Current Understanding of the Role of Cholesterol in the Life Cycle of Alphaviruses

Sousa, Ivanildo P.; Carvalho, Carlos Alberto Marques de; Gomes, Andre M. O.

doi:10.3390/v13010035

Cited by 16 publications

(13 citation statements)

References 87 publications

(121 reference statements)

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“…Further elucidation of the latter and how it is modulated by viruses thus presents as important aspect of focus. After cholesterol-dependent steps in endocytosis, shuttling of the lipid within virus-containing endosomes further is important for the uncoating, and therefore for final cellular entry, of enveloped viruses, such as members of the Filoviridae family, IAV, HIV, SARS-CoV-2, and Alphaviruses ( Schroeder, 2010 ; Carette et al, 2011 ; Côté et al, 2011 ; Garcia-Dorival et al, 2020 ; Martyna et al, 2020 ; Sousa et al, 2020 ). This process is reported to be mediated via cholesterol-shuttling proteins, such as NPC1.…”

Section: Endosomal Cholesterol Trafficking As Shared Feature In Viral Infectionsmentioning

confidence: 99%

Endosomal Cholesterol in Viral Infections – A Common Denominator?

Glitscher

Hildt

2021

Front. Physiol.

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Cholesterol has gained tremendous attention as an essential lipid in the life cycle of virtually all viruses. These seem to have developed manifold strategies to modulate the cholesterol metabolism to the side of lipid uptake and de novo synthesis. In turn, affecting the cholesterol homeostasis has emerged as novel broad-spectrum antiviral strategy. On the other hand, the innate immune system is similarly regulated by the lipid and stimulated by its derivatives. This certainly requires attention in the design of antiviral strategies aiming to decrease cellular cholesterol, as evidence accumulates that withdrawal of cholesterol hampers innate immunity. Secondly, there are exceptions to the rule of the abovementioned virus-induced metabolic shift toward cholesterol anabolism. It therefore is of interest to dissect underlying regulatory mechanisms, which we aimed for in this minireview. We further collected evidence for intracellular cholesterol concentrations being less important in viral life cycles as compared to the spatial distribution of the lipid. Various routes of cholesterol trafficking were found to be hijacked in viral infections with respect to organelle-endosome contact sites mediating cholesterol shuttling. Thus, re-distribution of cellular cholesterol in the context of viral infections requires more attention in ongoing research. As a final aim, a pan-antiviral treatment could be found just within the transport and re-adjustment of local cholesterol concentrations. Thus, we aimed to emphasize the importance of the regulatory roles the endosomal system fulfils herein and hope to stimulate research in this field.

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Section: Endosomal Cholesterol Trafficking As Shared Feature In Viral Infectionsmentioning

confidence: 99%

Endosomal Cholesterol in Viral Infections – A Common Denominator?

Glitscher

Hildt

2021

Front. Physiol.

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“…Targeting the endolysosomal cholesterol environment could be harnessed as an avenue for broadly acting antiviral drug development. Viruses from different families like coronaviruses, influenza A virus, filoviruses like Ebola, arthropod-borne alphaviruses (Sousa et al, 2020) and flaviviruses (Pombo and Sanyal, 2018) require endosomal escape of the infecting virion through fusion of viral and cellular membranes in the endosomal compartment. Modulation of endolysosomal cholesterol levels may thus influence the rate of this fusion event.…”

Section: Discussionmentioning

confidence: 99%

Posaconazole inhibits multiple steps of the alphavirus replication cycle

et al. 2022

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Repurposing drugs is a promising strategy to identify therapeutic interventions against novel and re-emerging viruses. Posaconazole is an antifungal drug used to treat invasive aspergillosis and candidiasis. Recently, posaconazole and its structural analog, itraconazole were shown to inhibit replication of multiple viruses by modifying intracellular cholesterol homeostasis. Here, we show that posaconazole inhibits replication of the alphaviruses Semliki Forest virus (SFV), Sindbis virus and chikungunya virus with EC 50 values ranging from 1.4 μM to 9.5 μM. Posaconazole treatment led to a significant reduction of virus entry in an assay using a temperature-sensitive SFV mutant, but time-of-addition and RNA transfection assays indicated that posaconazole also inhibits post-entry stages of the viral replication cycle. Virus replication in the presence of posaconazole was partially rescued by the addition of exogenous cholesterol. A transferrin uptake assay revealed that posaconazole considerably slowed down cellular endocytosis. A single point mutation in the SFV E2 glycoprotein, H255R, provided partial resistance to posaconazole as well as to methyl-β-cyclodextrin, corroborating the effect of posaconazole on cholesterol and viral entry. Our results indicate that posaconazole inhibits multiple steps of the alphavirus replication cycle and broaden the spectrum of viruses that can be targeted in vitro by posaconazole, which could be further explored as a therapeutic agent against emerging viruses.

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“…Furthermore, different cholesterol levels in hosts generate different envelope cholesterol levels in alphaviruses ( 177 ). When compared with mayaro virus particles from mosquito cells, virus particle envelopes from vertebrate cells have higher cholesterol levels ( 178 ). In terms of coronaviruses, Simons et al found that although MHV- S protein was localized to the Golgi, that contained cholesterol and lipid rafts, the assembled and released of MHV is not associated with cholesterol ( 167 ).…”

Section: The Role Of Cholesterol Metabolism During the Coronavirus Li...mentioning

confidence: 99%

Coronavirus Infection and Cholesterol Metabolism

et al. 2022

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Host cholesterol metabolism remodeling is significantly associated with the spread of human pathogenic coronaviruses, suggesting virus-host relationships could be affected by cholesterol-modifying drugs. Cholesterol has an important role in coronavirus entry, membrane fusion, and pathological syncytia formation, therefore cholesterol metabolic mechanisms may be promising drug targets for coronavirus infections. Moreover, cholesterol and its metabolizing enzymes or corresponding natural products exert antiviral effects which are closely associated with individual viral steps during coronavirus replication. Furthermore, the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 infections are associated with clinically significant low cholesterol levels, suggesting cholesterol could function as a potential marker for monitoring viral infection status. Therefore, weaponizing cholesterol dysregulation against viral infection could be an effective antiviral strategy. In this review, we comprehensively review the literature to clarify how coronaviruses exploit host cholesterol metabolism to accommodate viral replication requirements and interfere with host immune responses. We also focus on targeting cholesterol homeostasis to interfere with critical steps during coronavirus infection.

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Current Understanding of the Role of Cholesterol in the Life Cycle of Alphaviruses

Cited by 16 publications

References 87 publications

Endosomal Cholesterol in Viral Infections – A Common Denominator?

Endosomal Cholesterol in Viral Infections – A Common Denominator?

Posaconazole inhibits multiple steps of the alphavirus replication cycle

Coronavirus Infection and Cholesterol Metabolism

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