model that mimics the cardinal features of SSPE. This was achieved by initially infecting mice expressing the MV receptor with lymphocytic choriomeningitis virus Cl 13, a virus that transiently suppressed their immune system. Infection by MV 10 days later resulted in persistent MV infection of neurons. Analysis of brains from infected mice showed the biased U to C hypermutations in the MV M gene and T and B lymphocyte infiltration. These sera contained high titers of antibodies to MV. Thus, a small animal model is now available to both molecularly probe the pathogenesis of SSPE and to test a variety of therapies to treat the disease.

Animals↗
PubMed2005

Islet-specific expression of CXCL10 causes spontaneous islet infiltration and accelerates diabetes development.

During inflammation, chemokines are conductors of lymphocyte trafficking. The chemokine CXCL10 is expressed early after virus infection. In a virus-induced mouse model for type 1 diabetes, CXCL10 blockade abrogated disease by interfering with trafficking of autoaggressive lymphocytes to the pancreas. We have generated transgenic rat insulin promotor (RIP)-CXCL10 mice expressing CXCL10 in the beta cells of the islets of Langerhans to evaluate how bystander inflammation influences autoimmunity. RIP-CXCL10 mice have islet infiltrations by mononuclear cells and limited impairment of beta cell function, but not spontaneous diabetes. RIP-CXCL10 mice crossed to RIP-nucleoprotein (NP) mice expressing the NP of the lymphocytic choriomeningitis virus in the beta cells had massively accelerated type 1 diabetes after lymphocytic choriomeningitis virus infection. Mechanistically, we found a drastic increase in NP-specific, autoaggressive CD8 T cells in the pancreas after infection. In situ staining with H-2D(b)(NP(396)) tetramers revealed islet infiltration by NP-specific CD8 T cells in RIP-NP-CXCL10 mice early after infection. Our results indicate that CXCL10 expression accelerates the autoimmune process by enhancing the migration of Ag-specific lymphocytes to their target site.

Animals↗
PubMed2005

Viruses evade the immune system through type I interferon-mediated STAT2-dependent, but STAT1-independent, signaling.

Understanding, treating, and preventing diseases caused by immunosuppression and/or persistent infections remain both a major challenge in biomedical research and an important health goal. For a virus or any infectious agent to persist, it must utilize strategies to suppress or evade the host's immune response. Here, we report that two dissimilar viruses employ a common maneuver to cause a profound immunosuppression. Measles virus (MV) and lymphocytic choriomeningitis virus (LCMV) interfere with dendritic cell (DC) development and expansion in vivo and in vitro. The underlying mechanism for this is through the generation of type I interferon (IFN) that acts via a signal transducer and activator of a transcription (STAT)2-dependent, but STAT1-independent, pathway. Thus, viruses subvert the known antiviral effect of type I IFN through STAT2-specific signaling to benefit their survival. These observations have implications for understanding and developing therapies to treat diseases caused by immunosuppression and/or persistent infections.

Animals↗
PubMed2005

Characterization of the interaction of lassa fever virus with its cellular receptor alpha-dystroglycan.

The cellular receptor for the Old World arenaviruses Lassa fever virus (LFV) and lymphocytic choriomeningitis virus (LCMV) has recently been identified as alpha-dystroglycan (alpha-DG), a cell surface receptor that provides a molecular link between the extracellular matrix and the actin-based cytoskeleton. In the present study, we show that LFV binds to alpha-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on alpha-DG for infection of cells. Mapping of the binding site of LFV on alpha-DG revealed that LFV binding required the same domains of alpha-DG that are involved in the binding of LCMV. Further, LFV was found to efficiently compete with laminin alpha1 and alpha2 chains for alpha-DG binding. Together with our previous studies on receptor binding of the prototypic immunosuppressive LCMV isolate LCMV clone 13, these findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates.

Binding Sites↗
PubMed2005

Intrinsic functional dysregulation of CD4 T cells occurs rapidly following persistent viral infection.

Effective T-cell responses are critical to eradicate acute viral infections and prevent viral persistence. Emerging evidence indicates that robust, early CD4 T-cell responses are important in effectively sustaining CD8 T-cell activity. Herein, we illustrate that virus-specific CD4 T cells are functionally inactivated early during the transition into viral persistence and fail to produce effector cytokines (i.e., interleukin-2 and tumor necrosis factor alpha), thereby compromising an efficient and effective antiviral immune response. Mechanistically, the inactivation occurs at the cellular level and is not an active process maintained by regulatory T cells or antigen-presenting cells. Importantly, a small subpopulation of cells is able to resist inactivation and persist into the chronic phase of infection. However, the virus-specific CD4 T-cell population ultimately undergoes a second round of inactivation, and the cells that had retained functional capacity fail to respond to rechallenge in an acute time frame. Based on these results we propose a biological mechanism whereby early CD4 T-cell inactivation leads to a subsequent inability to sustain cytotoxic T-lymphocyte function, which in turn facilitates viral persistence. Moreover, these studies are likely relevant to chronic/persistent infections of humans (e.g., human immunodeficiency virus, hepatitis C virus, and hepatitis B virus) by providing evidence that a reservoir of virus-specific CD4 T cells can remain functional during chronic infection and represent a potential therapeutic target to stimulate the immune response and establish control of infection.

Animals↗
PubMed2005

Posttranslational modification of alpha-dystroglycan, the cellular receptor for arenaviruses, by the glycosyltransferase LARGE is critical for virus binding.

The receptor for lymphocytic choriomeningitis virus (LCMV), the human pathogenic Lassa fever virus (LFV), and clade C New World arenaviruses is alpha-dystroglycan (alpha-DG), a cell surface receptor for proteins of the extracellular matrix (ECM). Specific posttranslational modification of alpha-DG by the glycosyltransferase LARGE is critical for its function as an ECM receptor. In the present study, we show that LARGE-dependent modification is also crucial for alpha-DG's function as a cellular receptor for arenaviruses. Virus binding involves the mucin-type domain of alpha-DG and depends on modification by LARGE. A crucial role of the LARGE-dependent glycosylation of alpha-DG for virus binding is found for several isolates of LCMV, LFV, and the arenaviruses Mobala and Oliveros. Since the posttranslational modification by LARGE is crucial for alpha-DG recognition by both arenaviruses and the host-derived ligand laminin, it also influences competition between virus and laminin for alpha-DG. Hence, LARGE-dependent glycosylation of alpha-DG has important implications for the virus-host cell interaction and the pathogenesis of LFV in humans.

Animals↗
PubMed2004

Bone marrow plasmacytoid dendritic cells can differentiate into myeloid dendritic cells upon virus infection.

Two subsets of dendritic cell (DCs), plasmacytoid (p) and myeloid (m) DCs, have been described in humans and mice. These subsets are known to have divergent roles during an immune response, but their developmental course is unclear. Here we report that virus infection induces bone marrow pDCs to differentiate into mDCs, thereby undergoing profound phenotypic and functional changes including the acquisition of enhanced antigen-presenting capacity and the ability to recognize different microbial structures through Toll-like receptor 4. The conversion of pDCs into mDCs is also induced by the injection of double-stranded RNA and requires type I interferons. Our results establish a precursor-product developmental relationship between these two DC subsets and highlight unexpected plasticity of bone marrow pDCs.

Animals↗
PubMed2004

Decrease in measles virus-specific CD4 T cell memory in vaccinated subjects.

Since the licensure and generalization of an effective measles virus (MV) vaccine 41 years ago, antibody levels have been used as correlates of immunity. The long-lived MV-specific antibody response has been studied intensely, but the dynamics of MV-specific T cell immunity over time have not been well characterized. We thus characterized the profiles of MV vaccine-induced antigen-specific T cells over time since vaccination. In a cross-sectional study of healthy subjects with a history of MV vaccination, we found that MV-specific CD4 and CD8 T cells could be detected up to 34 years after vaccination. The levels of MV-specific CD8 T cells and MV-specific IgG remained stable, whereas the level of MV-specific CD4 T cells decreased significantly in subjects who had been vaccinated >21 years earlier. These results show that MV-specific T cell immunity after vaccination is long lasting and reveal different dynamics between CD4 and CD8 cells after vaccination.

Adolescent↗