Biomedical subjects

Deborah J Lenschow

Publications and source records attributed to Deborah J Lenschow.

5 recordsLinked to original sources

PubMed2007

IFN-stimulated gene 15 functions as a critical antiviral molecule against influenza, herpes, and Sindbis viruses.

Type I interferons (IFNs) play an essential role in the host response to viral infection through the induction of numerous IFN-stimulated genes (ISGs), including important antiviral molecules such as PKR, RNase L, Mx, and iNOS. Yet, additional antiviral ISGs likely exist. IFN-stimulated gene 15 (ISG15) is a ubiquitin homolog that is rapidly up-regulated after viral infection, and it conjugates to a wide array of host proteins. Although it has been hypothesized that ISG15 functions as an antiviral molecule, the initial evaluation of ISG15-deficient mice revealed no defects in their responses to vesicular stomatitis virus or lymphocytic choriomeningitis virus, leaving open the important question of whether ISG15 is an antiviral molecule in vivo. Here we demonstrate that ISG15 is critical for the host response to viral infection. ISG15-/- mice are more susceptible to influenza A/WSN/33 and influenza B/Lee/40 virus infections. ISG15-/- mice also exhibited increased susceptibility to both herpes simplex virus type 1 and murine gammaherpesvirus 68 infection and to Sindbis virus infection. The increased susceptibility of ISG15-/- mice to Sindbis virus infection was rescued by expressing wild-type ISG15, but not a mutant form of ISG15 that cannot form conjugates, from the Sindbis virus genome. The demonstration of ISG15 as a novel antiviral molecule with activity against both RNA and DNA viruses provides a target for the development of therapies against important human pathogens.

Animals↗

PubMed2005

Proteomic identification of proteins conjugated to ISG15 in mouse and human cells.

Though the interferon-inducible protein ISG15 was one of the first ubiquitin-like modifiers to be discovered, much remains unknown about the identity of proteins conjugated to ISG15 or the biologic consequences of modification. To gain a better understanding of the cellular pathways affected by ISG15, we identified proteins targeted for ISGylation using a proteomic approach. Mass spectrometric analysis identified 76 candidate ISGylation targets in anti-ISG15 immunoprecipitates from interferon-treated mouse or human cells. Twenty-one proteins were found in both mouse and human samples, including STAT1, a known target of ISGylation. Candidates identified in both species were tested for ISGylation in a transfection system: 18 of 19 proteins tested were ISGylated in this system. Two candidates, EF-2 and VCP, were also shown to be ISGylated in an interferon-dependent manner in the absence of exogenous over-expression. Seven proteins identified from a single species, but functionally related to candidates found in both species, were also ISGylated in the over-expression system. Proteins that can be ISGylated play important roles in translation, glycolysis, stress responses, and cell motility. These data indicate that ISGylation targets proteins found in several fundamentally important cellular pathways and will contribute to understanding the physiologic role of interferon-induced ISG15 and ISG15 conjugation.

Animals↗

PubMed2005

Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo.

The innate immune response, and in particular the alpha/beta interferon (IFN-alpha/beta) system, plays a critical role in the control of viral infections. Interferons alpha and beta exert their antiviral effects through the induction of hundreds of interferon-induced (or -stimulated) genes (ISGs). While several of these ISGs have characterized antiviral functions, their actions alone do not explain all of the effects mediated by IFN-alpha/beta. To identify additional IFN-induced antiviral molecules, we utilized a recombinant chimeric Sindbis virus to express selected ISGs in IFN-alpha/beta receptor (IFN-alpha/betaR)(-/-) mice and looked for attenuation of Sindbis virus infection. Using this approach, we identified a ubiquitin homolog, interferon-stimulated gene 15 (ISG15), as having antiviral activity. ISG15 expression protected against Sindbis virus-induced lethality and decreased Sindbis virus replication in multiple organs without inhibiting the spread of virus throughout the host. We establish that, much like ubiquitin, ISG15 requires its C-terminal LRLRGG motif to form intracellular conjugates. Finally, we demonstrate that ISG15's LRLRGG motif is also required for its antiviral activity. We conclude that ISG15 can be directly antiviral.

Alphavirus Infections↗

PubMed2004

Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu arteritis.

OBJECTIVE: Granulomatous inflammation is a typical feature of Takayasu arteritis (TA), and tumor necrosis factor (TNF) is important in the formation of granulomas. In this study, we assessed therapy with anti-TNF agents in patients with TA that was not controlled by glucocorticoid therapy or other immunosuppressants. METHODS: We conducted an open-label trial of anti-TNF therapy at 3 academic medical centers over a period of 4.25 years. Fifteen patients with active, relapsing TA (median 6 years) were selected. Seven received etanercept (later changed to infliximab in 3 patients), and 8 received infliximab. Relapses had occurred in all patients while they were receiving glucocorticoids and, in 13 patients, additional immunosuppressive drugs. No other agents were added to the treatment regimen concurrently with anti-TNF. If patients were receiving cytotoxic agents, the dosage was not increased. Clinical symptoms were recorded, and physical examinations, laboratory studies, and serial magnetic resonance imaging were performed. RESULTS: The median daily dose of prednisone required to maintain remission prior to anti-TNF therapy was 20 mg. Ten of the 15 patients achieved complete remission that was sustained for 1-3.3 years without glucocorticoid therapy. Four patients achieved partial remission, with a >50% reduction in the glucocorticoid requirement. At a median of 12 months of followup, the median dose of prednisone was 0. Therapy failed in 1 patient. In 9 of the 14 responders, an increase in the anti-TNF dosage was required to sustain remission. Two relapses occurred during periods when anti-TNF therapy (etanercept) was interrupted, but remission was reestablished upon reinstitution of therapy. CONCLUSION: In this pilot study of relapsing TA, addition of anti-TNF therapy resulted in improvement in 14 of 15 patients and sustained remission in 10 of 15 patients, who were able to discontinue glucocorticoid therapy. Anti-TNF may be a useful adjunct to glucocorticoids in the treatment of TA. Our results justify a randomized, controlled clinical trial of anti-TNF therapy for TA.

Adolescent↗

PubMed2002

Polymyalgia rheumatica/temporal arteritis: recent advances.

Polymyalgia rheumatica (PMR)/temporal arteritis (TA) frequently causes significant morbidity in patients older than 50 years of age. This review highlights recent trends in clinical findings, epidemiology, pathogenesis, and laboratory and radiologic assessment of the disease. Although steroids are the mainstay of therapy because of their effectiveness and ease of administration, they have numerous side effects, particularly in an aging population. Furthermore, recent evidence suggests that steroids only suppress clinical symptoms, while a smoldering level of damaging vascular inflammation persists. As a result, alternative agents are actively being investigated. We compare their successes and shortcomings and offer insight into their potential role in the treatment of this disease.

Adrenal Cortex Hormones↗