title: Down-regulation of the afferent phase of T cell-mediated pulmonary inflammation and immunity by a high melanin-producing strain of Cryptococcus neoformans.
abstract: The interaction(s) between cryptococcal virulence factors and leukocytes involved in generating protective cell-mediated immunity is not well defined. Intratracheal inoculation of Cryptococcus neoformans strain 52 induced a vigorous T cell-mediated pulmonary inflammatory response that controlled the growth of the organism. In contrast, strain 145 induced a pulmonary inflammatory response that was delayed in onset, slower to develop, and ineffective in controlling the infection. In addition, the expansion of cryptococcus-specific lymphocytes in the pulmonary lymph nodes and titer of specific Abs in the serum of strain 145-infected mice were both diminished markedly. Of the known cryptococcal virulence factors, these two strains differed only in melanin production (52-low and 145-high). Heat-killed strain 145 cryptococci (HKC-145) that had been rendered melanin-negative induced TNF-alpha production by alveolar macrophages in vitro and stimulated vigorous cryptococcus-specific lymphoproliferation. In contrast, high melanin-containing HKC-145 inhibited TNF-alpha production and lymphoproliferation. In vivo, mice infected with melanin low strain 52, but not melanin high strain 145, had elevated levels of TNF-alpha in the bronchoalveolar lavage fluid. Mice co-infected with strains 145 and 52 generated a pulmonary inflammatory response resulting in increased long-term survival. Taken together, these studies demonstrate that melanin does not protect cryptococci from being eliminated in vivo by recruited, activated effector cells; but melanin can inhibit the recognition of the organism by host defenses, thereby down-regulating the afferent phase of T cell-mediated immunity, e.g., TNF-alpha production and lymphoproliferation.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109, USA.
authors.forename: G B
authors.initials: GB
authors.lastname: Huffnagle
authors.forename: G H
authors.initials: GH
authors.lastname: Chen
authors.forename: J L
authors.initials: JL
authors.lastname: Curtis
authors.forename: R A
authors.initials: RA
authors.lastname: McDonald
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
authors.forename: G B
authors.initials: GB
authors.lastname: Toews
mesh_terms: D000818:Animals; D003455:Cryptococcus neoformans / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity; D005260:Female; D007111:Immunity, Cellular; D008543:Melanins / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011024:Pneumonia, Viral / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014774:Virulence
chemical_list: D008543:Melanins; D014409:Tumor Necrosis Factor-alpha