trehalose-6-phosphate synthase (tps1) promotes organ-specific virulence and fungal protection against multiple lines of host defenses.

Abstract

Trehalose-6-phosphate synthase (TPS1) was identified as a virulence factor forand a promising therapeutic target. This study reveals previously unknown roles of TPS1 in evasion of host defenses during pulmonary and disseminated phases of infection. In the pulmonary infection model, TPS1-deleted ()are rapidly cleared by mouse lungs whereas TPS1-sufficent WT (H99) and revertant (:) strains expand in the lungs and disseminate, causing 100% mortality. Rapid pulmonary clearance ofmutant is T-cell independent and relies on its susceptibility to lung resident factors and innate immune factors, exemplified bybut not H99 inhibition in a coculture with dispersed lung cells and its rapid clearance coinciding with innate leukocyte infiltration. In the disseminated model of infection, which bypasses initial lung-fungus interactions,strain remains highly attenuated. Specifically,mutant is unable to colonize the lungs from the bloodstream or expand in spleens but is capable of crossing into the brain, where it remains controlled even in the absence of T cells. In contrast, strains H99 andrapidly expand in all studied organs, leading to rapid death of the infected mice. Since the rapid pulmonary clearance ofmutant resembles a response to acapsular strains, the effect ofdeletion on capsule formationandwas examined.cryptococci form capsules but with a substantially reduced size. In conclusion, TPS1 is an important virulence factor, allowingevasion of resident pulmonary and innate defense mechanisms, most likelyits role in cryptococcal capsule formation.