AUTHOR=Goughenour Kristie , Creech Arianna , Xu Jintao , He Xiumiao , Hissong Rylan , Giamberardino Charles , Tenor Jennifer , Toffaletti Dena , Perfect John , Olszewski Michal 

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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2024.1392015

DOI=10.3389/fcimb.2024.1392015

ISSN=2235-2988

ABSTRACT=<p>Trehalose-6-phosphate synthase (TPS1) was identified as a virulence factor for <italic>Cryptococcus neoformans</italic> and 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 (<italic>tps1Δ</italic>) <italic>Cryptococci</italic> are rapidly cleared by mouse lungs whereas TPS1-sufficent WT (H99) and revertant (<italic>tps1Δ</italic>:<italic>TPS1</italic>) strains expand in the lungs and disseminate, causing 100% mortality. Rapid pulmonary clearance of <italic>tps1Δ</italic> mutant is T-cell independent and relies on its susceptibility to lung resident factors and innate immune factors, exemplified by <italic>tps1Δ</italic> but 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, <italic>tps1Δ</italic> strain remains highly attenuated. Specifically, <italic>tps1Δ</italic> 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 and <italic>tps1Δ:TPS1</italic> rapidly expand in all studied organs, leading to rapid death of the infected mice. Since the rapid pulmonary clearance of <italic>tps1Δ</italic> mutant resembles a response to acapsular strains, the effect of <italic>tps1</italic> deletion on capsule formation <italic>in vitro</italic> and <italic>in vivo</italic> was examined. <italic>Tps1Δ</italic> cryptococci form capsules but with a substantially reduced size. In conclusion, TPS1 is an important virulence factor, allowing <italic>C. neoformans</italic> evasion of resident pulmonary and innate defense mechanisms, most likely <italic>via</italic> its role in cryptococcal capsule formation.</p>