Calcium Ions Directly Interact with the Ebola Virus Fusion Peptide To Promote Structure-Function Changes That Enhance Infection.,ACS Infectious Diseases

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Calcium Ions Directly Interact with the Ebola Virus Fusion Peptide To Promote Structure-Function Changes That Enhance Infection.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2019-12-10 , DOI: 10.1021/acsinfecdis.9b00296
Lakshmi Nathan ₁ , Alex L Lai ₂ , Jean Kaoru Millet ₃ , Marco R Straus ₃ , Jack H Freed ₂ , Gary R Whittaker ₃ , Susan Daniel ₁

Affiliation

Ebola virus disease is a serious global health concern given its periodic occurrence, high lethality, and the lack of approved therapeutics. Certain drugs that alter intracellular calcium, particularly in endolysosomes, have been shown to inhibit Ebola virus infection; however, the underlying mechanism is unknown. Here, we provide evidence that Zaire ebolavirus (EBOV) infection is promoted in the presence of calcium as a result of the direct interaction of calcium with the EBOV fusion peptide (FP). We identify the glycoprotein residues D522 and E540 in the FP as functionally critical to EBOV's interaction with calcium. We show using spectroscopic and biophysical assays that interactions of the fusion peptide with Ca2+ ions lead to lipid ordering in the host membrane during membrane fusion, and these changes are promoted at low pH and can be correlated with infectivity. We further demonstrate using circular dichroism spectroscopy that calcium interaction with the fusion peptide promotes α-helical structure of the fusion peptide, a conformational change that enhances membrane fusion, as validated using functional assays of membrane fusion. This study shows that calcium directly targets the Ebola virus fusion peptide and influences its conformation. As these residues are highly conserved across the Filoviridae, calcium's impact on fusion, and subsequently infectivity, is a key interaction that can be leveraged for developing strategies to defend against Ebola infection. This mechanistic insight provides a rationale for the use of calcium-interfering drugs already approved by the FDA as therapeutics against Ebola and enables further development of novel drugs to combat the virus.

中文翻译：

钙离子与埃博拉病毒融合肽直接相互作用，以促进增强感染的结构功能变化。

埃博拉病毒病的周期性发作，高致死率和缺乏批准的治疗方法，已成为严重的全球性健康问题。某些改变细胞内钙的药物，特别是在溶酶体中，已显示抑制埃博拉病毒感染。但是，其潜在机制尚不清楚。在这里，我们提供的证据表明，由于钙与EBOV融合肽（FP）的直接相互作用，在钙存在下促进了扎伊尔埃博拉病毒（EBOV）感染。我们将FP中的糖蛋白残基D522和E540鉴定为对EBOV与钙相互作用的功能至关重要。我们使用光谱和生物物理分析方法表明，融合肽与Ca2 +离子的相互作用导致膜融合过程中宿主膜中的脂质有序化，这些变化在低pH值时会促进，并可能与传染性相关。我们进一步证明了使用圆二色性光谱，与融合肽的钙相互作用促进了融合肽的α螺旋结构，这是一种增强膜融合的构象变化，已通过膜融合的功能测定得到验证。这项研究表明钙直接靶向埃博拉病毒融合肽并影响其构象。由于这些残基在整个丝虫科中高度保守，因此钙对融合的影响以及随后的传染性是关键的相互作用，可以利用该相互作用来制定防御埃博拉病毒感染的策略。

更新日期：2019-12-11

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