Studies of Lassa Virus Cell Entry

Pasquato, Antonella; Fernandez, Antonio Herrador; Kunz, Stefan

doi:10.1007/978-1-4939-6981-4_9

Cited by 7 publications

(4 citation statements)

References 45 publications

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“…It is a reversible inhibitor and shows high specificity for Axl over other RTKs in cell-based assays [ 83 , 84 ], without affecting Axl RTK expression ( Figure 1 B). Because of the potential compensatory effect or off-target effects, such as Tie-2, Ftl-1, Flt-3, Ret, or Abl [ 83 ], we chose a short time window of drug action, combined with drug washout, assuring micro-reversibility, and therefore minimized potential consequences of the R428 administration and allowed us to dissect the Axl RTK role during LASV entry [ 85 ] ( Figure 1 C). Moreover, R428 is currently in phase II clinical trials for human anticancer therapy and has a favorable toxicity profile, suggesting minimal off-target effects [ 84 , 86 ].…”

Section: Resultsmentioning

confidence: 99%

The Role of Receptor Tyrosine Kinases in Lassa Virus Cell Entry

Fedeli¹,

Moreno²,

Kunz³

2020

Viruses

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The zoonotic Old World mammarenavirus Lassa (LASV) causes severe hemorrhagic fever with high mortality and morbidity in humans in endemic regions. The development of effective strategies to combat LASV infections is of high priority, given the lack of a licensed vaccine and restriction on available treatment to off-label use of ribavirin. A better understanding of the fundamental aspects of the virus’s life cycle would help to improve the development of novel therapeutic approaches. Host cell entry and restriction factors represent major barriers for emerging viruses and are promising targets for therapeutic intervention. In addition to the LASV main receptor, the extracellular matrix molecule dystroglycan (DG), the phosphatidylserine-binding receptors of the Tyro3/Axl/Mer (TAM), and T cell immunoglobulin and mucin receptor (TIM) families are potential alternative receptors of LASV infection. Therefore, the relative contributions of candidate receptors to LASV entry into a particular human cell type are a complex function of receptor expression and functional DG availability. Here, we describe the role of two receptor tyrosine kinases (RTKs), Axl and hepatocyte growth factor receptor (HGFR), in the presence and absence of glycosylated DG for LASV entry. We found that both RTKs participated in the macropinocytosis-related LASV entry and, regardless of the presence or absence of functional DG, their inhibition resulted in a significant antiviral effect.

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Section: Resultsmentioning

confidence: 99%

The Role of Receptor Tyrosine Kinases in Lassa Virus Cell Entry

Fedeli¹,

Moreno²,

Kunz³

2020

Viruses

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“…As bergamottin did not exert an inhibitory effect on the virucidal, binding, or fusion step, we hypothesized that it might inhibit endocytic trafficking. To address this, we quantitatively compared the inhibition of the endocytic efficiency by bergamottin with the acidification antagonist NH Cl (18,19). As shown in Fig.…”

Section: Bergamottin Blocks Lasv Endocytic Traffickingmentioning

confidence: 99%

Screening of Botanical Drugs against Lassa Virus Entry

Liu

Guo

Cao

et al. 2021

J Virol

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Lassa virus (LASV) belongs to the Old World Mammarenavirus genus (family Arenaviridae). At present, there are no approved drugs or vaccines specific for LASV. In this study, high-throughput screening of a botanical drug library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein complex (GPC). Two hit compounds, bergamottin and casticin, were identified as micromolar range inhibitors of LASV entry. A mechanistic study revealed that casticin inhibited LASV entry by blocking low pH-induced membrane fusion. Analysis of adaptive mutants demonstrated that the F446L mutation, located in the transmembrane domain of GP2, conferred resistance to casticin. Furthermore, casticin antiviral activity extends to the New World (NW) pathogenic mammarenaviruses, and mutation of the conserved F446 also conferred resistance to casticin in these viruses. Unlike casticin, bergamottin showed little effect on LASV GPC-mediated membrane fusion, instead inhibiting LASV entry by blocking endocytic trafficking. Notably, both compounds showed inhibitory effects on authentic lymphocytic choriomeningitis virus. Our study shows that both casticin and bergamottin are candidates for LASV therapy and that the conserved F446 in LASV GPC is important in drug resistance in mammarenaviruses. IMPORTANCE: Currently, there is no approved therapy to treat Lassa fever (LASF). Our goal was to identify potential candidate molecules for LASF therapy. Herein, we screened a botanical drug library and identified two compounds, casticin and bergamottin, that inhibited LASV entry via different mechanisms.

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“…We limit the scope of our review to virus binding and entry. Other publications detailing events post cell-entry and broader aspects of arenaviruses have been published [ 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Lassa Fever Virus Binds Matriglycan—A Polymer of Alternating Xylose and Glucuronate—On α-Dystroglycan

Joseph

Campbell

2021

Viruses

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Lassa fever virus (LASV) can cause life-threatening hemorrhagic fevers for which there are currently no vaccines or targeted treatments. The late Prof. Stefan Kunz, along with others, showed that the high-affinity host receptor for LASV, and other Old World and clade-C New World mammarenaviruses, is matriglycan—a linear repeating disaccharide of alternating xylose and glucuronic acid that is polymerized uniquely on α-dystroglycan by like-acetylglucosaminyltransferase-1 (LARGE1). Although α-dystroglycan is ubiquitously expressed, LASV preferentially infects vascular endothelia and professional phagocytic cells, which suggests that viral entry requires additional cell-specific factors. In this review, we highlight the work of Stefan Kunz detailing the molecular mechanism of LASV binding and discuss the requirements of receptors, such as tyrosine kinases, for internalization through apoptotic mimicry.

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Studies of Lassa Virus Cell Entry

Cited by 7 publications

References 45 publications

The Role of Receptor Tyrosine Kinases in Lassa Virus Cell Entry

The Role of Receptor Tyrosine Kinases in Lassa Virus Cell Entry

Screening of Botanical Drugs against Lassa Virus Entry

Lassa Fever Virus Binds Matriglycan—A Polymer of Alternating Xylose and Glucuronate—On α-Dystroglycan

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