M.B.A. Oldstone

The Scripps Research Institute, لا هویا, California, United States

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Publications (619)5078.95 Total impact

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    ABSTRACT: Although type I interferon (IFN-I) is thought to be beneficial against microbial infections, persistent viral infections are characterized by high interferon signatures suggesting that IFN-I signaling may promote disease pathogenesis. During persistent lymphocytic choriomeningitis virus (LCMV) infection, IFNα and IFNβ are highly induced early after infection, and blocking IFN-I receptor (IFNAR) signaling promotes virus clearance. We assessed the specific roles of IFNβ versus IFNα in controlling LCMV infection. While blockade of IFNβ alone does not alter early viral dissemination, it is important in determining lymphoid structure, lymphocyte migration, and anti-viral T cell responses that lead to accelerated virus clearance, approximating what occurs during attenuation of IFNAR signaling. Comparatively, blockade of IFNα was not associated with improved viral control, but with early dissemination of virus. Thus, despite their use of the same receptor, IFNβ and IFNα have unique and distinguishable biologic functions, with IFNβ being mainly responsible for promoting viral persistence. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 05/2015; 17(5):653-61. DOI:10.1016/j.chom.2015.04.005 · 12.33 Impact Factor
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    ABSTRACT: Author Summary Lymphocytic Choriomenengitis Virus (LCMV) is an important model for the investigation of the pathogenesis of persistent viral infections. As with humans infected with hepatitis C and Human Immunodeficiency Virus-1, adult mice persistently infected with immunosuppressive strains of LCMV express high levels of negative immune regulators that suppress the adaptive T cell immune response thereby facilitating viral persistence. Unknown, however, is whether and how very early interactions between the virus and the infected host affect the establishment of a persistent infection. Here, we describe host-virus interactions within the first 8–12 hours of infection are critical for establishing a persistent infection. While early induction of an anti-viral type-I interferons is essential for the subsequent adaptive immune response required to clear the virus, LCMV is able to overcome the programmed innate immune response by over-stimulating this response early. This affects not only the rate of viral growth in the host, but also the ability to infect specific immune cells that help shape an effective adaptive immune response. We further describe how and where LCMV is sensed by this early immune response, identify the critical timing of early virus-host interactions that lead to a persistent infection, and identify an early dysregulated immune signature associated with a persistent viral infection. Altogether, these observations are critical to understanding how early virus-host interactions determines the course of infection.
    PLoS Pathogens 01/2015; 11(1):e1004588. DOI:10.1371/journal.ppat.1004588 · 7.56 Impact Factor
  • Michael B. A. Oldstone · Richard W. Compans
    Current topics in microbiology and immunology 01/2015; 386:V-VI. · 4.10 Impact Factor
  • Cherie T Ng · Michael B A Oldstone
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    ABSTRACT: The clearance of viral infections is reliant on the coordination and balance of inflammatory factors necessary for viral destruction and immunoregulatory mechanisms necessary to prevent host pathology. In the case of persistent viral infections, immunoregulatory pathways prevent the immune response from clearing the virus, resulting in a long-term equilibrium between host and pathogen. Consequently, negative immune regulators are being considered as a therapeutic target to treat persistent and chronic viral infections. In this review, we will highlight the current understanding of the important negative immune regulator interleukin-10 (IL-10) in persistent viral infection. Though its main role for the host is to limit immune-mediated pathology, IL-10 is a multifunctional cytokine that differentially regulates a number of different hematopoietic cell types. IL-10 has been shown to play a role in a number of infectious diseases and many viral pathogens specifically exploit the IL-10 pathway to help evade host immunity. Recent advances have demonstrated that manipulation of IL-10 signaling during persistent viral infection can alter T cell responses in vivo and that this manipulation can lead to the clearance of persistent viral infection. Furthermore, there have been crucial advances in the understanding of factors that induce IL-10. We summarize lessons learned about IL-10 in model organisms and human persistent infections and conclude with the potential use of IL-10 to treat persistent viral infections.
    Current topics in microbiology and immunology 07/2014; 380:129-44. DOI:10.1007/978-3-662-43492-5_6 · 4.10 Impact Factor
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    ABSTRACT: The outcome of a viral infection reflects the balance between virus virulence and host susceptibility. The clone 13 (Cl13) variant of lymphocytic choriomeningitis virus-a prototype of Old World arenaviruses closely related to Lassa fever virus-elicits in C57BL/6 and BALB/c mice abundant negative immunoregulatory molecules, associated with T-cell exhaustion, negligible T-cell-mediated injury, and high virus titers that persist. Conversely, here we report that in NZB mice, despite the efficient induction of immunoregulatory molecules and high viremia, Cl13 generated a robust cytotoxic T-cell response, resulting in thrombocytopenia, pulmonary endothelial cell loss, vascular leakage, and death within 6-8 d. These pathogenic events required type I IFN (IFN-I) signaling on nonhematopoietic cells and were completely abrogated by IFN-I receptor blockade. Thus, IFN-I may play a prominent role in hemorrhagic fevers and other acute virus infections associated with severe vascular pathology, and targeting IFN-I or downstream effector molecules may be an effective therapeutic approach.
    Proceedings of the National Academy of Sciences 06/2014; 111(24). DOI:10.1073/pnas.1408148111 · 9.67 Impact Factor
  • Michael B A Oldstone · Hugh Rosen
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    ABSTRACT: Cytokine storm defines a dysregulation of and an excessively exaggerated immune response most often accompanying selected viral infections and several autoimmune diseases. Newly emerging and re-emerging infections of the respiratory tract, especially influenza, SARS, and hantavirus post considerable medical problems. Their morbidities and mortalities are often a direct result of cytokine storm. This chapter visits primarily influenza virus infection and resultant cytokine storm. It provides the compelling evidence that illuminates cytokine storm in influenza pathogenesis and the clear findings that cytokine storm is chemically tractable by therapy directed toward sphingosine-1-phosphate receptor (S1PR) modulation, specifically S1P1R agonist therapy. The mechanism(s) of how S1P1R signaling works and the pathways involved are subjects of this review.
    Current topics in microbiology and immunology 04/2014; 378:129-47. DOI:10.1007/978-3-319-05879-5_6 · 4.10 Impact Factor
  • Michael B.A. Oldstone
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    ABSTRACT: On a clonal level, certain antibodies and T cells can interact with dissimilar antigens found in microbes and in host cells. More than 5% of over 800 monoclonal antibodies derived from multiple RNA and DNA viruses, as well as from a large number of T cell clones, engage in such interactions. Several of these cross-reactions, which we termed molecular mimicry, are against unique host proteins involved in autoimmune responses and diseases. Thus, molecular mimicry initiated as a host response to a virus or a microbial infection, but alternatively cross-reacting with an appropriate host-antigen, can be a mechanism for instigating an autoimmune disease. Molecular mimicry provides an explanation for the genetic observation that identical twins rarely manifest the same autoimmune disease and the documented epidemiologic evidence that microbial and/or viral infections often precede autoimmune disorders.
    Monoclonal Antibodies in Immunodiagnosis and Immunotherapy 04/2014; 2(3). DOI:10.1089/mab.2013.0090
  • Experimental Biology Meeting; 04/2014
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    ABSTRACT: Cytokine storm is an intensified, dysregulated, tissue injurious inflammatory response driven by cytokine and immune cell components. Cytokine storm has been well characterized during influenza virus infection whereby the amplified innate immune response is primarily responsible for pulmonary damage. Now we describe a novel event where virus-specific T cells induce cytokine storm. The paramyxovirus, pneumonia virus of mice (PVM), is a model of human respiratory syncytial virus (hRSV). Unexpectedly, when C57Bl/6 mice were infected with PVM the innate inflammatory response was undetectable until day 5 post-infection, at which time CD8(+) T cells infiltrated into the lung initiating cytokine storm by their production of IFN-γ and TNF-α. Administration of an immunomodulatory sphingosine-1-phosphate (S1P) receptor 1 (S1P1R) agonist significantly inhibited PVM-elicited cytokine storm by blunting the PVM-specific CD8(+) T cell response resulting in diminished pulmonary disease and enhanced survival. Dysregulated overly exuberant immune response termed "cytokine storm" accompanies virus-induced acute respiratory diseases (VARV), is primarily responsible for the accompanying high morbidity and mortality and can be controlled therapeutically in influenza virus infection of mice and ferrets by administration of sphingosine-1-phosphate 1 receptor (S1P1R) agonists. Here two novel findings are recorded. First, in contrast to influenza infection where cytokine storm is initiated early by the innate immune system, for pneumonia virus of mice (PVM), a model of RSV, cytokine storm is initiated late in infection by the adoptive immune response specifically by virus-specific CD8 T cells via their release of interferon-γ and TNF-α. Blockading these cytokines with neutralizing antibodies blunts cytokine storm and protects the host. Second, PVM infection is controlled by administration of S1P1R agonist.
    Journal of Virology 03/2014; 88(11). DOI:10.1128/JVI.00464-14 · 4.44 Impact Factor
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    ABSTRACT: Influenza infection of humans remains an important public health problem. Vaccine strategies result in a significant but only partial control (65–85%) of infection. Thus, chemotherapeutic approaches are needed to provide a solution both for vaccine failures and to limit infection in the unvaccinated population. Previously (9 and 10) documented that sphingosine-1-phosphate 1 receptor (S1P1R) agonists significantly protected mice against pathogenic H1N1 influenza virus by limiting immunopathologic damage while allowing host control of the infection. Here we extend that observation by documenting S1P1R agonist can control pathogenic H1N1 influenza infection in ferrets. S1P1R agonist was more effective in reducing pulmonary injury than the antiviral drug oseltamivir but, importantly, combined therapy was significantly more effective than either therapy alone.
    Virology 03/2014; s 452–453:152–157. DOI:10.1016/j.virol.2014.01.003 · 3.32 Impact Factor
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    John R Teijaro · Kevin B Walsh · Stephanie Rice · Hugh Rosen · Michael B A Oldstone
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    ABSTRACT: During pathogenic influenza virus infection, robust cytokine production (cytokine storm), excessive inflammatory infiltrates, and virus-induced tissue destruction all contribute to morbidity and mortality. Earlier we reported that modulation of sphingosine-1-phosphate-1 receptor (S1P1R) signaling provided a chemically tractable approach for the effective blunting of cytokine storm, leading to the improvement of clinical and survival outcomes. Here, we show that S1P1R agonist treatment suppresses global cytokine amplification. Importantly, S1P1R agonist treatment was able to blunt cytokine/chemokine production and innate immune cell recruitment in the lung independently of endosomal and cytosolic innate sensing pathways. S1P1R signaling suppression of cytokine amplification was independent of multiple innate signaling adaptor pathways for myeloid differentiation primary response gene 88 (MyD88) and IFN-β promoter stimulator-1 signaling, indicating a common pathway inhibition of cytokine storm. We identify the MyD88 adaptor molecule as responsible for the majority of cytokine amplification observed following influenza virus challenge.
    Proceedings of the National Academy of Sciences 02/2014; 111(10). DOI:10.1073/pnas.1400593111 · 9.67 Impact Factor
  • Michael B. A. Oldstone · Richard W. Compans
    Current topics in microbiology and immunology 01/2014; 385:V-VI. · 4.10 Impact Factor
  • Michael B. A. Oldstone · Hugh Rosen
    Current topics in microbiology and immunology 01/2014; 378:V-VI. · 4.10 Impact Factor
  • Source
    Michael B.A. Oldstone
    Virology 07/2013; 442(1):1-2. DOI:10.1016/j.virol.2013.04.011 · 3.32 Impact Factor
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    ABSTRACT: The paramyxovirus, pneumonia virus of mice (PVM), is a rodent model of human respiratory syncytial virus (hRSV) pathogenesis. Here we characterized the PVM-specific CD8(+) T-cell repertoire in susceptible C57Bl/6 mice. In total, 15 PVM-specific CD8(+) T-cell epitopes restricted by H-2D(b) and/or K(b) were identified. These data open the door for using widely profiled, genetically manipulated, C57Bl/6 mice to study the contribution of epitope-specific CD8(+) T-cells to PVM pathogenesis.
    Journal of Virology 07/2013; 87(17). DOI:10.1128/JVI.00339-13 · 4.44 Impact Factor
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    ABSTRACT: Follicular helper T cells (TFH cells) provide critical help to B cells during humoral immune responses. Here we report that mice with T cell-specific deletion of the miR-17∼92 family of microRNAs (miRNAs) had substantially compromised TFH differentiation, germinal-center formation and antibody responses and failed to control chronic viral infection. Conversely, mice with T cell-specific expression of a transgene encoding miR-17∼92 spontaneously accumulated TFH cells and developed a fatal immunopathology. Mechanistically, the miR-17∼92 family controlled the migration of CD4(+) T cells into B cell follicles by regulating signaling intensity from the inducible costimulator ICOS and kinase PI(3)K by suppressing expression of the phosphatase PHLPP2. Our findings demonstrate an essential role for the miR-17∼92 family in TFH differentiation and establish PHLPP2 as an important mediator of their function in this process.
    Nature Immunology 06/2013; 14(8). DOI:10.1038/ni.2648 · 20.00 Impact Factor
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    ABSTRACT: In most forms of prion disease, infectivity is present primarily in the central nervous system or immune system organs such as spleen and lymph node. However, a transgenic mouse model of prion disease has demonstrated that prion infectivity can also be present as amyloid deposits in heart tissue. Deposition of infectious prions as amyloid in human heart tissue would be a significant public health concern. Although abnormal disease-associated prion protein (PrP(Sc)) has not been detected in heart tissue from several amyloid heart disease patients, it has been observed in the heart tissue of a patient with sporadic Creutzfeldt-Jakob Disease (sCJD), the most common form of human prion disease. In order to determine whether prion infectivity can be found in heart tissue, we have inoculated formaldehyde fixed brain and heart tissue from two sCJD patients, as well as prion protein positive fixed heart tissue from two amyloid heart disease patients, into transgenic mice overexpressing the human prion protein. While the sCJD brain samples led to clinical or subclinical prion infection and deposition of PrP(Sc) in the brain, none of the inoculated heart samples resulted in disease or accumulation of PrP(Sc). Thus, our results suggest that prion infectivity is not likely present in cardiac tissue from sCJD or amyloid heart disease patients.
    Journal of Virology 06/2013; 87(17). DOI:10.1128/JVI.00692-13 · 4.44 Impact Factor
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    Cherie T Ng · Laura M Snell · David G Brooks · Michael B.A. Oldstone
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    ABSTRACT: Persistent viral infections are the result of a series of connected events that culminate in diminished immunity and the inability to eliminate infection. By building our understanding of how distinct components of the immune system function both individually and collectively in productive versus abortive responses, new potential therapeutic targets can be developed to overcome immune dysfunction and thus fight persistent infections. Using lymphocytic choriomeningitis virus (LCMV) as a model of a persistent virus infection and drawing parallels to persistent human viral infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), we describe the cellular relationships and interactions that determine the outcome of initial infection and highlight immune targets for therapeutic intervention to prevent or treat persistent infections. Ultimately, these findings will further our understanding of the immunologic basis of persistent viral infection and likely lead to strategies to treat human viral infections.
    Cell host & microbe 06/2013; 13(6):652-64. DOI:10.1016/j.chom.2013.05.014 · 12.33 Impact Factor
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    Andrew M Lee · Justin Cruite · Megan J Welch · Brian Sullivan · Michael B.A. Oldstone
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    ABSTRACT: Lassa virus (LASV) is a BSL-4 restricted agent. To allow study of infection by LASV under BSL-2 conditions, we generated a recombinant virus in which the LASV glycoprotein (Gp) was placed on the backbone of lymphocytic choriomeningitis virus (LCMV) Cl13 nucleoprotein, Z and polymerase genes (rLCMV Cl13/LASV Gp). The recombinant virus displayed high tropism for dendritic cells following in vitro or in vivo infection. Inoculation of immunocompetent adults resulted in an acute infection, generation of virus-specific CD8(+) T cells and clearance of the infection. Inoculation of newborn mice with rLCMV Cl13/LASV Gp resulted in a life-long persistent infection. Interestingly, adoptive transfer of rLCMV Cl13/LASV Gp immune memory cells into such persistently infected mice failed to purge virus but, in contrast, cleared virus from mice persistently infected with wt LCMV Cl13.
    Virology 05/2013; 442(2). DOI:10.1016/j.virol.2013.04.010 · 3.32 Impact Factor
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    ABSTRACT: During persistent viral infections, chronic immune activation, negative immune regulator expression, an elevated interferon signature, and lymphoid tissue destruction correlate with disease progression. We demonstrated that blockade of type I interferon (IFN-I) signaling using an IFN-I receptor neutralizing antibody reduced immune system activation, decreased expression of negative immune regulatory molecules, and restored lymphoid architecture in mice persistently infected with lymphocytic choriomeningitis virus. IFN-I blockade before and after establishment of persistent virus infection resulted in enhanced virus clearance and was CD4 T cell-dependent. Hence, we demonstrate a direct causal link between IFN-I signaling, immune activation, negative immune regulator expression, lymphoid tissue disorganization, and virus persistence. Our results suggest that therapies targeting IFN-I may help control persistent virus infections.
    Science 04/2013; 340(6129):207-11. DOI:10.1126/science.1235214 · 33.61 Impact Factor

Publication Stats

36k Citations
5,078.95 Total Impact Points


  • 1980–2015
    • The Scripps Research Institute
      • • Department of Immunology and Microbial Science
      • • Department of Molecular and Experimental Medicine
      لا هویا, California, United States
  • 2009
    • Berand Neuropharmacology
      Dublin, Leinster, Ireland
  • 1971–2006
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 2004
    • La Jolla Institute for Allergy & Immunology
      • Division of Developmental Immunology
      La Jolla, CA, United States
  • 2003
    • Vaccine & Gene Therapy Institute of Florida
      Port St. Lucie, Florida, United States
  • 2002
    • Centers for Disease Control and Prevention
      Atlanta, Michigan, United States
  • 1998
    • University of Iowa
      Iowa City, Iowa, United States
  • 1996
    • Harvard University
      • Department of Molecular and Cell Biology
      Cambridge, Massachusetts, United States
  • 1995
    • National Institute of Allergy and Infectious Diseases
      Maryland, United States
  • 1992–1995
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 1994
    • Carnegie Mellon University
      Pittsburgh, Pennsylvania, United States
  • 1993
    • Massachusetts Department of Public Health
      Boston, Massachusetts, United States
  • 1991
    • Albert Einstein College of Medicine
      • Department of Microbiology & Immunology
      New York, New York, United States
  • 1990
    • University of Washington Seattle
      Seattle, Washington, United States
  • 1989
    • Harvard Medical School
      Boston, Massachusetts, United States
    • University of Alabama at Birmingham
      • Division of Infectious Diseases
      Birmingham, Alabama, United States
  • 1987–1988
    • University of California, Los Angeles
      Los Angeles, California, United States
    • Jefferson College
      Хиллсборо, Missouri, United States
  • 1986
    • Mayo Clinic - Rochester
      • Department of Neurology
      Рочестер, Minnesota, United States
  • 1985
    • Thomas Jefferson University
      Filadelfia, Pennsylvania, United States
    • Naval Medical Center San Diego
      • Infectious Diseases Clinic
      San Diego, California, United States
  • 1984
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 1983
    • CSU Mentor
      Long Beach, California, United States
  • 1974–1983
    • University of California, San Diego
      • Department of Pathology
      San Diego, California, United States
    • National Cancer Institute (USA)
      베서스다, Maryland, United States
  • 1976
    • Karolinska Institutet
      • Department of Microbiology, Tumor and Cell Biology (MTC)
      Solna, Stockholm, Sweden
  • 1973
    • Stanford Medicine
      Stanford, California, United States