title: Robust Th1 and Th17 immunity supports pulmonary clearance but cannot prevent systemic dissemination of highly virulent Cryptococcus neoformans H99.
abstract: The present study dissected the role of a Th2 bias in pathogenesis of Cryptococcus neoformans H99 infection by comparing inhalational H99 infections in wild-type BALB/c and IL-4/IL-13 double knockout mice. H99-infected wild-type mice showed all major hallmarks of Th2 but not Th1/Th17 immunity in the lungs and lung-associated lymph nodes. In contrast, the IL-4/13(-/-) mice developed robust hallmarks of Th1 and Th17 but not Th2 polarization. The IL-4/IL-13 deletion prevented pulmonary eosinophilia, goblet cell metaplasia in the airways and resulted in elevated serum IgE, and a switch from alternative to classical activation of macrophages. The development of a robust Th1/Th17 response and classical activation of macrophages resulted in significant containment of H99 in the lungs of IL-4/13(-/-) mice compared with unopposed growth of H99 in the lungs of wild-type mice. However, IL-4/13(-/-) mice showed only 1-week longer survival compared with wild-type mice. The comparison of brain and spleen cryptococcal loads at weeks 2, 3, and 4 postinfection revealed that the systemic dissemination in IL-4/13(-/-) mice occurred with an approximate 1-week delay but subsequently progressed with similar rate as in the wild-type mice. Furthermore, wild-type and IL-4/13(-/-) mice developed equivalently severe meningitis/encephalitis at the time of death. These data indicate that the Th2 immune bias is a crucial mechanism for pulmonary virulence of H99, whereas other mechanisms are largely responsible for its central nervous system tropism and systemic dissemination.
authors.affiliation: VA Ann Arbor Health System, Ann Arbor, Michigan 48105, USA.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fuyuan
authors.initials: F
authors.lastname: Wang
authors.forename: Kristin C
authors.initials: KC
authors.lastname: Tompkins
authors.forename: Andrew
authors.initials: A
authors.lastname: McNamara
authors.forename: Aditya V
authors.initials: AV
authors.lastname: Jain
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Gary B
authors.initials: GB
authors.lastname: Huffnagle
authors.forename: Michal A
authors.initials: MA
authors.lastname: Olszewski
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte; D003453:Cryptococcosis / Q000276:immunology* / Q000473:pathology; D003455:Cryptococcus neoformans / Q000276:immunology / Q000472:pathogenicity*; D018450:Disease Progression; D018793:Interleukin-13 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology*; D015847:Interleukin-4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014774:Virulence
chemical_list: D018793:Interleukin-13; D020381:Interleukin-17; D015847:Interleukin-4