title: Role of extracellular phospholipases and mononuclear phagocytes in dissemination of cryptococcosis in a murine model.
abstract: Secreted phospholipase B (PLB) activity promotes the survival and replication of Cryptococcus neoformans in macrophages in vitro. We therefore investigated the role of mononuclear phagocytes and cryptococcal PLB in the dissemination of infection in a mouse model, using C. neoformans var. grubii wild-type strain H99, a PLB1 deletion mutant (Delta plb1), and a reconstituted strain (Delta plb1(rec)). PLB facilitated the entry of endotracheally administered cryptococci into lung IM. PLB was also required for lymphatic spread from the lung to regional lymph nodes and for entry into the blood. Langhans-type giant cells containing budding cryptococci were seen free in the lymphatic sinuses of hilar nodes of H99- and Delta plb1(rec)-infected mice, suggesting that they may have a role in the dissemination of cryptococcal infection. The transfer of infected lung macrophages to recipient mice by tail vein injections demonstrated that these cells can facilitate hematogenous dissemination of cryptococci to the brain, independent of cryptococcal PLB secretion. PLB activities of cryptococci isolated from lung macrophages or infected brains were not persistently increased. We conclude that mononuclear phagocytes are a vehicle for cryptococcal dissemination and that PLB activity is necessary for the initiation of interstitial pulmonary infections and for dissemination from the lung via the lymphatics and blood. PLB is not, however, essential for the establishment of neurological infections when cryptococci are presented within, or after passage through, mononuclear phagocytes.
authors.affiliation: Centre for Infectious Diseases and Microbiology, University of Sydney at Westmead and Department of Infectious Diseases, Westmead Hospital, NSW 2145, Australia.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Santangelo
authors.forename: Hans
authors.initials: H
authors.lastname: Zoellner
authors.forename: Tania
authors.initials: T
authors.lastname: Sorrell
authors.forename: Christabel
authors.initials: C
authors.lastname: Wilson
authors.forename: Christine
authors.initials: C
authors.lastname: Donald
authors.forename: Julianne
authors.initials: J
authors.lastname: Djordjevic
authors.forename: Yi
authors.initials: Y
authors.lastname: Shounan
authors.forename: Lesley
authors.initials: L
authors.lastname: Wright
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology / Q000382:microbiology*; D003453:Cryptococcosis / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000472:pathogenicity*; D004195:Disease Models, Animal; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000382:microbiology*; D008172:Lung Diseases, Fungal / Q000382:microbiology; D008245:Lysophospholipase / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000382:microbiology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology; D016919:Meningitis, Cryptococcal / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000382:microbiology; D010586:Phagocytes / Q000382:microbiology; D014774:Virulence
chemical_list: D005656:Fungal Proteins; D008245:Lysophospholipase