Immunoprotection against Cryptococcosis Offered by Znf2 Depends on Capsule and the Hyphal Morphology.
Immunoprotection against Cryptococcosis Offered by Znf2 Depends on Capsule and the Hyphal Morphology.
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作者：
Lin J;Pham T;Hipsher K;Glueck N;Fan Y;Lin X
系统性隐球菌病如不治疗是致命的。在全球范围内，即使使用抗真菌治疗，这种疾病每年也会导致225，000名感染者中的180，000人死亡。目前，还没有疫苗来预防隐球菌病。以前，我们发现，Znf2，一个形态发生调节器，指导隐球菌酵母菌丝的过渡，深刻地影响隐球菌与宿主的ZNF 2过表达的相互作用驱动丝状生长，减弱隐球菌的毒力，并eliminating保护性宿主免疫反应。重要的是，用过表达ZNF2的隐球菌细胞免疫，无论是活的还是热灭活的形式，都为宿主提供了显著的保护，使其免受随后的致命野生型H99菌株的攻击。我们假设ZNF 2oe细胞中富集的细胞成分具有免疫保护作用。在这里，我们发现用灭活的ZNF 2oe细胞接种的受保护动物的血清识别存在于囊内的隐球菌抗原。因此，ZNF 20e细胞提供的免疫保护需要胶囊。有趣的是，来自保护动物的血清识别野生型酵母细胞和ZNF 2oe细胞中的抗原，后者中的丰度更高。因此，即使是热灭活的野生型细胞也会随着疫苗接种剂量的增加而变得具有免疫保护性。我们还发现，中断的染色质重塑因子Brf1，这是重要的启动Znf2，降低ZNF 2oe细胞中的抗原水平。尽管ZNF 2oebrf1 Δ菌株本身是无毒的，但BRF 1的缺失显著降低了ZNF 2oe细胞在活细胞和热灭活细胞中的保护作用。总的来说，我们的研究结果强调了确定隐球菌表面因子的子集是有益的主机保护的重要性。
Systemic cryptococcosis is fatal without treatment. Globally, this disease kills 180,000 of the 225,000 infected people each year, even with the use of antifungal therapies. Currently, there is no vaccine to prevent cryptococcosis. Previously, we discovered that Znf2, a morphogenesis regulator that directs Cryptococcus yeast-to-hyphal transition, profoundly affects cryptococcal interaction with the host—overexpression of ZNF2 drives filamentous growth, attenuates cryptococcal virulence, and elicits protective host immune responses. Importantly, immunization with cryptococcal cells overexpressing ZNF2, either in live or heat-inactivated form, offers significant protection to the host from a subsequent challenge by the otherwise lethal wild-type H99 strain. We hypothesize that cellular components enriched in ZNF2oe cells are immunoprotective. Here, we discovered that serum from protected animals vaccinated with inactivated ZNF2oe cells recognizes cryptococcal antigens that reside within the capsule. Consistently, capsule is required for immunoprotection offered by ZNF2oe cells. Interestingly, the serum from protective animals recognizes antigens in both wild-type yeast cells and ZNF2oe cells, with higher abundance in the latter. Consequently, even the heat-inactivated wild-type cells become immunoprotective with an increased vaccination dose. We also found that disruption of a chromatin remodeling factor Brf1, which is important for initiation of filamentation by Znf2, reduces the antigen level in ZNF2oe cells. Deletion of BRF1 drastically reduces the protective effect of ZNF2oe cells in both live and heat-killed forms even though the ZNF2oebrf1Δ strain itself is avirulent. Collectively, our findings underscore the importance of identifying the subset of cryptococcal surface factors that are beneficial in host protection.
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影响因子：
64.5
作者：
Brown JCS;Nelson J;VanderSluis B;Deshpande R;Butts A;Kagan S;Polacheck I;Krysan DJ;Myers CL;Madhani HD
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Madhani HD
影响因子：
3.4
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通讯作者：
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影响因子：
4.5
作者：
Chacko N;Zhao Y;Yang E;Wang L;Cai JJ;Lin X
通讯作者：
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影响因子：
6.4
作者：
Fu MS;Liporagi-Lopes LC;Dos Santos SR Júnior;Tenor JL;Perfect JR;Cuomo CA;Casadevall A
通讯作者：
Casadevall A
影响因子：
3
作者：
Idnurm, Alexander;Lin, Xiaorong
通讯作者：
Lin, Xiaorong