title: Cryptococcus neoformans variants generated by phenotypic switching differ in virulence through effects on macrophage activation.
abstract: Macrophages have a central role in the pathogenesis of cryptococcosis since they are an important line of defense, serve as a site for fungal replication, and also can contribute to tissue damage. The objective of this study was to investigate the interaction of macrophages with cells from smooth-colony variants (SM) and mucoid-colony variants (MC) arising from phenotypic switching of Cryptococcus neoformans. Alveolar macrophages (AMs) isolated from SM- and MC-infected mice exhibited differences in gene and surface expression of PD-L1, PD-L2, and major histocompatibility class II (MHC-II). PD-L1 and PD-L2 are the ligands for PD1 and are differentially regulated in Th1- and Th2-type cells. In addition, macrophage activation in SM- and MC-infected mice was characterized as alternatively activated. Flow cytometric and cytokine analysis demonstrated that MC infection was associated with the emergence of Th17 cells and higher levels of interleukin-17 (IL-17) in lung tissue, which were reduced by AM depletion. In conclusion, our results indicate that macrophages play a significant role in maintaining damage-promoting inflammation in the lung during MC infection, which ultimately results in death.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: A
authors.initials: A
authors.lastname: Guerrero
authors.forename: N
authors.initials: N
authors.lastname: Jain
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.forename: B C
authors.initials: BC
authors.lastname: Fries
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000032:analysis; D060890:B7-H1 Antigen; D003455:Cryptococcus neoformans / Q000276:immunology* / Q000472:pathogenicity*; D020869:Gene Expression Profiling; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000737:chemistry / Q000276:immunology* / Q000382:microbiology*; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000032:analysis; D010641:Phenotype; D061027:Programmed Cell Death 1 Ligand 2 Protein; D014774:Virulence
chemical_list: D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein