Bumsuk Hahm

University of Missouri, Columbia, Missouri, United States

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Publications (21)125.85 Total impact

  • Young-Jin Seo, Bumsuk Hahm
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    ABSTRACT: Abstract Sphingosine analogs display diverse immunoregulatory activities with curative potential in autoimmune diseases and viral infections. Recently, the sphingosine analog AAL-R was shown to increase DC activation upon TLR7 stimulation. Here, we investigated the effect of AAL-R on activation of dendritic cells (DCs) infected by lymphocytic choriomeningitis virus (LCMV). Concomitant treatment of LCMV-infected DCs with AAL-R enhanced DC maturation and DC ability to stimulate and expand antiviral CD8(+) T cells. Importantly, AAL-R's stimulatory activity was abrogated in type I interferon (IFN) receptor-deficient DCs following LCMV infection. In support of this observation, AAL-R increased type I IFN production from DCs infected with LCMV. Taken together, the sphingosine analog could directly act on DCs to promote defensive host DC responses to the viral invasion via type I IFN signaling.
    Viral immunology 03/2014; 27(2):82-86. · 1.78 Impact Factor
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    ABSTRACT: Measles virus (MV) manipulates host factors to facilitate virus replication. Sphingosine kinase (SK) is an enzyme catalyzing the formation of sphingosine 1-phosphate and modulates multiple cellular processes including the host defense system. Here, we determined the role of SK1 in MV replication. Overexpression of SK1 enhanced MV replication. In contrast, inhibition of SK impaired viral protein expression and infectious virus production from cells expressing MV receptor, SLAM or Nectin-4. The inhibition of virus replication was observed when the cells were infected by vaccine strain or wild type MV or V/C gene-deficient MV. Importantly, SK inhibition suppressed MV-induced activation of NF-κB. The inhibitors specific to NF-κB signal pathway repressed the synthesis of MV proteins, revealing the importance of NF-κB activation for efficient MV replication. Therefore, SK inhibition restricts MV replication and modulates the NF-κB signal pathway, demonstrating that SK is a cellular factor critical for MV replication.
    Virology 01/2014; s 450–451:55–63. · 3.35 Impact Factor
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    ABSTRACT: Microfluidic devices are becoming a standard method of lab analysis of many different types of samples. This letter presents a uniquely shaped micropost structure set in an arrayed fashion for sensing and cell capture purposes. After simulating the design to confirm its improved functionality, a model cell line was used to determine the capture yield and capture rate of the device. Specific capture was achieved by coating the array of microposts with antibodies that target the epithelial cell adhesion molecule, a common biomarker for many types of metastatic cancer.
    IEEE Sensors Journal 01/2014; 14(1):5-6. · 1.48 Impact Factor
  • Madhuvanthi Vijayan, Bumsuk Hahm
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    ABSTRACT: Viruses attempt to create a distinctive cellular environment to favor viral replication and spread. Recent studies uncovered new functions of the sphingolipid signaling/metabolism during pathogenic virus infections. While sphingolipids such as sphingomyelin and ceramide were reported to influence the entry step of several viruses, sphingolipid-metabolizing enzymes could directly alter viral replication processes. Influenza virus was shown to increase the level of sphingosine kinase (SK) 1 to promote virus propagation. The mechanism involves regulation of intracellular signaling pathways, leading to the amplification of influenza viral RNA synthesis and nuclear export of viral ribonucleoprotein (RNP) complex. However, bovine viral diarrhea virus inhibits SK1 to enhance the efficacy of virus replication, demonstrating the presence of virus-specific strategies for modulation of the sphingolipid system. Therefore, investigating the sphingolipid metabolism and signaling in the context of virus replication could help us design innovative therapeutic approaches to improve human health.
    Scientifica. 01/2014; 2014:793815.
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    ABSTRACT: Influenza continues to pose a threat to humans by causing significant morbidity and mortality. Thus, it is imperative to investigate mechanisms by which influenza virus manipulates the function of host factors and cellular signal pathways. In this study, we demonstrate that influenza virus increases the expression and activation of sphingosine kinase (SK) 1, which in turn regulates diverse cellular signaling pathways. Inhibition of SK suppressed virus-induced NF-κB activation and markedly reduced the synthesis of viral RNAs and proteins. Further, SK blockade interfered with activation of Ran-binding protein 3 (RanBP3), a cofactor of chromosome region maintenance 1 (CRM1), to inhibit CRM1-mediated nuclear export of the influenza viral ribonucleoprotein complex. In support of this observation, SK inhibition altered the phosphorylation of ERK, p90RSK, and AKT, which is the upstream signal of RanBP3/CRM1 activation. Collectively, these results indicate that SK is a key pro-viral factor regulating multiple cellular signal pathways triggered by influenza virus infection.
    PLoS ONE 01/2013; 8(8):e75005. · 3.73 Impact Factor
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    ABSTRACT: Sphingosine analogues display immunosuppressive activities and thus have therapeutic potential in the treatment of autoimmune diseases. In this study, we investigated the effects of the sphingosine analogue AAL-R (FTY720 derivative) on dendritic cell (DC) response upon TLR stimulation. Unlike its known immunosuppressive activity, AAL-R increased TLR7-mediated DC responses by elevating the levels of MHC class I and costimulatory molecules and type I IFN expression and by enhancing the capacity of DCs to induce CD8(+) T cell proliferation. Importantly, the stimulatory activity of AAL-R was dependent on type I IFN signaling, as type I IFN receptor-deficient DCs failed to respond to AAL-R. Also, AAL-R activated p38 MAPK to increase type I IFN synthesis and TLR7-mediated DC maturation. These findings enhance our understanding of sphingosine regulation of the host immune system, in particular upon pathogenic infections.
    The Journal of Immunology 04/2012; 188(10):4759-68. · 5.52 Impact Factor
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    ABSTRACT: Immune responses lead to expression of immunoregulatory molecules on T cells, including natural killer (NK) receptors, such as CD94/NKG2A on CD8(+) T cells; these receptors restrain CD8(+) responses, thereby preventing T-cell exhaustion in chronic infections and limiting immunopathology. Here, we examined the requirements for inducing CD94/NKG2A on T cells responding to antigen. In vitro, moderate induction of CD94/NKG2A expression occurred after exposure of naive CD8(+) (but not CD4(+)) cells to CD3 ligation or specific peptide. Surprisingly, expression was inhibited by CD28/B7 costimulation. Such inhibition applied only to CD94/NKG2A and not other NK receptors (NKG2D) and was mediated by IL-2. Inhibition by IL-2 occurred via a NFAT cell-independent component of the calcineurin pathway, and CD94/NKG2A induction was markedly enhanced in the presence of calcineurin blockers, such as FK506 or using calcineurin-deficient T cells, both in vitro and in vivo. In addition to CD28-dependent inhibition by IL-2, CD94/NKG2A expression was impaired by several other cytokines (IL-4, IL-23, and transforming growth factor-β) but enhanced by others (IL-6, IL-10, and IL-21). The complex interplay between these various stimuli may account for the variable expression of CD94/NKG2A during responses to different pathogens in vivo.
    Blood 05/2011; 118(1):116-28. · 9.06 Impact Factor
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    ABSTRACT: Measles virus (MV), a member of the family Paramyxoviridae and an exclusively human pathogen, is among the most infectious viruses. A progressive fatal neurodegenerative complication, subacute sclerosing panencephalitis (SSPE), occurs during persistent MV infection of the CNS and is associated with biased hypermutations of the viral genome. The observed hypermutations of A-to-G are consistent with conversions catalyzed by the adenosine deaminase acting on RNA (ADAR1). To evaluate the role of ADAR1 in MV infection, we selectively disrupted expression of the IFN-inducible p150 ADAR1 isoform and found it caused embryonic lethality at embryo day (E) 11-E12. We therefore generated p150-deficient and WT mouse embryo fibroblast (MEF) cells stably expressing the MV receptor signaling lymphocyte activation molecule (SLAM or CD150). The p150(-/-) but not WT MEF cells displayed extensive syncytium formation and cytopathic effect (CPE) following infection with MV, consistent with an anti-MV role of the p150 isoform of ADAR1. MV titers were 3 to 4 log higher in p150(-/-) cells compared with WT cells at 21 h postinfection, and restoration of ADAR1 in p150(-/-) cells prevented MV cytopathology. In contrast to infection with MV, p150 disruption had no effect on vesicular stomatitis virus, reovirus, or lymphocytic choriomeningitis virus replication but protected against CPE resulting from infection with Newcastle disease virus, Sendai virus, canine distemper virus, and influenza A virus. Thus, ADAR1 is a restriction factor in the replication of paramyxoviruses and orthomyxoviruses.
    Proceedings of the National Academy of Sciences 01/2011; 108(1):331-6. · 9.74 Impact Factor
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    ABSTRACT: Sphingosine 1-phosphate (S1P)-metabolizing enzymes regulate the level of bioactive sphingolipids that have curative potential. Recently, S1P-metabolizing enzymes such as sphingosine kinase 1 and S1P lyase were shown to regulate influenza virus replication and the virus-induced cytopathogenicity. The mechanism appeared to employ a JAK/STAT type I interferon signaling pathway that induces anti-viral status. Further, sphingosine analogs altered cytokine responses upon influenza virus infection. This article focuses on recent discoveries about the sphingolipid system that influences on host protection from viral virulence and the involvement of cytokine signaling in its underlying mechanisms. Deciphering the steps of this pathway could help us envision how the modulation of sphingolipid metabolism can be applied as a therapeutic approach to overcome infectious diseases.
    Cytokine & growth factor reviews 01/2011; 22(1):55-61. · 6.49 Impact Factor
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    ABSTRACT: Sphingosine 1-phosphate (S1P)-metabolizing enzymes regulate the level of sphingolipids and have important biological functions. However, the effects of S1P-metabolizing enzymes on host defense against invading viruses remain unknown. In this study, we investigated the role of S1P-metabolizing enzymes in modulating cellular responses to influenza virus infection. Overexpression of S1P lyase (SPL), which induces the degradation of S1P, interfered with the amplification of infectious influenza virus. Accordingly, SPL-overexpressing cells were much more resistant than control cells to the cytopathic effects caused by influenza virus infection. SPL-mediated inhibition of virus-induced cell death was supported by impairment of the upregulation of the proapoptotic protein Bax, a critical factor for influenza virus cytopathogenicity. Importantly, influenza virus infection of SPL-overexpressing cells induced rapid activation of extracellular signal-regulated kinase (ERK) and STAT1 but not of p38 mitogen-activated protein kinase (MAPK), Akt, or c-Jun N-terminal kinase (JNK). Blockade of STAT1 expression or inhibition of Janus kinase (JAK) activity elevated the level of influenza virus replication in the cells, indicating that SPL protects cells from influenza virus via the activation of JAK/STAT signaling. In contrast to that of SPL, the overexpression of S1P-producing sphingosine kinase 1 heightened the cells' susceptibility to influenza virus infection, an effect that was reversed by the inhibition of its kinase activity, representing opposed enzymatic activity. These findings indicate that the modulation of S1P-metabolizing enzymes is crucial for controlling the host defense against infection with influenza virus. Thus, S1P-metabolizing enzymes are novel potential targets for the treatment of diseases caused by influenza virus infection.
    Journal of Virology 08/2010; 84(16):8124-31. · 5.08 Impact Factor
  • Young-Jin Seo, Bumsuk Hahm
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    ABSTRACT: Type I interferon (IFN), as its name implies, 'interferes' with virus replication by activating numerous genes. Further, virus-induced type I IFN regulates the magnitude and functions of cells directing the host immune system. Importantly, recent exploration into how type I IFN operates following virus infection has advanced our understanding of its role with respect to modulation of host innate and adaptive immune responses. Such activities include the activation of antigen-presenting dendritic cells and the localization, expansion or differentiation of virus-specific T lymphocytes and antibody-producing B lymphocytes. However, type I IFN not only benefits the host but can also induce unnecessary or extremely pathogenic immune responses. This review focuses on such interactions and the manner in which type I IFN induces dynamic changes in the host immune network, particularly adaptive immune responses to viral invasion. Manipulating the type I IFN-mediated host immune response during virus infections could provide new immunotherapeutic interventions to remedy viral diseases and implement more effective and sustainable type I IFN therapy.
    Advances in applied microbiology 01/2010; 73:83-101. · 4.97 Impact Factor
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    ABSTRACT: Pulmonary tissue damage resulting from influenza virus infection is caused by both the cytolytic activity of the virus and the host immune response. Immune-mediated injury results from T cell-mediated destruction of virus-infected cells and by release of cytokines and chemokines that attract polymorphonuclear leukocytes (PML) and macrophages to the infected site. The cytokines/chemokines potentiate dendritic cell (DC) activation and T cell expansion, which further enhances local damage. Here we report that immune modulation by local administration to the respiratory tract of sphingosine analog AAL-R significantly dampens the release of cytokines and chemokines while maintaining protective neutralizing antibody and cytotoxic T cell responses. As a result there was a marked reduction of infiltrating PML and macrophages into the lung and resultant pulmonary tissue injury. DC maturation was suppressed, which limited proliferation of specific antiviral T cells in the lung and draining lymph nodes. Further, AAL-R was effective in controlling CD8(+) T cell accumulation in the lungs even when given 4 days after initiation of influenza virus infection. These data indicate that sphingosine analogs display useful potential for controlling the immunopathology caused by influenza virus.
    Proceedings of the National Academy of Sciences 02/2009; 106(5):1560-5. · 9.74 Impact Factor
  • B Hahm
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    ABSTRACT: Following measles virus (MV) infection, host innate immune responses promptly operate to purge the virus. Detection of alerting measles viral components or replication intermediates by pattern-recognizing host machinery of Toll-like receptors and RNA helicases triggers signaling to synthesize array of anti-viral and immunoregulatory molecules, including type I interferon (IFN). Diverse subtypes of dendritic cells (DCs) play pivotal roles in both host innate immunity on the primary MV-infected site and initiating adaptive immune responses on secondary lymphoid tissues. Responding to the predictable host immune responses, MV appears to have devised multiple strategies to evade, suppress, or even utilize host innate immunity and DC responses. This review focuses on versatile actions of MV-induced type I IFNs causing beneficial or deleterious influence on host immunity and the interplay between MV and heterogeneous DCs at distinct locations.
    Current topics in microbiology and immunology 02/2009; 330:271-87. · 4.86 Impact Factor
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    ABSTRACT: The mechanism by which locally delivered sphingosine analogs regulate host response to localized viral infection has never been addressed. In this report, we show that intratracheal delivery of the chiral sphingosine analog (R)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol (AAL-R) or its phosphate ester inhibits the T-cell response to influenza virus infection. In contrast, neither intraperitoneal delivery of AAL-R nor intratracheal instillation of the non-phosphorylatable stereoisomer AAL-S suppressed virus-specific T-cell response, indicating that in vivo phosphorylation of AAL-R and sphingosine 1-phosphate (S1P) receptor modulation in lungs is essential for immunomodulation. Intratracheal delivery of water-soluble S1P(1) receptor agonist at doses sufficient to induce systemic lymphopenia did not inhibit virus-specific T-cell response, indicating that S1P(1) is not involved in the immunosuppressive activities of AAL-R and that immunosuppression acts independently of naive lymphocyte recirculation. Accumulation of dendritic cells (DCs) in draining lymph nodes was inhibited by intratracheal but not intraperitoneal delivery of AAL-R. Direct modulation of DCs is demonstrated by the impaired ability of virus-infected bone marrow-derived DCs treated in vitro with AAL-R to trigger in vivo T-cell response after adoptive transfer to the airways. Thus, our results suggest that locally delivered sphingosine analogs induce immunosuppression by modulating S1P receptors other than S1P(1) or S1P(2) on dendritic cells in the lungs after influenza virus infection.
    Molecular pharmacology 07/2008; 74(3):896-903. · 4.53 Impact Factor
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    ABSTRACT: In conditions of T lymphopenia, interleukin (IL) 7 levels rise and, via T cell receptor for antigen-self-major histocompatibility complex (MHC) interaction, induce residual naive T cells to proliferate. This pattern of lymphopenia-induced "homeostatic" proliferation is typically quite slow and causes a gradual increase in total T cell numbers and differentiation into cells with features of memory cells. In contrast, we describe a novel form of homeostatic proliferation that occurs when naive T cells encounter raised levels of IL-2 and IL-15 in vivo. In this situation, CD8(+) T cells undergo massive expansion and rapid differentiation into effector cells, thus closely resembling the T cell response to foreign antigens. However, the responses induced by IL-2/IL-15 are not seen in MHC-deficient hosts, implying that the responses are driven by self-ligands. Hence, homeostatic proliferation of naive T cells can be either slow or fast, with the quality of the response to self being dictated by the particular cytokine (IL-7 vs. IL-2/IL-15) concerned. The relevance of the data to the gradual transition of naive T cells into memory-phenotype (MP) cells with age is discussed.
    Journal of Experimental Medicine 09/2007; 204(8):1787-801. · 13.21 Impact Factor
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    ABSTRACT: 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.
    Virology 03/2007; 358(2):251-7. · 3.37 Impact Factor
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    ABSTRACT: Type I interferons (IFN-I) orchestrate numerous biological and cellular processes and are essential elements during host antiviral defense. After recognition of highly conserved virus signatures, a complex network of signaling events is rapidly initiated and leads to IFN-I synthesis. These cytokines directly induce a strong antiviral state and exert several immune-regulatory actions aimed at preventing virus spread. On the other hand, viruses evolved to evade or subvert the IFN-I system for their own benefit. In the present article, we review selective aspects of IFN-I induction and functions during several viral infections and discuss the beneficial and detrimental roles of IFN-I illustrated during lymphocytic choriomeningitis virus (LCMV) infection in its natural host, the mouse.
    Current topics in microbiology and immunology 02/2007; 316:337-57. · 4.86 Impact Factor
  • The Journal of Infectious Diseases 10/2006; 194 Suppl 1:S3-10. · 5.85 Impact Factor
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    ABSTRACT: 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.
    Immunity 03/2005; 22(2):247-57. · 19.80 Impact Factor
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    ABSTRACT: Measles virus (MV) infects dendritic cells (DCs) resulting in immunosuppression. Human DCs express two MV receptors: CD46 and human signaling lymphocyte activation molecule (hSLAM); thus, the role played by either alone is unclear. Because wild-type (wt) MV uses hSLAM receptor preferentially, we dissected the molecular basis of MV-DC interaction and resultant immunosuppression through the hSLAM receptor by creating transgenic (tg) mice expressing hSLAM on DCs. After infection with wt MV, murine splenic DCs expressing hSLAM receptor had less B7-1, B7-2, CD40, MHC class I, and MHC class II molecules on their surfaces and displayed an increased rate of apoptosis when compared to uninfected DCs. Further, MV-infected DCs failed to stimulate allogeneic T cells and inhibited mitogen-dependent T-cell proliferation. Individual expression of human SLAM, interferon alpha/beta receptor, tumor necrosis factor-alpha, and lymphotoxin-alpha or beta from T cells was not required for MV-infected DCs to inhibit the proliferation of T cells.
    Virology 07/2004; 323(2):292-302. · 3.37 Impact Factor

Publication Stats

438 Citations
13 Downloads
905 Views
125.85 Total Impact Points

Institutions

  • 2009–2014
    • University of Missouri
      • Department of Surgery
      Columbia, Missouri, United States
  • 2003–2009
    • The Scripps Research Institute
      • • Department of Immunology and Microbial Science
      • • Department of Molecular and Cellular Neuroscience
      • • Department of Infectious Diseases
      La Jolla, CA, United States