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Astrocytes have important roles in the central nervous system (CNS) during health and disease. Through genome-wide analyses we detected a transcriptional response to type I interferons (IFN-Is) in astrocytes during experimental CNS autoimmunity and also in CNS lesions from patients with multiple sclerosis (MS). IFN-I signaling in astrocytes reduces inflammation and experimental autoimmune encephalomyelitis (EAE) disease scores via the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) and the suppressor of cytokine signaling 2 (SOCS2). The anti-inflammatory effects of nasally administered interferon (IFN)-[beta] are partly mediated by AHR. Dietary tryptophan is metabolized by the gut microbiota into AHR agonists that have an effect on astrocytes to limit CNS inflammation. EAE scores were increased following ampicillin treatment during the recovery phase, and CNS inflammation was reduced in antibiotic-treated mice by supplementation with the tryptophan metabolites indole, indoxyl-3-sulfate, indole-3-propionic acid and indole-3-aldehyde, or the bacterial enzyme tryptophanase. In individuals with MS, the circulating levels of AHR agonists were decreased. These findings suggest that IFN-Is produced in the CNS function in combination with metabolites derived from dietary tryptophan by the gut flora to activate AHR signaling in astrocytes and suppress CNS inflammation., Author(s): Veit Rothhammer [1]; Ivan D Mascanfroni [1]; Lukas Bunse [1]; Maisa C Takenaka [1]; Jessica E Kenison [1]; Lior Mayo [1]; Chun-Cheih Chao [1]; Bonny Patel [1]; Raymond Yan [...]

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance.sup.1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies.sup.5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-[gamma] exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy. Retroelements located in antisense orientation within interferon-regulated genes are reactivated in a subset of cancer cells and initiate a STING- and MAVS-dependent feed-forward inflammatory loop, driving antitumor immunity and exhaustion., Author(s): Israel Cañadas [sup.1] , Rohit Thummalapalli [sup.1] , Jong Wook Kim [sup.1] [sup.2] , Shunsuke Kitajima [sup.1] , Russell William Jenkins [sup.1] [sup.3] , Camilla Laulund Christensen [sup.1] , [...]

Pneumococcal infection of the respiratory tract is often secondary to recent influenza virus infection and accounts for much of the morbidity and mortality during seasonal and pandemic influenza. Here, we show that coinfection of the upper respiratory tract of mice with influenza virus and pneumococcus leads to synergistic stimulation of type I IFNs and that this impairs the recruitment of macrophages, which are required for pneumococcal clearance, due to decreased production of the chemokine CCL2. Type I IFN expression was induced by pneumococcal colonization alone. Colonization followed by influenza coinfection led to a synergistic type I IFN response, resulting in increased density of colonizing bacteria and susceptibility to invasive infection. This enhanced type I IFN response inhibited production of the chemokine CCL2, which promotes the recruitment of macrophages and bacterial clearance. Stimulation of CCL2 by macrophages upon pneumococcal infection alone required the pattern recognition receptor Nod2 and expression of the pore-forming toxin pneumolysin. Indeed, the increased colonization associated with concurrent influenza virus infection was not observed in mice lacking Nod2 or the type I IFN receptor, or in mice challenged with pneumococci lacking pneumolysin. We therefore propose that the synergistic stimulation of type I IFN production during concurrent influenza virus and pneumococcal infection leads to increased bacterial colonization and suggest that this may contribute to the higher rates of disease associated with coinfection in humans., Introduction Streptococcus pneumoniae (the pneumococcus) transiently colonizes the mucosal surfaces of the human upper respiratory tract (URT) (1). Colonizing organisms in the nasopharynx provide the reservoir for transmission of the [...]

Balanced induction of proinflammatory and type I IFN responses upon activation of Toll-like receptors (TLRs) determines the outcome of microbial infections and the pathogenesis of autoimmune and other inflammatory diseases. Mast cells, key components of the innate immune system, are known for their debilitating role in allergy and autoimmunity. However, their role in antimicrobial host defenses is being acknowledged increasingly. How mast cells interact with microbes and the nature of responses triggered thereby is not well characterized. Here we show that in response to TLR activation by Gram-positive and -negative bacteria or their components, mast cells elicit proinflammatory but not type I IFN responses. We demonstrate that in mast cells, bound bacteria and TLR ligands remain trapped at the cell surface and do not undergo internalization, a prerequisite for type I IFN induction. Such cells, however, can elicit type I IFNs in response to vesicular stomatitis virus which accesses the cytosolic retinoic acid-inducible gene I receptor. Although important for antiviral immunity, a strong I IFN response is known to contribute to pathogenesis of several bacterial pathogens such as Listeria monocytogenes. Interestingly, we observed that the mast cell-dependent neutrophil mobilization upon L. monocytogenes infection is highly impaired by IFN-[beta]. Thus, the fact that mast cells, although endowed with the capacity to elicit type I IFNs in response to viral infection, elicit only proinflammatory responses upon bacterial infection shows that mast cells, key effector cells of the innate immune system, are well adjusted for optimal antibacterial and antiviral responses. endolysosome | innate immunity | Listeria | Salmonella | vesicular stomatitis virus doi/10.1073/pnas.0912551107

A study distinguishes a relatively high expression of interferon-[alpha] (IFN[alpha]) and RANTES in HIV-1-infected versus low-risk control subjects. Induction of IFN[alpha] and RANTES expression in cervical mucosa could lead to protection of sexual HIV-1 transmission in subjects with a higher risk behavior.

Neutrophil recruitment to the lung after lipopolysaccharide (LPS; endotoxin) inhalation is primarily dependent on Toll-like receptor 4 (Tlr4) signaling, because it is virtually absent in mice deficient in Tlr4. However, among strains wild type for Tlr4, the magnitude of neutrophil recruitment to the lung after LPS inhalation is variable, suggesting the involvement of genes other than Tlr4. To identify genes associated with the inflammatory response to inhaled LPS, we evaluated the transcriptional response in lungs of 12 inbred strains of mice, 8 which are wild type for Tlr4 and 4 of which lack functional Tlr4. Using the promoter integration in microarray analysis algorithm, we scanned our gene list for transcription factor-binding sites significantly overrepresented among Tlr4 wild-type strains with high neutrophil influx in the lung after LPS inhalation. This analysis identified the interferon (IFN)-stimulated response element (ISRE) as the most overrepresented transcription factor (present in 24% of the promoters) associated with the neutrophil influx to the lower respiratory tract. To test the validity of this observation, we evaluated IFN-[alpha]-deficient mice and found that the presence of IFN-[gamma] is essential for robust neutrophil recruitment to the lower respiratory tract and modulation of key regulatory cytokines and chemokines after LPS inhalation. In conclusion, using a genomic approach, we identified the ISRE as a transcriptional element associated with the neutrophil response to inhaled LPS and demonstrated for the first time that IFN-[gamma] plays a critical role in LPS-induced neutrophil recruitment to the lower airways. endotoxin; environmental airway disease; murine; microarray; transcription factor

HIV/hepatitis C virus (HCV)-coinfected individuals have accelerated liver disease, increased drug toxicities, and modest responses to peginterferon and ribavirin. Hematologic toxicities necessitating dose reduction or discontinuation are limiting factors to HCV treatment in the coinfected patient. This study aimed to identify predictors for the need of filgrastim and darbepoetin to manage hematologic toxicities so as to maintain patients on full doses of study drugs for the duration of study. The primary study was a single-center, open-label, prospective study to evaluate the safety, efficacy, and viral kinetics of 48-week peginterferon alfa 2b and ribavirin in HIV/HCV-coinfected patients. Complete blood count was monitored at baseline, days 3, 7, 10, 14, and then weekly for the first month, fortnightly until week 8, then monthly from week 12 to 48. Filgrastim was initiated when absolute neutrophil count (ANC) fell below 750 cells/[mm.sup.3] and darbepoetin was used when hemoglobin dropped to less than 10 g/dL. All patients experienced decrease in ANC and hemoglobin. Twenty of 30 (66.6%) of patients required hematopoeitic growth factors, 15 (50%) received filgrastirn, and 12 (40%) received darbepoetin. Seven (23.3%) required both. Baseline ANC of less than 2250 cells per millimeter and negative rate of change of hemoglobin on day 3 of therapy were excellent predictors for filgrastim and darbepoetin use, respectively. Supplemental growth factors were associated with substantial increase in overall cost for HCV treatment. Larger clinical trials will be needed to address the cost effectiveness of supplemental growth factor use in the HIV/HCV-coinfected patients.

The prognostic significance of autoimmunity in patients with stage IIB, IIC, or III melanoma who were treated with high-dose adjuvant interferon alfa-2b is assessed. The appearance of autoantibodies or clinical manifestations of autoimmunity during the treatment with interferon alfa-2b is associated with statistically significant improvements in relapse-free survival and overall survival in patients with melanoma.

The safety and maximum tolerated dose of interferon (IFN)alpha2b in combination with protease inhibitor-based highly active antiretroviral therapy (HAART) in a phase 1 study in 14 patients with AIDS-association Kaposi sarcoma (KS) is evaluated. A safe dose of IFN that can be used with HAART and, potentially, with other inhibitors of KS in future clinical trails is established.

Byline: H. Sax (1), A. Friedl (2), E. Renner (3), M.H. Steuerwald (4), R. Weber (2) Keywords: Key Words HIV; Hepatitis C; Treatment; Interferon; Amantadine Abstract: Background: Concurrent potent therapy of hepatitis C (HCV) and HIV includes at least five antiviral drugs. Drug interactions, toxicity, tolerance and acceptance by patients of such treatment regimens are unknown. Study design: A prospective open randomized pilot trial was conducted to test interferon-[alpha] (6 million units/day for the 1st month followed by 6 million thrice weekly) and amantadine versus interferon-[alpha] monotherapy for tolerability and feasibility among HIV and HCV co-infected patients on stable antiretroviral combination therapy. Results: 1,013 HIV-infected patients were consecutively evaluated. 314 were anti-HCV antibody positive only eight (2.4%) were eligible. Major reasons for exclusion were: normal transaminase levels (34%), ongoing intravenous drug use (33%), or recent change in antiretroviral therapy (31%). Study drugs were stopped in all of the seven patients enrolled because of side effects and/or failure of anti-HCV-therapy. CD4 lymphocyte counts and HIV-1 RNA remained stable. Conclusion: Among patients on highly active antiretroviral therapy, the addition of interferon-[alpha] with or without amantadine was inefficient and poorly tolerated, but had no negative influence on HIV infection. Eligibility for the study was unexpectedly low. Author Affiliation: (1) Division of Infectious Diseases, University of Geneva Hospitals, Rue Micheli-du-Crest 24, CH-1211 Geneva, Switzerland e-mail: hugo.sax@hcuge.ch, CH (2) Division of Infectious Diseases and Hospital Epidemiology, University Hospital, Ramistr. 100, CH-8091 Zurich, Switzerland Phone: (+41/1) 2553826, Fax: -3291, e-mail: infweb@usz.unizh.ch, CH (3) Division of Gastroenterology and Hepatology, University Hospital, Ramistr. 100, CH-8091 Zurich, Switzerland, CH (4) Division of Gastroenterology, University Hospital, Petersgraben 4, CH-4056 Basel, Switzerland, CH Article note: Received: March 27, 2001 * Revision accepted: July 12, 2001

Myelin-specific T lymphocytes are considered essential in the pathogenesis of multiple sclerosis. The myelin basic protein peptide (a.a. 83-99) represents one candidate antigen; therefore, it was chosen to design an altered peptide ligand, CGP77116, for specific immunotherapy of multiple sclerosis. A magnetic resonance imaging-controlled phase II clinical trial with this altered peptide ligand documented that it was poorly tolerated at the dose tested, and the trial had therefore to be halted. Improvement or worsening of clinical or magnetic resonance imaging parameters could not be demonstrated in this small group of individuals because of the short treatment duration. Three patients developed exacerbations of multiple sclerosis, and in two this could be linked to altered peptide ligand treatment by immunological studies demonstrating the encephalitogenic potential of the myelin basic protein peptide (a.a. 83-99) in a subgroup of patients. These data raise important considerations for the use of specific immunotherapies in general., Author(s): Bibiana Bielekova [1]; Bonnie Goodwin [1]; Nancy Richert [2]; Irene Cortese [1]; Takayuki Kondo [1]; Ghazaleh Afshar [1]; Bruno Gran [1]; Joan Eaton [1]; Jack Antel [3]; Joseph A. [...]