SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle

Walia et al., Nature Communications, doi:10.1038/s41467-024-46417-2

Mar 2024

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In Vitro study showing that SARS-CoV-2 ORF3a protein hyperactivates the Rab7 GTPase to block lysosomal degradation and promote viral replication. Authors found that the chemical compound CID-1067700, a Rab7 inhibitor, reduced SARS-CoV-2 replication in infected Vero E6 cells, while the Rab7 activator ML-098 enhanced viral replication. The results suggest that Rab7 hyperactivation by the viral ORF3a protein is beneficial for SARS-CoV-2, likely by preventing the degradation of viral components in lysosomes. Inhibiting Rab7 with CID-1067700 impaired viral replication, indicating Rab7 could be a potential therapeutic target.

Niclosamide was used as a positive control and showed the most potent inhibition of SARS-CoV-2 replication in this study.

9 preclinical studies support the efficacy of niclosamide for COVID-19:

1 In Silico study1

8 In Vitro studies2-9

In Silico studies predict inhibition of SARS-CoV-2 with niclosamide or metabolites via binding to the spikeA,1, M^proB,1, RNA-dependent RNA polymeraseC,1, PLproD,1, nucleocapsidE,1, and helicaseF,1 proteins. Niclosamide inhibits endolysosomal acidification and suppresses TLR3-mediated pro-inflammatory signaling in human small airway epithelial cells stimulated with TLR3 agonists mimicking viral RNA2, modulates host lipid metabolism and reduces infectious SARS-CoV-2 virion production in Vero E6 cells4, reduces CD147 protein levels and inhibits SARS-CoV-2-induced upregulation of CD147 in A549-ACE2 cells, including the highly glycosylated form of CD147 which has been implicated in COVID-19 disease progression and post-COVID-19 cardiac complications5, blocked the formation of syncytia mediated by SARS-CoV-2 spike protein pseudovirus-producing cells6, may reduce inflammation, NLRP3 formation, and caspase-1 activity9, may inhibit viral uncoating, replication, and assembly via disruption of pH gradients and reduced ATP production in host cells8, and shows strong synergy when combined with ivermectin7.

Important missing comments or errors? Let us know.

1. Haque et al., Exploring potential therapeutic candidates against COVID-19: a molecular docking study, Discover Molecules, doi:10.1007/s44345-024-00005-5.springer.com, doi.org.

2. Pejler et al., Blockade of endolysosomal acidification suppresses TLR3-mediated pro-inflammatory signaling in airway epithelial cells, Journal of Allergy and Clinical Immunology, doi:10.1016/j.jaci.2024.05.031.sciencedirect.com, doi.org.

3. Walia et al., SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle, Nature Communications, doi:10.1038/s41467-024-46417-2.nature.com, doi.org.

4. Garrett et al., Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism, Frontiers in Microbiology, doi:10.3389/fmicb.2023.1251065.frontiersin.org, doi.org.

5. Yang et al., Repurposing Niclosamide as a Novel Anti-SARS-CoV-2 Drug by Restricting Entry Protein CD147, Biomedicines, doi:10.3390/biomedicines11072019.mdpi.com, doi.org.

6. Sheng et al., A pseudovirus-based method to dynamically mimic SARS-CoV-2-associated cell-to-cell fusion and transmission, Acta Biochimica et Biophysica Sinica, doi:10.3724/abbs.2023129.scichina.com, doi.org.

7. Jitobaom et al., Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations, BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8.biomedcentral.com, doi.org.

8. Needham, D., The pH Dependence of Niclosamide Solubility, Dissolution, and Morphology: Motivation for Potentially Universal Mucin-Penetrating Nasal and Throat Sprays for COVID19, its Variants and other Viral Infections, Pharmaceutical Research, doi:10.1007/s11095-021-03112-x.springer.com, doi.org.

9. Munson et al., Niclosamide and ivermectin modulate caspase-1 activity and proinflammatory cytokine secretion in a monocytic cell line, British Society For Nanomedicine Early Career Researcher Summer Meeting, 2021, web.archive.org/web/20230401070026/https://michealmunson.github.io/COVID.pdf.archive.org.

a. The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.

b. The main protease or M^pro, also known as 3CL^pro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting M^pro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.

c. RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.

d. The papain-like protease (PLpro) has multiple functions including cleaving viral polyproteins and suppressing the host immune response by deubiquitination and deISGylation of host proteins. Inhibiting PLpro may block viral replication and help restore normal immune responses.

e. The nucleocapsid (N) protein binds and encapsulates the viral genome by coating the viral RNA. N enables formation and release of infectious virions and plays additional roles in viral replication and pathogenesis. N is also an immunodominant antigen used in diagnostic assays.

f. The helicase, or nsp13, protein unwinds the double-stranded viral RNA, a crucial step in replication and transcription. Inhibition may prevent viral genome replication and the creation of new virus components.

Walia et al., 6 Mar 2024, peer-reviewed, 8 authors. Contact: atuli@imtech.res.in.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Niclosamide All

Abstract: Article https://doi.org/10.1038/s41467-024-46417-2 SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5dependent Rab7 GTPase cycle Received: 12 June 2023 Check for updates 1234567890():,; 1234567890():,; Accepted: 26 February 2024 Kshitiz Walia1,2, Abhishek Sharma1, Sankalita Paul3, Priya Chouhan1,2, Gaurav Kumar 1, Rajesh Ringe1, Mahak Sharma 3 & Amit Tuli 1,2 SARS-CoV-2, the causative agent of COVID-19, uses the host endolysosomal system for entry, replication, and egress. Previous studies have shown that the SARS-CoV-2 virulence factor ORF3a interacts with the lysosomal tethering factor HOPS complex and blocks HOPS-mediated late endosome and autophagosome fusion with lysosomes. Here, we report that SARS-CoV-2 infection leads to hyperactivation of the late endosomal and lysosomal small GTPbinding protein Rab7, which is dependent on ORF3a expression. We also observed Rab7 hyperactivation in naturally occurring ORF3a variants encoded by distinct SARS-CoV-2 variants. We found that ORF3a, in complex with Vps39, sequesters the Rab7 GAP TBC1D5 and displaces Rab7 from this complex. Thus, ORF3a disrupts the GTP hydrolysis cycle of Rab7, which is beneﬁcial for viral production, whereas the Rab7 GDP-locked mutant strongly reduces viral replication. Hyperactivation of Rab7 in ORF3a-expressing cells impaired CIM6PR retrieval from late endosomes to the trans-Golgi network, disrupting the biosynthetic transport of newly synthesized hydrolases to lysosomes. Furthermore, the tethering of the Rab7- and Arl8b-positive compartments was strikingly reduced upon ORF3a expression. As SARS-CoV-2 egress requires Arl8b, these ﬁndings suggest that ORF3a-mediated hyperactivation of Rab7 serves a multitude of functions, including blocking endolysosome formation, interrupting the transport of lysosomal hydrolases, and promoting viral egress. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the agent responsible for coronavirus disease 2019 (COVID-19), is a positive sense single-stranded RNA virus belonging to the beta-coronavirus (β-CoV) genus. Positive-sense RNA viruses are known to modify endomembrane compartments to produce replication compartments (RCs). These RCs contain viral RNA and proteins, in addition to host proteins and lipids, and provide a barrier between viral replication and the host cytosol, which contains the viral RNA degradation machinery and innate immune sensors1,2. The viral particles formed from structural proteins assemble in the ER-Golgi intermediate compartment. Ultimately, virions transit in vesicles and undergo exocytosis via the biosynthetic secretory pathway3. Interestingly, another mechanism for extracellular release, in which virions reside in deacidiﬁed lysosomes that fuse with the plasma membrane has recently been reported for β-CoVs, including SARS-CoV-24. The genomic size of SARS-CoV-2 ranges from 29.8 kb to 29.9 kb, encompassing eleven genes with open reading frames (ORFs)5,6. The 5’ genomic region constitutes more than two-thirds of the genome and 1 Division of Cell Biology and Immunology, CSIR-Institute of Microbial Technology (IMTECH), Chandigarh, India. 2Academy of Scientiﬁc and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India. 3Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Mohali, e-mail: atuli@imtech.res.in Punjab, India. Nature Communications | (2024)15:2053 1 Article encodes the ORF1ab polyproteins. In..

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