Neurons Fight Back
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RESEARCH HIGHLIGHTS URLsHIGHLIGHT ADVISORS ADRIANO AGUZZI VIRAL INFECTION UNIVERSITY HOSPITAL OF ZÜRICH, ZÜRICH, SWITZERLAND NORMA ANDREWS Neurons fight back YALE UNIVERSITY SCHOOL OF MEDICINE, NEW HAVEN, CT, USA Viral infection induces an innate ARTURO CASADEVALL immune response in neurons, a THE ALBERT EINSTEIN COLLEGE OF MEDICINE, BRONX, NY, USA group led by Monique Lafon at the Pasteur Institute in Paris, France, has RITA COLWELL UNIVERSITY OF MARYLAND found. It was previously thought that BIOTECHNOLOGY INSTITUTE, the nervous system relied solely on BALTIMORE, MD, USA glial cells to detect infection. STANLEY FALKOW Lafon and colleagues used in vitro STANFORD UNIVERSITY SCHOOL cultures of a human post mitotic OF MEDICINE, STANFORD, neuron-derived cell line, NT2-N, CA, USA which displays characteristics of TIMOTHY FOSTER fully mature human neurons upon TRINITY COLLEGE, DUBLIN, transplantation into the brain, and IRELAND infected them with rabies virus KEITH GULL (RABV) or herpes simplex type 1 UNIVERSITY OF OXFORD, virus (HSV-1). OXFORD, UK Searching for neuronal genes of NEIL GOW which transcription is upregulated UNIVERSITY OF ABERDEEN, during infection through microarray ABERDEEN, UK analysis (using cut-off of a twofold HANS-DIETER KLENK increase to identify upregulated PHILIPPS UNIVERSITY, MARBURG, GERMANY genes), they found that RABV infec- tion increased the transcription of other hand, did not upregulate IFN-β of Gram-negative bacteria, had BERNARD MOSS 228 genes, and HSV-1 infection gene transcripts. Microarray results limited effect. In addition, human NIAID, NATIONAL INSTITUTES OF HEALTH, BETHESDA, MD, increased the transcription of 263 were confirmed by real-time PCR, postmitotic neurons were responsive USA genes. RABV upregulated 56 genes of immuno cytochemistry and ELISA. to a treatment with IFN-β, suggest- JOHN REX the immunity cluster of genes (24% Microarray analysis also revealed ing that they also express receptors α/β α/β). ASTRAZENECA, CHESHIRE, UK of all genes upregulated by RABV), that NT2-N cells express genes that to IFN- (IFN-R whereas HSV-1 upregulated only 13 code for molecules which can sense These results establish that human DAVID ROOS UNIVERSITY OF PENNSYLVANIA, genes in this cluster (4.9% of all genes double-stranded RNA (dsRNA, neurons are capable of sensing and PHILADELPHIA, PA, USA upregulated by HSV-1). Of all the a molecular signature of RNA responding to viral infection, and PHILIPPE SANSONETTI genes upregulated by RABV, the 25 viruses), including Toll-like recep- that dsRNA could be the main viral INSTITUT PASTEUR, genes for which expression was most tor 3 (TLR3). This was confirmed element that is sensed by human neu- PARIS, FRANCE strongly stimulated were all involved by immunocytochemistry using rons as a trigger of an innate immune CHIHIRO SASAKAWA in the innate immune response, antibody directed against the human response. UNIVERSITY OF TOKYO, including the interferon-β (IFN-β) TLR3. Treatment of NT2-N cells Annie Tremp TOKYO, JAPAN β gene, IFN- primary and secondary with dsRNA led to the upregulation References and links ROBIN WEISS response genes, as well as genes for of some genes that are involved in ORIGINAL RESEARCH PAPER Préhaud, C., UNIVERSITY COLLEGE LONDON, chemokines, inflammatory cytokines innate immunity. Similar treatment Mégret, F., Lafage, M. & Lafon, M. Virus infection LONDON, UK switches TLR-3-positive human neurons to and molecules with antiviral activi- with lipopolysaccharide, found on the become strong producers of beta interferon. ties. Infection with HSV-1, on the outer leaflet of the outer membrane J. Virol. 79, 12893–12904 (2005) NATURE REVIEWS | MICROBIOLOGY VOLUME 3 | DECEMBER 2005 | 907 RESEARCH HIGHLIGHTS BACTERIAL SECRETION that their vast quantities of secreted providing evidence to support their proteins are folded correctly have suggestion that it provides a special- been largely unknown until recently. ized environment in which newly In the streptococci, it was known formed proteins can interact with Specialized ExPort that, although only the general chaperones and accessory proteins. secretory (Sec) pathway is present, Their recent experimental work has Gram-positive microorganisms face secretion is a complex process that focused on HtrA (DegP), an extra- a unique challenge when it comes involves chaperones and accessory cellular serine protease also known to protein folding and secretion. factors. In addition, the existence of to function as a chaperone for several Although all microorganisms lack the a putative secretion microdomain S. pyogenes secreted proteins, includ- endoplasmic reticulum (ER) found in Streptococcus pyogenes was first ing SpeB. Using immunoelectron in eukaryotes, Gram-negatives have revealed by Jason Rosch and Michael microscopy, it was found that the dis- a periplasmic space where nascent Caparon in Science last year. Then, tribution of HtrA on the streptococcal polypeptides can be folded before immunogold electron microscopy surface was similar to the distribution secretion. This space is lacking in showed that SpeB — a cysteine pro- of the ExPortal — clustered at a single Gram-positives, and the mecha- tease, and one of the most abundant discrete location distal from both cell nisms these organisms use to ensure S. pyogenes secreted proteins — was poles. Further work showed that HtrA localized to a discrete location at the co-localizes with SpeB, providing cell hemisphere. Given that they also evidence that the ExPortal provides detected a high concentration of Sec an environment in which chaperones translocons in this area, Rosch and and substrates can interact. Caparon proposed that this location Previous work had shown that was a specialized microdomain for both the proteolytic and chaperone protein export, which they termed functions of HtrA can be involved the ExPortal. in protein folding and maturation. Now, in a paper available online Here, Rosch and Caparon found that in Molecular Microbiology, Rosch and the serine-protease activity of HtrA Immunogold electron micrographs showing the co-localization of HtrA tagged at the C terminus (18-nm beads) and SecA (12-nm beads). Reproduced with permission from Caparon have undertaken a more was crucial for SpeB maturation, Molecular Microbiology © (2005) Blackwell Publishing. detailed analysis of the ExPortal, although they did not show directly ANTIFUNGALS HSP90 might actually potentiate the strongly reduced fluconazole resistance in all appearance of new phenotypes. Hsp90-dependent resistant strains. Leah Cowen and Susan Lindquist These findings reveal an attractive A helping hand examined the role of Hsp90 in the evolution therapeutic strategy against fungal infection, of resistance to antifungal drugs. Using rapid as similar results were seen with several Hsp90 is well known for its role as a selection of three strains of Saccharomyces fungal pathogens. It is particularly significant molecular chaperone — a protein that assists cerevisiae with varying levels of Hsp90, that Hsp90 was crucial for the evolution of the folding of other proteins (‘clients’). Now, they demonstrated that the development antifungal resistance in clinical isolates of research published in Science reveals that of resistance depended on high-level Candida albicans collected from an Hsp90 might also influence the evolution expression of Hsp90. Moreover, Hsp90 was HIV-infected individual. With continued of new traits by potentiating the phenotypic required to maintain resistance rather than exposure to fluconazole, the clinical isolates effect of genetic variation. Studies of the just to cope with the initial selection stress. evolved towards Hsp90-independent evolution of drug resistance in several The Hsp90-dependent effect was specific resistance, prompting speculation that Hsp90 strains of pathogenic fungi demonstrate an to mutants generated by rapid selection, initially allows the phenotype to be expressed essential role for Hsp90 and its client protein which favours mutations that prevent the but that environmental stress drives the cell calcineurin, and implicate Hsp90 as a novel accumulation of toxic metabolites, rather towards stabilizing the resistant phenotype. antifungal target. than gradual selection which involves Inhibiting Hsp90 early in infection could As a chaperone for many signal upregulation of a multidrug transporter. therefore render resistant fungal pathogens transducers, Hsp90 is able to ‘buffer’ the However, in 11 previously identified sensitive to conventional treatment or could effects of genetic variation by enabling the S. cerevisiae drug-resistant deletion strains, all prevent the initial development of antifungal- cell to tolerate mutations. Although Hsp90 were found to be Hsp90-dependent, showing drug resistance. Moreover, Hsp90 inhibitors is highly inducible following environmental that Hsp90 can influence the resistance are already being evaluated in clinical trials stress, the demands of stress-induced protein caused by a variety of different genetic lesions. for cancer, and seem to be well tolerated at misfolding can outpace its induction, But how does Hsp90 achieve this? One levels that achieve significant inhibition. enabling previously silent mutations to possibility is that a common regulator exists Joanna Owens, Associate Editor, act combinatorially and generate new to mediate Hsp90-dependent effects on Nature Reviews Drug Discovery phenotypes. It now seems that Hsp90 has yet different mutations. An obvious candidate another role in the emergence