Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage.
Immunity 43(5):974 (2015)
Tissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus-induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1(-/-...
Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection.
PLoS Pathogens 11(11):e1005276 (2015)
Arenaviruses such as Lassa virus (LASV) can cause severe hemorrhagic fever in humans. As a major impediment to vaccine development, delayed and weak neutralizing antibody (nAb) responses represent a unifying characteristic of both natural infection and all vaccine candidates tested to date. To i...
A novel Cd8-cis-regulatory element preferentially directs expression in CD44hiCD62L+ CD8+ T cells and in CD8αα+ dendritic cells.
Journal of Leukocyte Biology 97(4):635 (2015)
CD8 coreceptor expression is dynamically regulated during thymocyte development and is tightly controlled by the activity of at least 5 different cis-regulatory elements. Despite the detailed characterization of the Cd8 loci, the regulation of the complex expression pattern of CD8 cannot be full...
Protective efficacy of individual CD8+ T cell specificities in chronic viral infection.
Journal of Immunology 194(4):1755 (2015)
Specific CD8(+) T cells (CTLs) play an important role in resolving protracted infection with hepatitis B and C virus in humans and lymphocytic choriomeningitis virus (LCMV) in mice. The contribution of individual CTL specificities to chronic virus control, as well as epitope-specific patterns in...
T-cell STAT3 is required for the maintenance of humoral immunity to LCMV.
European Journal of Immunology 45(2):418 (2015)
STAT3 is a critical transcription factor activated downstream of cytokine signaling and is integral for the function of multiple immune cell types. Human mutations in STAT3 cause primary immunodeficiency resulting in impaired control of a variety of infections, including reactivation of latent v...
The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection.
Nature Immunology 16(1):67 (2015)
Immune responses are tightly regulated to ensure efficient pathogen clearance while avoiding tissue damage. Here we report that Setdb2 was the only protein lysine methyltransferase induced during infection with influenza virus. Setdb2 expression depended on signaling via type I interferons, and ...
Evolution of recombinant lymphocytic choriomeningitis virus/Lassa virus in vivo highlights the importance of the GPC cytosolic tail in viral fitness.
Journal of Virology 88(15):8340 (2014)
A key characteristic of arenaviruses is their ability to establish persistent infection in their natural host. Different factors like host age, viral dose strain, and route of infection may contribute to the establishment of persistence. However, the molecular mechanisms governing persistence ar...
Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss.
Journal of Experimental Medicine 210(10):2087 (2013)
Neurons are postmitotic and thus irreplaceable cells of the central nervous system (CNS). Accordingly, CNS inflammation with resulting neuronal damage can have devastating consequences. We investigated molecular mediators and structural consequences of CD8(+) T lymphocyte (CTL) attack on neurons...
Functional limitations of plasmacytoid dendritic cells limit type I interferon, T cell responses and virus control in early life.
PLoS ONE 8(12):e85302 (2013)
Infant mortality from viral infection remains a major global health concern: viruses causing acute infections in immunologically mature hosts often follow a more severe course in early life, with prolonged or persistent viral replication. Similarly, the WE strain of lymphocytic choriomeningitis ...
A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses.
Nature 490(7420):421 (2012)
Antiviral responses must be tightly regulated to defend rapidly against infection while minimizing inflammatory damage. Type 1 interferons (IFN-I) are crucial mediators of antiviral responses and their transcription is regulated by a variety of transcription factors; principal among these is the...
Viral replicative capacity is the primary determinant of lymphocytic choriomeningitis virus persistence and immunosuppression.
PNAS 107(50):21641 (2010)
The Clone 13 (Cl13) strain of lymphocytic choriomeningitis virus is widely studied as a model of chronic systemic viral infection. Here, we used reverse genetic techniques to identify the molecular basis of Cl13 persistence and immunosuppression, the characteristics differentiating it from the c...
Innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes.
International Immunology 22(9):749 (2010)
Arenaviruses such as Lassa virus (LASV) cause significant morbidity and mortality in endemic areas. Using a glycoprotein (GP) exchange strategy, we have recently developed live-attenuated arenavirus vaccine prototypes (rLCMV/VSVG) based on lymphocytic choriomeningitis virus (LCMV), a close relat...
T cells can mediate viral clearance from ependyma but not from brain parenchyma in a major histocompatibility class I- and perforin-independent manner.
Brain 133(Pt 4):1054 (2010)
Viral infection of the central nervous system can lead to disability and death. Yet the majority of viral infections with central nervous system involvement resolve with only mild clinical manifestations, if any. This is generally attributed to efficient elimination of the infection from the bra...
Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity.
Nature Medicine 16(3):339 (2010)
Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8(+) T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using...
T cell-dependence of Lassa fever pathogenesis.
PLoS Pathogens 6(3):e1000836 (2010)
Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resis...
Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions.
Immunity 32(1):116 (2010)
Current T cell differentiation models invoke separate T helper 2 (Th2) and Th1 cell lineages governed by the lineage-specifying transcription factors GATA-3 and T-bet. However, knowledge on the plasticity of Th2 cell lineage commitment is limited. Here we show that infection with Th1 cell-promot...
Impaired antibody response causes persistence of prototypic T cell-contained virus.
PLoS Biology 7(4):e1000080 (2009)
CD8 T cells are recognized key players in control of persistent virus infections, but increasing evidence suggests that assistance from other immune mediators is also needed. Here, we investigated whether specific antibody responses contribute to control of lymphocytic choriomeningitis virus (LC...
Hematopoietic cell-derived interferon controls viral replication and virus-induced disease.
Blood 113(5):1045 (2009)
Type I interferon (IFN-I) strongly inhibits viral replication and is a crucial factor in controlling virus infections and diseases. Cellular activation through pattern recognition receptors induces interferon production in a wide variety of hematopoietic and nonhematopoietic cell types, includin...
Extralymphatic virus sanctuaries as a consequence of potent T-cell activation.
Nature Medicine 13(11):1316 (2007)
T helper cells can support the functions of CD8(+) T cells against persistently infecting viruses such as murine lymphocytic choriomeningitis virus (LCMV), cytomegalovirus, hepatitis C virus and HIV. These viruses often resist complete elimination and remain detectable at sanctuary sites, such a...
MyD88 protects from lethal encephalitis during infection with vesicular stomatitis virus.
European Journal of Immunology 37(9):2434 (2007)
MyD88 is a key adaptor molecule in innate resistance, engaged in most Toll-like receptor, as well as IL-1 and IL-18, signalling. Here, we analyzed the role of MyD88 in innate resistance during infection with vesicular stomatitis virus (VSV) using myd88(-/-) mice. We found an increased susceptibi...