Abstract
The aim of this research is twofold: 1) to shed light on zika’s binding and entry mechanism while 2) demonstrating the effectiveness of our magnetic relaxation platform to achieve this goal. Magnetic relaxation-sensitive nanoparticles (MRNPs) are used in a novel fashion to analyze binding interactions between the zika envelope protein (ZENV) and proposed host cell receptors: AXL, HSP70, and TIM-1. Computational analysis is also utilized to examine these binding interactions for the first time. In addition, the role of crizotinib as a potential binding inhibitor is demonstrated and the possibility of ligand-independent phosphatidylserine-mediated binding is explored. Our findings suggest that while the extracellular domain of AXL has the highest affinity for ZENV; HSP70, TIM-1, and phosphatidylserine might also play active roles in zika tropism, which offers a potential explanation for the variety of zika-associated symptoms. This is, to our knowledge, the first time that MRNPs have been used to examine and quantify host-zika interactions. Our magnetic relaxation platform allows for timely and sensitive analysis of these intricate binding relationships, and it is easily customizable for further examination of additional host-pathogen interactions.
Highlights
Often, infection by ZIKV results in mild to non-observable symptoms[6]
Receptors and antibodies are conjugated to the surface carboxylic acid groups of iron oxide nanoparticles28 (IONPs) using EDC/NHS chemistry which functionalizes the nanoparticles (MRNPs) for targeted binding with ZENV
When binding occurs between the MRNPs and ZENV in solution, the surrounding water molecules are displaced from the nanoparticle and magnetic relaxation times (T2) increase
Summary
What makes zika an outlier when compared to other viruses is the rare appearance of additional symptoms, including microcephaly and Guillain-Barre syndrome[6, 7]. This unexplained array of symptoms may be the result of promiscuous and ambiguous activity of ZENV. Ligand independent activation of AXL is known to occur with its overexpression and does not depend upon its kinase activity[15] Based upon these reports, AXL was selected for this study. PS has been associated with apoptotic mimicry and host-cell entry in a number of viruses, including other flaviviruses[25,26,27], and may have a role in ZIKV binding and entry. In contrast to other flaviviruses, ZIKV remains infective at a wider range of temperatures[22] and pH values[23], which have been further characterized in this work
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