Article

The Battle over mTOR: An Emerging Theatre in Host-Pathogen Immunity.

Department of Microbiology, Abramson Family Cancer Research Institute, Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
PLoS Pathogens (Impact Factor: 8.06). 09/2012; 8(9):e1002894. DOI: 10.1371/journal.ppat.1002894
Source: PubMed
1 Bookmark
 · 
163 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ageing and infectious disease are common health concerns global wide. Considering the emergence of MERS-CoV in the Middle East, H7N9 in Mainland China and first human case of H6N1 in Taiwan, it is imperative to look into the mechanisms underlying these problems and thereby developing effective countermeasures. Based on well established relationship between viral infections and various IFN signaling including STAT pathway and leads to modulation of T cells immunity, peruse of the role of mTOR plays upon pathogen intrusion is warranted. After the overview on the mTOR signaling, this review series now provides a recapitulation on heretofore findings of immunity and viral replication regulation upon infections provision by mTOR. Using influenza A virus as an illustration, we underscore the research opportunity on the potential linkage connecting these two physiological events with the final goal of identifying pharmaceutical targets to improve human health with minimal side effects.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study, we used a systems biology approach to investigate changes in the proteome and metabolome of shrimp hemocytes infected by the invertebrate virus WSSV (white spot syndrome virus) at the viral genome replication stage (12 hpi) and the late stage (24 hpi). At 12 hpi, but not at 24 hpi, there was significant up-regulation of the markers of several metabolic pathways associated with the vertebrate Warburg effect (or aerobic glycolysis), including glycolysis, the pentose phosphate pathway, nucleotide biosynthesis, glutaminolysis and amino acid biosynthesis. We show that the PI3K-Akt-mTOR pathway was of central importance in triggering this WSSV-induced Warburg effect. Although dsRNA silencing of the mTORC1 activator Rheb had only a relatively minor impact on WSSV replication, in vivo chemical inhibition of Akt, mTORC1 and mTORC2 suppressed the WSSV-induced Warburg effect and reduced both WSSV gene expression and viral genome replication. When the Warburg effect was suppressed by pretreatment with the mTOR inhibitor Torin 1, even the subsequent up-regulation of the TCA cycle was insufficient to satisfy the virus's requirements for energy and macromolecular precursors. The WSSV-induced Warburg effect therefore appears to be essential for successful viral replication.
    PLoS Pathogens 06/2014; 10(6):e1004196. DOI:10.1371/journal.ppat.1004196 · 8.14 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Human cytomegalovirus congenital infection represents an unmet medical issue and attempts are ongoing to develop an effective vaccine. The virion fusion players of this enveloped virus are the natural targets to achieve this goal and to develop novel anti-viral therapies. The secreted ectodomain of the viral fusion factor glycoprotein B (gB) has been exploited so far as an alternative to the cumbersome expression of the wild type trans-membrane protein. In the soluble form, gB showed encouraging but limited potential as antigen candidate calling for further efforts. Here, the exhaustive evaluation of the Baculovirus/insect cell expression system has been coupled to an orthogonal screening for expression additives to produce full-length gB. In detail, rapamycin was found to prolong gB intracellular accumulation while inhibiting the infection-induced cell swelling. Not obvious to predict, this inhibition did not affect Baculovirus growth, revealing that the virus-induced cell size increase is a dispensable side phenotype. In parallel, a feeding strategy for the limiting nutrient cysteine has been set up which improved gB stability. This multi-modal scheme allowed the production of full-length, mutation-free gB in the milligram scale. The recombinant full-length gB obtained was embedded into a stable mono-dispersed particle substantially larger than the protein trimer itself, according to the reported association of this protein with detergent-resistant lipid domains.
    PLoS ONE 03/2014; 9(3):e90753. DOI:10.1371/journal.pone.0090753 · 3.53 Impact Factor

Preview

Download
8 Downloads
Available from