Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner.
Activation of Cph1 causes ß(1,3)-glucan unmasking in Candida albicans and attenuates virulence in mice in a neutrophil-dependent manner.
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DOI：
10.1371/journal.ppat.1009839
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发表时间：
2021-08
期刊：
影响因子：
6.7
通讯作者：
Reynolds TB
中科院分区：
文献类型：
--
作者：
Wagner AS;Hancock TJ;Lumsdaine SW;Kauffman SJ;Mangrum MM;Phillips EK;Sparer TE;Reynolds TB
掩盖免疫原性细胞壁表位ß(1,3)-葡聚糖在甘露糖糖蛋白的外层是白色念珠菌在感染过程中部署的一个重要毒力因子。因此，增加ß(1,3)-葡聚糖暴露（揭露）使白色念珠菌暴露于宿主的免疫系统并减弱其毒力。我们之前已经证明，通过表达上游激酶的一个过度活跃的等位基因（STE11ΔN467）激活Cek1 MAPK通路可诱导解除屏蔽。在小鼠播散性念珠菌病模型中，它还提高了小鼠的存活率，并将肾脏真菌负荷减轻了≥33倍。在这篇通讯中，我们利用环磷酰胺诱导的免疫抑制来测试揭开的STE11ΔN467突变体的清除是否依赖于宿主免疫系统。环磷酰胺抑制免疫应答可降低STE11ΔN467等位基因引起的真菌负荷衰减。此外，通过1A8抗体处理，中性粒细胞的特异性消耗也减少了STE11ΔN467-dependent真菌负荷的衰减，但程度低于环磷酰胺，这表明中性粒细胞在介导真菌清除未被掩盖的STE11ΔN467细胞中的重要作用。为了了解Ste11ΔN467导致揭膜的机制，转录组学被用来揭示Cek1 MAPK通路中的几个成分上调，包括转录因子CPH1和细胞壁传感器DFI1。在本报告中，我们发现cph1ΔΔ突变使STE11ΔN467菌株的ß(1,3)-葡聚糖暴露恢复到野生型水平，证实了Cph1是介导Ste11ΔN467-induced揭开的转录因子。此外，Cph1被证明可以诱导增加Cek1激活的正反馈循环。此外，STE11ΔN467的完全揭开依赖于上游细胞壁传感器DFI1。然而，虽然DFI1的缺失显著减少了Ste11ΔN467-induced的揭开，但它并不影响下游激酶Cek1的激活。因此，似乎一旦受到Ste11ΔN467的刺激，Dfi1激活了一个平行的信号通路，该通路参与了Ste11ΔN467-induced的揭开。白色念珠菌是真菌血流感染的重要原因。然而，为了使其有效诱导疾病，必须实现宿主免疫逃避。白色念珠菌通常通过掩盖其细胞壁内可被宿主免疫系统识别的结构来实现这一目标，例如ß(1,3)-葡聚糖。因此，不适当地暴露（揭开）这个表位可能是增加免疫系统对入侵真菌细胞的识别以增强宿主清除的一种方法。我们之前的研究表明，我们可以通过调节ce1 MAPK通路中MAP3K - STE11的高活性突变体的表达，诱导白色念珠菌不适当的脱模，并且这可以减少小鼠全身感染期间的真菌定植。我们假设观察到的毒力衰减是由典型的Cek1 MAPK通路诱导的揭膜引起的宿主免疫系统识别增强的结果。在本报告中，我们发现Ste11ΔN467-induced的揭开确实是由其已知的下游转录因子之一Cph1介导的，并且其在体内的毒力衰减在很大程度上依赖于功能性免疫应答。因此，利用Cek1通路可以作为一个模型来研究白色念珠菌的揭膜是如何发生的，以及宿主如何在体内对这种表型做出反应。
Masking the immunogenic cell wall epitope ß(1,3)-glucan under an outer layer of mannosylated glycoproteins is an important virulence factor deployed by Candida albicans during infection. Consequently, increased ß(1,3)-glucan exposure (unmasking) reveals C. albicans to the host’s immune system and attenuates its virulence. We have previously shown that activation of the Cek1 MAPK pathway via expression of a hyperactive allele of an upstream kinase (STE11ΔN467) induced unmasking. It also increased survival of mice in a murine disseminated candidiasis model and attenuated kidney fungal burden by ≥33 fold. In this communication, we utilized cyclophosphamide-induced immunosuppression to test if the clearance of the unmasked STE11ΔN467 mutant was dependent on the host immune system. Suppression of the immune response by cyclophosphamide reduced the attenuation in fungal burden caused by the STE11ΔN467 allele. Moreover, specific depletion of neutrophils via 1A8 antibody treatment also reduced STE11ΔN467-dependent fungal burden attenuation, but to a lesser extent than cyclophosphamide, demonstrating an important role for neutrophils in mediating fungal clearance of unmasked STE11ΔN467 cells. In an effort to understand the mechanism by which Ste11ΔN467 causes unmasking, transcriptomics were used to reveal that several components in the Cek1 MAPK pathway were upregulated, including the transcription factor CPH1 and the cell wall sensor DFI1. In this report we show that a cph1ΔΔ mutation restored ß(1,3)-glucan exposure to wild-type levels in the STE11ΔN467 strain, confirming that Cph1 is the transcription factor mediating Ste11ΔN467-induced unmasking. Furthermore, Cph1 is shown to induce a positive feedback loop that increases Cek1 activation. In addition, full unmasking by STE11ΔN467 is dependent on the upstream cell wall sensor DFI1. However, while deletion of DFI1 significantly reduced Ste11ΔN467-induced unmasking, it did not impact activation of the downstream kinase Cek1. Thus, it appears that once stimulated by Ste11ΔN467, Dfi1 activates a parallel signaling pathway that is involved in Ste11ΔN467-induced unmasking. Candida albicans is a significant cause of fungal bloodstream infections. Yet, in order for it to effectively induce disease, host immune evasion must be achieved. C. albicans often accomplishes this by masking structures within its cell wall that are recognized by the host immune system, such as ß(1,3)-glucan. Thus, inappropriately exposing (unmasking) this epitope may be a way to increase immune system recognition of invading fungal cells to enhance host clearance. We have previously shown that we can induce inappropriate unmasking in C. albicans by regulated expression of a hyperactive mutant of the MAP3K STE11 of the Cek1 MAPK pathway, and that this reduces fungal colonization during systemic infection in mice. We hypothesized that the observed virulence attenuation was a consequence of enhanced host immune system recognition caused by unmasking induced by the canonical Cek1 MAPK pathway. In this report, we found that Ste11ΔN467-induced unmasking was indeed mediated by one of its known downstream transcription factors, Cph1, and that its virulence attenuation in vivo was largely dependent on a functional immune response. Thus, leveraging the Cek1 pathway may serve as a model to study how unmasking occurs in C. albicans, and how the host responds to this phenotype in vivo.
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Dectin-1介导β-葡聚糖的生物学作用。
DOI：
10.1084/jem.20021890
发表时间：
2003-05-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Brown GD;Herre J;Williams DL;Willment JA;Marshall AS;Gordon S
通讯作者：
Gordon S
DOI：
10.4049/jimmunol.1300748
发表时间：
2013-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Carrion Sde J;Leal SM Jr;Ghannoum MA;Aimanianda V;Latgé JP;Pearlman E
通讯作者：
Pearlman E
影响因子：
6.7
作者：
Gravelat FN;Beauvais A;Liu H;Lee MJ;Snarr BD;Chen D;Xu W;Kravtsov I;Hoareau CM;Vanier G;Urb M;Campoli P;Al Abdallah Q;Lehoux M;Chabot JC;Ouimet MC;Baptista SD;Fritz JH;Nierman WC;Latgé JP;Mitchell AP;Filler SG;Fontaine T;Sheppard DC
通讯作者：
Sheppard DC
影响因子：
28.3
作者：
Ballou ER;Avelar GM;Childers DS;Mackie J;Bain JM;Wagener J;Kastora SL;Panea MD;Hardison SE;Walker LA;Erwig LP;Munro CA;Gow NA;Brown GD;MacCallum DM;Brown AJ
通讯作者：
Brown AJ
DOI：
10.1086/523110
发表时间：
2007-11-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Gow NA;Netea MG;Munro CA;Ferwerda G;Bates S;Mora-Montes HM;Walker L;Jansen T;Jacobs L;Tsoni V;Brown GD;Odds FC;Van der Meer JW;Brown AJ;Kullberg BJ
通讯作者：
Kullberg BJ