Cek1 regulates ß(1,3)-glucan exposure through calcineurin effectors in Candida albicans.
Cek1 regulates ß(1,3)-glucan exposure through calcineurin effectors in Candida albicans.
复制标题
DOI：
10.1371/journal.pgen.1010405
复制
发表时间：
2022-09
期刊：
影响因子：
4.5
通讯作者：
中科院分区：
文献类型：
--
作者：
为了成功地诱导疾病，真菌病原体白色念珠菌调节抗原如细胞壁多糖β（1，3）-葡聚糖暴露于宿主免疫系统。C.白色念珠菌用一层甘露糖基化糖蛋白覆盖（掩蔽）β（1，3）-葡聚糖，其通过充当宿主模式识别受体识别的屏障来帮助免疫系统逃避。因此，增强的β（1，3）-葡聚糖暴露（暴露）使宿主免疫细胞更容易看到真菌细胞，并促进更稳健的真菌清除。然而，理解C.白念珠菌调节其β（1，3）-葡聚糖的暴露水平是利用这种表型所必需的。介导这些变化的信号转导途径及其相应的效应基因才刚刚开始被定义。在这里，我们报告了磷酸酶钙调神经磷酸酶介导的β（1，3）-葡聚糖的解蔽，以响应来自Cek 1 MAPK途径的输入和卡泊芬净暴露。相反，钙调神经磷酸酶减少β-葡聚糖暴露，以响应高水平的细胞外钙。因此，根据输入，钙调神经磷酸酶作为开关板调节β（1，3）-葡聚糖暴露水平。通过利用这些不同的β（1，3）-葡聚糖暴露表型，我们在钙调磷酸酶调节子中鉴定了两种新型效应基因FGR 41和C1_11990W_A，它们编码推定的细胞壁蛋白并介导掩蔽/解蔽。在小鼠全身感染过程中，任一效应子的缺失导致暴露和毒力减弱。此外，免疫抑制使感染fgr 41 Δ/Δ突变体的小鼠中观察到的定殖减少恢复至野生型水平，表明毒力衰减依赖于宿主免疫系统。因此，钙调磷酸酶及其下游调节子是一般的调节剂的解蔽。白色念珠菌是医院内系统性感染的常见原因，并且具有高达~40- 60%的归因死亡率。因此，疾病管理策略具有很高的医学意义。一种潜在的控制疾病进展的免疫学方法是影响C.白念珠菌有效地逃避宿主免疫细胞。这可以通过增加高免疫原性细胞壁表位β（1，3）-葡聚糖对宿主免疫系统的暴露来实现。然而，需要阐明β-葡聚糖暴露是如何调节的，以利用这种方法，并且介导这种表型的信号转导途径和效应基因才刚刚开始被定义。在这里，我们表明钙调神经磷酸酶作为一个通用的开关板，可以增加和减少β（1，3）-葡聚糖暴露在多种刺激。此外，我们确定了两个新的下游效应基因内的钙调磷酸酶调节子，驱动这种表型和影响小鼠全身感染期间的毒力。
In order to successfully induce disease, the fungal pathogen Candida albicans regulates exposure of antigens like the cell wall polysaccharide ß(1,3)-glucan to the host immune system. C. albicans covers (masks) ß(1,3)-glucan with a layer of mannosylated glycoproteins, which aids in immune system evasion by acting as a barrier to recognition by host pattern recognition receptors. Consequently, enhanced ß(1,3)-glucan exposure (unmasking) makes fungal cells more visible to host immune cells and facilitates more robust fungal clearance. However, an understanding of how C. albicans regulates its exposure levels of ß(1,3)-glucan is needed to leverage this phenotype. Signal transduction pathways and their corresponding effector genes mediating these changes are only beginning to be defined. Here, we report that the phosphatase calcineurin mediates unmasking of ß(1,3)-glucan in response to inputs from the Cek1 MAPK pathway and in response to caspofungin exposure. In contrast, calcineurin reduces ß-glucan exposure in response to high levels of extracellular calcium. Thus, depending on the input, calcineurin acts as a switchboard to regulate ß(1,3)-glucan exposure levels. By leveraging these differential ß(1,3)-glucan exposure phenotypes, we identified two novel effector genes in the calcineurin regulon, FGR41 and C1_11990W_A, that encode putative cell wall proteins and mediate masking/unmasking. Loss of either effector caused unmasking and attenuated virulence during systemic infection in mice. Furthermore, immunosuppression restored the colonization decrease seen in mice infected with the fgr41Δ/Δ mutant to wild-type levels, demonstrating a reliance on the host immune system for virulence attenuation. Thus, calcineurin and its downstream regulon are general regulators of unmasking. Candida albicans is a common cause of nosocomial systemic infections, and has an attributed mortality rate as high as ~40–60%. Thus, disease management strategies are of high medical significance. One potential immunotherapeutic approach to control disease progression is to impact the ability of C. albicans to effectively evade host immune cells. This may be achieved by increasing the exposure of the highly immunogenic cell wall epitope ß(1,3)-glucan to the host immune system. Yet, elucidation of how ß-glucan exposure is regulated is needed to leverage this approach, and signal transduction pathways and effector genes mediating this phenotype are only beginning to be defined. Here, we show that calcineurin acts as a general switchboard that can both increase and decrease ß(1,3)-glucan exposure in response to multiple stimuli. Furthermore, we identify two novel downstream effector genes within the calcineurin regulon that drive this phenotype and impact virulence during systemic infection in mice.
登录
查看更多内容
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：
10.4049/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
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
影响因子：
3.1
作者：
Bader, Teresa;Schroeppel, Klaus;Morschhaeuser, Joachim
通讯作者：
Morschhaeuser, Joachim