Untargeted Lipidomics of Vesicular Stomatitis Virus-Infected Cells and Viral Particles

Havranek, Katherine E.; Ballista, Judith Mary Reyes; Hines, Kelly M.; Brindley, Melinda A.

doi:10.3390/v14010003

Cited by 8 publications

(4 citation statements)

References 59 publications

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“…Thus, it is reasonable to propose that the accumulation of dhSM may result in the stiffening of the cellular membranes and that this would severely affect multiple steps of WNV infection. The antiviral activity of AL-088 and AL-274 exerted against VSV is also consistent with previous reports indicating that sphingolipids may account for multiple roles during VSV infection ( 56 – 58 ).…”

Section: Discussionsupporting

confidence: 91%

Pharmacological Elevation of Cellular Dihydrosphingomyelin Provides a Novel Antiviral Strategy against West Nile Virus Infection

Oya

San‐Félix

Casasampere

et al. 2023

Antimicrob Agents Chemother

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Section: Discussionsupporting

confidence: 91%

Pharmacological Elevation of Cellular Dihydrosphingomyelin Provides a Novel Antiviral Strategy against West Nile Virus Infection

Oya

San‐Félix

Casasampere

et al. 2023

Antimicrob Agents Chemother

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“…Lipidomic analyses. Lipids were extracted from T. cruzi samples using a modified Bligh & Dyer method (54,55). Dried lipid extracts were reconstituted in 500 µL of 1:1 chloroform/methanol.…”

Section: Discussionmentioning

confidence: 99%

Endocytosis inTrypanosoma cruziDepends on Proper Recruitment and Regulation of Functionally Redundant Myosin Motors

Chasen

Etheridge

Campbell

et al. 2022

Preprint

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The cytostome-cytopharynx complex (SPC) is an endocytic organelle absent from all human trypanosomatid pathogens save Trypanosoma cruzi. Building upon our previous work identifying the myosin motor MyoF as the first enzymatic component of the T. cruzi SPC, we sought to expand our understanding of this organelle by identifying additional protein machinery which contribute to endocytosis. While deletion of MyoF alone did not fully ablate endocytosis, we found that deletion of both MyoF and the similarly localized MyoC produced an endocytic-null phenotype that was rescued upon complementation. To identify potential regulatory components of this motor complex, we pulled down MyoF and identified an SPC-targeted protein that was conserved across a wide range of protozoan lineages. Deletion of this myosin associated protein (MyAP) alone was sufficient to produce an endocytic-null phenotype, which we were able to fully rescue via complementation. The deletion of MyAP also caused the mis-localization of both cytopharynx myosins to the cytosol. While MyAP lacking the EF-hand domain was unable to complement endocytosis, it was sufficient to restore proper myosin localization. This suggested that MyAP plays two distinct roles, one in targeting myosins to the SPC and a second in regulating myosin motor activity. Lipidomic analysis subsequently revealed a dramatic reduction in the scavenged cholesterol content in the endocytic-null mutants. Overall, this work showcases the first viable endocytic-null mutants generated in T. cruzi through specific gene deletion and highlights the feasibility of leveraging this strategy towards a full dissection of the endocytic machinery and biogenesis of the SPC.

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“…The antiviral activity of AL-088 and AL-274 exerted against VSV is also consistent with previous reports indicating that sphingolipids may account for multiple roles during VSV infection. (63)(64)(65).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological elevation of cellular dihydrosphingomyelin provides a novel antiviral strategy against West Nile virus infection

Oya¹,

San‐Félix

Casasampere

et al. 2022

Preprint

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Flavivirus life cycle is strictly dependent on cellular lipid metabolism. Polyphenols like gallic acid and its derivatives are promising lead compounds for new therapeutic agents as they can exert multiple pharmacological activities, including the alteration of lipid metabolism. The evaluation of our own collection of polyphenols against West Nile virus, a representative medically relevant flavivirus, led to the identification of N,N'-(dodecane-1,12-diyl)bis(3,4,5-trihydroxybenzamide) and its 2,3,4-trihydroxybenzamide regioisomer as selective antivirals with low cytotoxicity and high antiviral activity (EC50of 2.2 and 0.24 μM, respectively in Vero cells; EC50of 2.2 and 1.9 μM, respectively in SH-SY5Y cells). These polyphenols also inhibited the multiplication of other flaviviruses, namely Usutu, dengue, and Zika viruses, exhibiting lower antiviral or negligible antiviral activity against other RNA viruses. The mechanism underlying their antiviral activity against WNV involved the alteration of sphingolipid metabolism. These compounds inhibited ceramide desaturase (Des1) promoting the accumulation of dihydrosphingomyelin (dhSM), a minor component of cellular sphingolipids with important roles on membrane properties. Addition of exogenous dhSM, or Des1 blockage by using the reference inhibitor GT-11, confirmed the involvement of this pathway in WNV infection. These results unveil the potential of novel antiviral strategies based on the modulation of the cellular levels of dhSM and Des1 activity for the control of flavivirus infection.

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Untargeted Lipidomics of Vesicular Stomatitis Virus-Infected Cells and Viral Particles

Cited by 8 publications

References 59 publications

Pharmacological Elevation of Cellular Dihydrosphingomyelin Provides a Novel Antiviral Strategy against West Nile Virus Infection

Pharmacological Elevation of Cellular Dihydrosphingomyelin Provides a Novel Antiviral Strategy against West Nile Virus Infection

Endocytosis inTrypanosoma cruziDepends on Proper Recruitment and Regulation of Functionally Redundant Myosin Motors

Pharmacological elevation of cellular dihydrosphingomyelin provides a novel antiviral strategy against West Nile virus infection

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