Cryptococcus neoformans Evades Pulmonary Immunity by Modulating Xylose Precursor Transport

• Published in: Infection and immunity 2020-07, Vol.88 (8)
• Main Authors: Li, Lucy X, Hole, Camaron R, Rangel-Moreno, Javier, Khader, Shabaana A, Doering, Tamara L
• Format: Article
• Language: English
• Subjects: Animals; Biological Transport; Cryptococcosis - genetics; Cryptococcosis - immunology; Cryptococcosis - microbiology; Cryptococcosis - mortality; Cryptococcus neoformans - immunology; Cryptococcus neoformans - pathogenicity; Dendritic Cells - immunology; Dendritic Cells - microbiology; Disease Models, Animal; Fungal and Parasitic Infections; Gene Expression Regulation; Homeodomain Proteins - genetics; Homeodomain Proteins - immunology; Humans; Immune Evasion; Immunity, Mucosal; Interleukin-12 Subunit p40 - genetics; Interleukin-12 Subunit p40 - immunology; Interleukin-17 - genetics; Interleukin-17 - immunology; Lung - immunology; Lung - microbiology; Lung Diseases, Fungal - genetics; Lung Diseases, Fungal - immunology; Lung Diseases, Fungal - microbiology; Lung Diseases, Fungal - mortality; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Monosaccharide Transport Proteins - genetics; Monosaccharide Transport Proteins - immunology; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; Signal Transduction; Spotlight; Survival Analysis; Th2 Cells - immunology; Th2 Cells - microbiology; Xylose - immunology; Xylose - metabolism
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00288-20

is a fungal pathogen that kills almost 200,000 people each year and is distinguished by abundant and unique surface glycan structures that are rich in xylose. A mutant strain of that cannot transport xylose precursors into the secretory compartment is severely attenuated in virulence in mice yet surprisingly is not cleared. We found that this strain failed to induce the nonprotective T helper cell type 2 (Th2) responses characteristic of wild-type infection, instead promoting sustained interleukin 12p40 (IL-12p40) induction and increased IL-17A (IL-17) production. It also stimulated dendritic cells to release high levels of proinflammatory cytokines, a behavior we linked to xylose expression. We further discovered that inducible bronchus-associated lymphoid tissue (iBALT) forms in response to infection with either wild-type cryptococci or the mutant strain with reduced surface xylose; although iBALT formation is slowed in the latter case, the tissue is better organized. Finally, our temporal studies suggest that lymphoid structures in the lung restrict the spread of mutant fungi for at least 18 weeks after infection, which is in contrast to ineffective control of the pathogen after infection with wild-type cells. These studies demonstrate the role of xylose in modulation of host response to a fungal pathogen and show that cryptococcal infection triggers iBALT formation.