Critical role for cholesterol in Lassa fever virus entry identified by a novel small molecule inhibitor targeting the viral receptor LAMP1

Wang, May Kwang-Mei; Ren, Tao; Liu, Hu; Lim, Sun-Young; Lee, Kyung-Ae; Honko, Anna N.; Zhou, Huanying; Dyall, Julie; Hensley, Lisa E.; K, Gartin Ashley; Cunningham, James M.

doi:10.1371/journal.ppat.1007322

Cited by 20 publications

(13 citation statements)

References 37 publications

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“…Promising new compounds against LASV have been identified (6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), but the limited geographical endemicity of LASV, its inefficient person-to-person transmission, and low reinfection rates make the prospect of collecting adequate clinical trial data on new drugs challenging. Thus, a practical approach to more expeditiously grow the arsenal of drugs against these highly pathogenic viruses is to screen approved drugs for antiviral activity.…”

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confidence: 99%

“…Viral entry inhibitors are valuable as therapeutics, since blocking infection early in the life cycle will reduce cellular and tissue damage associated with the replication of incoming viruses and the production of viral progeny. LASV employs several key features in common with EBOV for its entry: (i) it is internalized into the endocytic pathway by a macropinocytotic-like process after initial contact with surface receptors/ attachment factors, (ii) low pH is needed to trigger fusion, and (iii) an endosomal, cholesterol binding receptor promotes endosomal escape (Lamp1 for LASV and NPC1 for EBOV) (12,(25)(26)(27)(28)(29)(30)(31)(32). Hence, for this study, we selected eight low-molecular-weight drugs shown to inhibit EBOV entry and directly compared their inhibitory activities against LASV and EBOV.…”

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confidence: 99%

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Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses

Hulseberg

Fénéant

Wijs

et al. 2019

J Virol

128

138

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Antiviral therapies that impede virus entry are attractive because they act on the first phase of the infectious cycle. Drugs that target pathways common to multiple viruses are particularly desirable when laboratory-based viral identification may be challenging, e.g., in an outbreak setting. We are interested in identifying drugs that block both Ebola virus (EBOV) and Lassa virus (LASV), two unrelated but highly pathogenic hemorrhagic fever viruses that have caused outbreaks in similar regions in Africa and share features of virus entry: use of cell surface attachment factors, macropinocytosis, endosomal receptors, and low pH to trigger fusion in late endosomes. Toward this goal, we directly compared the potency of eight drugs known to block EBOV entry with their potency as inhibitors of LASV entry. Five drugs (amodiaquine, apilimod, arbidol, niclosamide, and zoniporide) showed roughly equivalent degrees of inhibition of LASV and EBOV glycoprotein (GP)-bearing pseudoviruses; three (clomiphene, sertraline, and toremifene) were more potent against EBOV. We then focused on arbidol, which is licensed abroad as an anti-influenza drug and exhibits activity against a diverse array of clinically relevant viruses. We found that arbidol inhibits infection by authentic LASV, inhibits LASV GP-mediated cell-cell fusion and virus-cell fusion, and, reminiscent of its activity on influenza virus hemagglutinin, stabilizes LASV GP to low-pH exposure. Our findings suggest that arbidol inhibits LASV fusion, which may partly involve blocking conformational changes in LASV GP. We discuss our findings in terms of the potential to develop a drug cocktail that could inhibit both LASV and EBOV. IMPORTANCE Lassa and Ebola viruses continue to cause severe outbreaks in humans, yet there are only limited therapeutic options to treat the deadly hemorrhagic fever diseases they cause. Because of overlapping geographic occurrences and similarities in mode of entry into cells, we seek a practical drug or drug cocktail that could be used to treat infections by both viruses. Toward this goal, we directly compared eight drugs, approved or in clinical testing, for the ability to block entry mediated by the glycoproteins of both viruses. We identified five drugs with approximately equal potencies against both. Among these, we investigated the modes of action of arbidol, a drug licensed abroad to treat influenza infections. We found, as shown for influenza virus, that arbidol blocks fusion mediated by the Lassa virus glycoprotein. Our findings encourage the development of a combination of approved drugs to treat both Lassa and Ebola virus diseases. FIG 2 Comparative effects of arbidol on infection by MLV pseudoviruses bearing LASV or other viral glycoproteins: LASV, LCMV, and Junin GP (A) and LASV GP and influenza virus HA (B). MLV pseudoviruses bearing LASV GP, LCMV GP, Junin GP, or WSN influenza HA and NA were prepared as described in Materials and Methods. BSC-1 cells were pretreated with the indicated concentrations of arbidol and then processed an...

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confidence: 99%

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confidence: 99%

Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses

Hulseberg

Fénéant

Wijs

et al. 2019

J Virol

128

138

View full text Add to dashboard Cite

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“…The autoantibodies we identified against TRIM proteins, other than TRIM33 and TRIM21, have not been observed previously in IIM. TRIM69 inhibits vesicular stomatitis virus transcription and mediates poly-ubiquitination and degradation of dengue virus non-structural protein 3 40 , 41 . TRIMs also regulate antiviral pathways indirectly by mediating innate immunity, influencing the transcription of TI-IFNs, interferon-stimulated genes and pro-inflammatory cytokines 6 .…”

Section: Discussionmentioning

confidence: 99%

Analysis of human total antibody repertoires in TIF1γ autoantibody positive dermatomyositis

Megremis

Walker

et al. 2021

Commun Biol

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We investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. We observe antibodies recognizing a wider repertoire of microbial antigens in dermatomyositis. Antibodies recognizing viruses and Poxviridae family species are significantly enriched. The identified autoantibodies recognise a large portion of the human proteome, including interferon regulated proteins; these proteins cluster in specific biological processes. In addition to TRIM33, we identify autoantibodies against eleven further TRIM proteins, including TRIM21. Some of these TRIM proteins share epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis.

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“…The autoantibodies we identified against TRIM proteins, other than TRIM33 and TRIM21, have not been observed previously in IIM. TRIM69 inhibits vesicular stomatitis virus transcription and interacts with dengue virus non-structural protein 3 to mediate its poly-ubiquitination and degradation (Kueck et al, 2019;Wang et al, 2018). TRIMs also regulate antiviral pathways indirectly by mediating innate immunity, influencing the transcription of TI-IFNs, pro-inflammatory cytokines and interferon-stimulated genes (van Tol et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Microbial and autoantibody immunogenic repertoires in TIF1γ autoantibody positive dermatomyositis

Megremis

Walker

et al. 2020

Preprint

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We investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. Increased microbial diversity was observed in dermatomyositis. Viruses were over-represented and species of the Poxviridae family were significantly enriched. The autoantibodies identified recognised a large portion of the human proteome, including interferon regulated proteins; these proteins were clustered in specific biological processes. Apart from TRIM33, autoantibodies against eleven further TRIM proteins, including TRIM21, were identified. Some of these TRIM proteins shared epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a significant role in the pathogenesis of dermatomyositis.

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Critical role for cholesterol in Lassa fever virus entry identified by a novel small molecule inhibitor targeting the viral receptor LAMP1

Cited by 20 publications

References 37 publications

Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses

Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses

Analysis of human total antibody repertoires in TIF1γ autoantibody positive dermatomyositis

Microbial and autoantibody immunogenic repertoires in TIF1γ autoantibody positive dermatomyositis

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