title: Cryptococcal urease promotes the accumulation of immature dendritic cells and a non-protective T2 immune response within the lung.
abstract: Urease, a major virulence factor for Cryptococcus neoformans, promotes lethal meningitis/encephalitis in mice. The effect of urease within the lung, the primary site of most invasive fungal infections, is unknown. An established model of murine infection that utilizes either urease-producing (wt and ure1::URE1) or urease-deficient (ure1) strains (H99) of C. neoformans was used to characterize fungal clearance and the resultant immune response evoked by these strains within the lung. Results indicate that mice infected with urease-producing strains of C. neoformans demonstrate a 100-fold increase in fungal burden beginning 2 weeks post-infection (as compared with mice infected with urease-deficient organisms). Infection with urease-producing C. neoformans was associated with a highly polarized T2 immune response as evidenced by increases in the following: 1) pulmonary eosinophils, 2) serum IgE levels, 3) T2 cytokines (interleukin-4, -13, and -4 to interferon-gamma ratio), and 4) alternatively activated macrophages. Furthermore, the percentage and total numbers of immature dendritic cells within the lung-associated lymph nodes was markedly increased in mice infected with urease-producing C. neoformans. Collectively, these data define cryptococcal urease as a pulmonary virulence factor that promotes immature dendritic cell accumulation and a potent, yet non-protective, T2 immune response. These findings provide new insights into mechanisms by which microbial factors contribute to the immunopathology associated with invasive fungal disease.
authors.affiliation: Veterans Affairs Ann Arbor Health System, Ann Arbor, 2215 Fuller Rd., Ann Arbor, MI 48105, USA. olszewsm@umich.edu
authors.forename: John J
authors.initials: JJ
authors.lastname: Osterholzer
authors.forename: Rishi
authors.initials: R
authors.lastname: Surana
authors.forename: Jami E
authors.initials: JE
authors.lastname: Milam
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Montano
authors.forename: Gwo-Hsiao
authors.initials: GH
authors.lastname: Chen
authors.forename: Joanne
authors.initials: J
authors.lastname: Sonstein
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Curtis
authors.forename: Gary B
authors.initials: GB
authors.lastname: Huffnagle
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Michal A
authors.initials: MA
authors.lastname: Olszewski
mesh_terms: D000818:Animals; D003114:Colony-Forming Units Assay; D003453:Cryptococcosis / Q000276:immunology; D003454:Cryptococcus / Q000201:enzymology*; D003455:Cryptococcus neoformans / Q000201:enzymology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005656:Fungal Proteins / Q000494:pharmacology; D006801:Humans; D016867:Immunocompromised Host; D007962:Leukocytes / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014510:Urease / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*
chemical_list: D005656:Fungal Proteins; D014510:Urease