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Human Cathelicidin Inhibits SARS-CoV-2 Infection: Killing Two Birds with One Stone.

ABSTRACT: SARS-CoV-2 infection begins with the association of its spike 1 (S1) protein with host angiotensin-converting enzyme-2 (ACE2). Targeting the interaction between S1 and ACE2 is a practical strategy against SARS-CoV-2 infection. Herein, we show encouraging results indicating that human cathelicidin LL37 can simultaneously block viral S1 and cloak ACE2. LL37 binds to the receptor-binding domain (RBD) of S1 with high affinity (11.2 nM) and decreases subsequent recruitment of ACE2. Owing to the RBD blockade, LL37 inhibits SARS-CoV-2 S pseudovirion infection, with a half-maximal inhibitory concentration of 4.74 μg/mL. Interestingly, LL37 also binds to ACE2 with an affinity of 25.5 nM and cloaks the ligand-binding domain (LBD), thereby decreasing S1 adherence and protecting cells against pseudovirion infection in vitro. Intranasal administration of LL37 to C57 mice infected with adenovirus expressing human ACE2 either before or after pseudovirion invasion decreased lung infection. The study identified a versatile antimicrobial peptide in humans as an inhibitor of SARS-CoV-2 attachment using dual mechanisms, thus providing a potential candidate for coronavirus disease 2019 (COVID-19) prevention and treatment.

SUBMITTER: Wang C

PROVIDER: S-EPMC8056948 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Human Cathelicidin Inhibits SARS-CoV-2 Infection: Killing Two Birds with One Stone.

Wang Cheng C Wang Shaobo S Li Daixi D Chen Peiqin P Han Songling S Zhao Gaomei G Chen Yin Y Zhao Jianqi J Xiong Jiachuan J Qiu Jingfei J Wei Dong-Qing DQ Zhao Jinghong J Wang Junping J

ACS infectious diseases 20210414 6

SARS-CoV-2 infection begins with the association of its spike 1 (S1) protein with host angiotensin-converting enzyme-2 (ACE2). Targeting the interaction between S1 and ACE2 is a practical strategy against SARS-CoV-2 infection. Herein, we show encouraging results indicating that human cathelicidin LL37 can simultaneously block viral S1 and cloak ACE2. LL37 binds to the receptor-binding domain (RBD) of S1 with high affinity (11.2 nM) and decreases subsequent recruitment of ACE2. Owing to the RBD b ...[more]

PMID: 33849267

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Project description:Background and objectiveThe videofluoroscopic swallowing study (VFSS) is a gold-standard imaging technique for assessing swallowing, but analysis and rating of VFSS recordings is time consuming and requires specialized training and expertise. Researchers have recently demonstrated that it is possible to automatically detect the pharyngeal phase of swallowing and to localize the bolus in VFSS recordings via computer vision approaches, fostering the development of novel techniques for automatic VFSS analysis. However, training of algorithms to perform these tasks requires large amounts of annotated data that are seldom available. In this paper, we demonstrate that the challenges of pharyngeal phase detection and bolus localization can be solved together using a single approach.MethodsWe propose a deep-learning framework that jointly tackles pharyngeal phase detection and bolus localization in a weakly-supervised manner, requiring only the initial and final frames of the pharyngeal phase as ground truth annotations for the training. Our approach stems from the observation that bolus presence in the pharynx is the most prominent visual feature upon which to infer whether individual VFSS frames belong to the pharyngeal phase. We conducted extensive experiments with multiple convolutional neural networks (CNNs) on a dataset of 1245 bolus-level clips from 59 healthy subjects.ResultsWe demonstrated that the pharyngeal phase can be detected with an F1-score higher than 0.9. Moreover, by processing the class activation maps of the CNNs, we were able to localize the bolus with promising results, obtaining correlations with ground truth trajectories higher than 0.9, without any manual annotations of bolus location used for training purposes.ConclusionsOnce validated on a larger sample of participants with swallowing disorders, our framework will pave the way for the development of intelligent tools for VFSS analysis to support clinicians in swallowing assessment.

Dataset Information

Human Cathelicidin Inhibits SARS-CoV-2 Infection: Killing Two Birds with One Stone.

Publications

Human Cathelicidin Inhibits SARS-CoV-2 Infection: Killing Two Birds with One Stone.

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