title: Low dose aerosol infection of mice with virulent type A Francisella tularensis induces severe thymus atrophy and CD4+CD8+ thymocyte depletion.
abstract: Francisella tularensis is a gram-negative facultative intracellular bacterium and the causative agent of tularemia. Two subspecies (type A and B strains) of the pathogen exist, the former being much more virulent than the latter for humans and other higher mammals. In this study, we examined the effect of virulent strains of F. tularensis infection on the thymus and thymocytes and the potential mechanisms involved. Low-dose aerosol exposure of C57BL/6 mice with type A, but not type B, F. tularensis caused severe reduction in thymus weight and destruction of thymocytes, particularly CD4+CD8+ thymocytes, by day 4 after infection. The depletion of thymocytes was accompanied by a significant increase in circulating cortisone levels and could be partially prevented by adrenalectomy. Moreover, thymus atrophy and thymocyte depletion following infection were abolished in mice deficient in tumor necrosis factor receptors 1 and 2, but not in FasL-deficient mice. The severe destruction of the thymus and selective depletion of immature thymocytes during type A F. tularensis infection may represent a key pathogenic mechanism in tularemia and could hinder the development of an effective primary immune response against this highly virulent pathogen.
authors.affiliation: Institute for Biological Sciences, National Research Council Canada, 100 Sussex Drive, Ottawa, Ont., Canada K1A 0R6. wangxue.chen@nrc.gc.ca
authors.forename: Wangxue
authors.initials: W
authors.lastname: Chen
authors.forename: Rhonda
authors.initials: R
authors.lastname: Kuolee
authors.forename: John W
authors.initials: JW
authors.lastname: Austin
authors.forename: Hua
authors.initials: H
authors.lastname: Shen
authors.forename: Yanming
authors.initials: Y
authors.lastname: Che
authors.forename: J Wayne
authors.initials: JW
authors.lastname: Conlan
mesh_terms: D000311:Adrenal Glands / Q000502:physiology; D000315:Adrenalectomy; D000336:Aerosols; D000818:Animals; D015704:CD4 Antigens; D016827:CD8 Antigens; D003348:Cortisone / Q000097:blood; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D005604:Francisella tularensis / Q000472:pathogenicity*; D016131:Lymphocyte Subsets; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology* / Q000648:ultrastructure; D014406:Tularemia / Q000276:immunology / Q000382:microbiology / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000336:Aerosols; D015704:CD4 Antigens; D016827:CD8 Antigens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D003348:Cortisone