title: Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics.
abstract: Injection of the LP-BM5 murine leukemia virus into mice causes murine AIDS, a disease characterized by many dysfunctions of immunocompetent cells. To establish whether the disease is characterized by glutathione imbalance, reduced glutathione (GSH) and cysteine were quantified in different organs. A marked redox imbalance, consisting of GSH and/or cysteine depletion, was found in the lymphoid organs, such as the spleen and lymph nodes. Moreover, a significant decrease in cysteine and GSH levels in the pancreas and brain, respectively, was measured at 5 weeks postinfection. The Th2 immune response was predominant at all times investigated, as revealed by the expression of Th1/Th2 cytokines. Furthermore, investigation of the activation status of peritoneal macrophages showed that the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arginase1, was induced. Conversely, expression of inducible nitric oxide synthase, a marker of classical activation of macrophages, was detected only when Th1 cytokines were expressed at high levels. In vitro studies revealed that during the very early phases of infection, GSH depletion and the downregulation of interleukin-12 (IL-12) p40 mRNA were correlated with the dose of LP-BM5 used to infect the macrophages. Treatment of LP-BM5-infected mice with N-(N-acetyl-l-cysteinyl)-S-acetylcysteamine (I-152), an N-acetyl-cysteine supplier, restored GSH/cysteine levels in the organs, reduced the expression of alternatively activated macrophage markers, and increased the level of gamma interferon production, while it decreased the levels of Th2 cytokines, such as IL-4 and IL-5. Our findings thus establish a link between GSH deficiency and Th1/Th2 disequilibrium in LP-BM5 infection and indicate that I-152 can be used to restore the GSH level and a balanced Th1/Th2 response in infected mice.
  
  
  
  The first report of an association between Th2 polarization and alteration of the redox state in LP-BM5 infection is presented. Moreover, it provides evidence that LP-BM5 infection causes a decrease in the thiol content of peritoneal macrophages, which can influence IL-12 production. The restoration of GSH levels by GSH-replenishing molecules can represent a new therapeutic avenue to fight this retroviral infection, as it reestablishes the Th1/Th2 balance. Immunotherapy based on the use of pro-GSH molecules would permit LP-BM5 infection and probably all those viral infections characterized by GSH deficiency and a Th1/Th2 imbalance to be more effectively combated.
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Brundu
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Palma
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Giusi Giada
authors.initials: GG
authors.lastname: Picceri
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ligi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Orlandi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Galluzzi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Chiarantini
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Casabianca
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Giuditta Fiorella
authors.initials: GF
authors.lastname: Schiavano
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Santi
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Mannello
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, USA.
authors.forename: Kathy
authors.identifier: http://orcid.org/0000-0002-0681-2937
authors.initials: K
authors.lastname: Green
authors.affiliation: Institut des Biomolécules Max Mousseron, UMR 5247, CNRS, Université de Montpellier, Montpellier, France.
authors.forename: Michaël
authors.initials: M
authors.lastname: Smietana
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Magnani
authors.affiliation: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy alessandra.fraternale@uniurb.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fraternale
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000172:deficiency*; D009052:Leukemia Virus, Murine / Q000472:pathogenicity*; D007942:Leukemia, Experimental / Q000150:complications* / Q000276:immunology / Q000821:virology; D008213:Lymphocyte Activation; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012192:Retroviridae Infections / Q000150:complications* / Q000276:immunology / Q000821:virology; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014412:Tumor Virus Infections / Q000150:complications* / Q000276:immunology / Q000821:virology
chemical_list: D016207:Cytokines; D005978:Glutathione