Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism

Timothy J Garrett; Heather Coatsworth; Iqbal Mahmud; Timothy Hamerly; Caroline J Stephenson; Jasmine B Ayers; Hoda S Yazd; Megan R Miller; John A Lednicky; Rhoel R Dinglasan

doi:10.3389/fmicb.2023.1251065

Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism

Front Microbiol. 2023 Oct 11:14:1251065. doi: 10.3389/fmicb.2023.1251065. eCollection 2023.

Authors

Timothy J Garrett^{1

2}, Heather Coatsworth^{3

4}, Iqbal Mahmud^{1

2}, Timothy Hamerly^{3

4}, Caroline J Stephenson^{3

5}, Jasmine B Ayers^{3

4}, Hoda S Yazd⁶, Megan R Miller^{3

4}, John A Lednicky^{3

5}, Rhoel R Dinglasan^{3

4}

Affiliations

¹ Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, United States.
² Southeast Center for Integrated Metabolomics, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, United States.
³ Emerging Pathogens Institute, University of Florida, Gainesville, FL, United States.
⁴ Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States.
⁵ Department of Environmental and Global Health, College of Public Health and Health Professions, University of Florida, Gainesville, FL, United States.
⁶ Department of Chemistry, University of Florida, Gainesville, FL, United States.

Abstract

Introduction: SARS-CoV-2 subverts host cell processes to facilitate rapid replication and dissemination, and this leads to pathological inflammation.

Methods: We used niclosamide (NIC), a poorly soluble anti-helminth drug identified initially for repurposed treatment of COVID-19, which activates the cells' autophagic and lipophagic processes as a chemical probe to determine if it can modulate the host cell's total lipid profile that would otherwise be either amplified or reduced during SARS-CoV-2 infection.

Results: Through parallel lipidomic and transcriptomic analyses we observed massive reorganization of lipid profiles of SARS-CoV-2 infected Vero E6 cells, especially with triglycerides, which were elevated early during virus replication, but decreased thereafter, as well as plasmalogens, which were elevated at later timepoints during virus replication, but were also elevated under normal cell growth. These findings suggested a complex interplay of lipid profile reorganization involving plasmalogen metabolism. We also observed that NIC treatment of both low and high viral loads does not affect virus entry. Instead, NIC treatment reduced the abundance of plasmalogens, diacylglycerides, and ceramides, which we found elevated during virus infection in the absence of NIC, resulting in a significant reduction in the production of infectious virions. Unexpectedly, at higher viral loads, NIC treatment also resulted in elevated triglyceride levels, and induced significant changes in phospholipid metabolism.

Discussion: We posit that future screens of approved or new partner drugs should prioritize compounds that effectively counter SARS-CoV-2 subversion of lipid metabolism, thereby reducing virus replication, egress, and the subsequent regulation of key lipid mediators of pathological inflammation.

Keywords: COVID-19; RNA sequencing; antiviral; autophagy; lipidomics; lipophagy; metabolism.

Grants and funding

This work was funded in part by support from the University of Florida Preeminence Initiative through the College of Veterinary Medicine and the Emerging Pathogens Institute (RRD).