PDF(Pubmed)
Abstract：
Trehalose-6-phosphate synthase (TPS1) was identified as a virulence factor for Cryptococcus neoformans 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 (tps1Δ) Cryptococci are rapidly cleared by mouse lungs whereas TPS1-sufficent WT (H99) and revertant (tps1Δ:TPS1) strains expand in the lungs and disseminate, causing 100% mortality. Rapid pulmonary clearance of tps1Δ mutant is T-cell independent and relies on its susceptibility to lung resident factors and innate immune factors, exemplified by tps1Δ 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, tps1Δ strain remains highly attenuated. Specifically, tps1Δ 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 tps1Δ:TPS1 rapidly expand in all studied organs, leading to rapid death of the infected mice. Since the rapid pulmonary clearance of tps1Δ mutant resembles a response to acapsular strains, the effect of tps1 deletion on capsule formation in vitro and in vivo was examined. Tps1Δ cryptococci form capsules but with a substantially reduced size. In conclusion, TPS1 is an important virulence factor, allowing C. neoformans evasion of resident pulmonary and innate defense mechanisms, most likely via its role in cryptococcal capsule formation.
摘要：
海藻糖-6-磷酸合酶（TPS1）被确定为新生隐球菌的毒力因子和有希望的治疗靶标。这项研究揭示了TPS1在肺部和传播感染阶段逃避宿主防御中先前未知的作用。在肺部感染模型中,TPS1缺失的（tps1Δ）隐球菌被小鼠肺迅速清除，而TPS1足够的WT（H99）和回复体（tps1Δ：TPS1）菌株在肺中扩张并传播，造成100%的死亡率。tps1Δ突变体的快速肺清除是T细胞独立的，并且依赖于其对肺驻留因子和先天免疫因子的易感性。例如，在与分散的肺细胞共培养中，tps1Δ而不是H99抑制，其快速清除与先天白细胞浸润相吻合。在传播感染模型中，绕过最初的肺-真菌相互作用，tps1Δ菌株保持高度减毒。具体来说,tps1Δ突变体不能从血液中定植于肺部或在脾脏中扩张，但能够进入大脑，即使在没有T细胞的情况下，它仍然受到控制。相比之下,菌株H99和tps1Δ：TPS1在所有研究的器官中快速扩张，导致被感染的老鼠迅速死亡。由于tps1Δ突变体的快速肺清除类似于对无囊菌株的反应，研究了tps1缺失对体外和体内囊膜形成的影响。Tps1Δ隐球菌形成胶囊，但尺寸大大减小。总之,TPS1是一种重要的毒力因子,允许新生梭菌逃避常驻肺和先天防御机制，最有可能通过其在隐球菌囊形成中的作用。
