Toxoplasma gondii induces prolonged host epidermal growth factor receptor signalling to prevent parasite elimination by autophagy: Perspectives for in vivo control of the parasite
Toxoplasma gondii induces prolonged host epidermal growth factor receptor signalling to prevent parasite elimination by autophagy: Perspectives for in vivo control of the parasite
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DOI：
10.1111/cmi.13084
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发表时间：
2019-07-17
影响因子：
3.4
通讯作者：
Subauste, Carlos S.
中科院分区：
文献类型：
--
作者：
Corcino, Yalitza Lopez;Ferrer, Shekina Gonzalez;Subauste, Carlos S.
弓形虫引起视网膜炎和脑炎。避免被自噬体靶向是其存活的关键，因为T。弓形虫不能抵抗溶酶体降解。T.弓形虫触发表皮生长因子受体（EGFR）信号传导，使寄生虫能够避免最初的自噬靶向。然而，自噬是一个组成性过程，表明寄生虫也可能使用一种超越入侵的策略来维持自噬靶向的阻断。发现这种策略的存在将是重要的，因为它可能导致抑制宿主细胞信号传导，作为一种新的方法来杀死先前感染细胞中的寄生虫并治疗弓形虫病。我们报告T. gondii诱导EGFR自身磷酸化延长。这种作用是由PKC α/PKC β Src介导的，因为T.弓形虫引起这些分子的长期激活，并且在宿主细胞侵袭后，它们的敲除或与PKC α/PKC β或Src抑制剂的孵育损害了持续的EGFR自磷酸化。将EGFR酪氨酸激酶抑制剂（TKI）添加到先前感染的细胞中导致LC 3和LAMP-1的寄生虫截留以及依赖于自噬蛋白ULK 1和Beclin 1以及溶酶体酶的病原体杀灭。对患有眼部和脑部弓形虫病的小鼠给予吉非替尼（EGFR TKI）可导致依赖于Beclin 1的疾病控制。因此，T.弓形虫通过PKC α/β Src驱动的持续EGFR信号传导促进其存活，并且抑制EGFR控制预先建立的弓形虫病。
Toxoplasma gondii causes retinitis and encephalitis. Avoiding targeting by autophagosomes is key for its survival because T. gondii cannot withstand lysosomal degradation. During invasion of host cells, T. gondii triggers epidermal growth factor receptor (EGFR) signalling enabling the parasite to avoid initial autophagic targeting. However, autophagy is a constitutive process indicating that the parasite may also use a strategy operative beyond invasion to maintain blockade of autophagic targeting. Finding that such a strategy exists would be important because it could lead to inhibition of host cell signalling as a novel approach to kill the parasite in previously infected cells and treat toxoplasmosis. We report that T. gondii induced prolonged EGFR autophosphorylation. This effect was mediated by PKC alpha/PKC beta Src because T. gondii caused prolonged activation of these molecules and their knockdown or incubation with inhibitors of PKC alpha/PKC beta or Src after host cell invasion impaired sustained EGFR autophosphorylation. Addition of EGFR tyrosine kinase inhibitor (TKI) to previously infected cells led to parasite entrapment by LC3 and LAMP-1 and pathogen killing dependent on the autophagy proteins ULK1 and Beclin 1 as well as lysosomal enzymes. Administration of gefitinib (EGFR TKI) to mice with ocular and cerebral toxoplasmosis resulted in disease control that was dependent on Beclin 1. Thus, T. gondii promotes its survival through sustained EGFR signalling driven by PKC alpha/beta Src, and inhibition of EGFR controls pre-established toxoplasmosis.