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Article ; Online: Polyamine-Linked Cholesterol Incorporation in Rift Valley Fever Virus Particles Promotes Infectivity.

Mastrodomenico, Vincent / LoMascolo, Natalie J / Cruz-Pulido, Yazmin E / Cunha, Christina R / Mounce, Bryan C

ACS infectious diseases

2022 Volume 8, Issue 8, Page(s) 1439–1448

Abstract: Viruses rely on an array of cellular metabolites to replicate and form progeny virions. One set of these molecules, polyamines, are small aliphatic molecules, which are abundant in most cells, that support virus infection; however, the precise roles of ... ...

Abstract	Viruses rely on an array of cellular metabolites to replicate and form progeny virions. One set of these molecules, polyamines, are small aliphatic molecules, which are abundant in most cells, that support virus infection; however, the precise roles of polyamines in virus infection remain incompletely understood. Recent work demonstrated that polyamine metabolism supports cellular cholesterol synthesis through translation of the key transcription factor SREBP2. Here, we show that the bunyavirus Rift Valley fever virus (RVFV) relies on both cholesterol and polyamines for virus infection. Depletion of cellular cholesterol or interruption of cholesterol trafficking negatively impacts RVFV infection. Cholesterol is incorporated into RVFV virions and mediates their infectivity in a polyamine-dependent manner; we find that the virus derived from polyamine-depleted cells lacks cholesterol within the virion membrane. Conversely, we find that virion-associated cholesterol is linked to the incorporation of spermidine within the virion. Our prior work demonstrated that polyamines facilitate pH-mediated fusion and genome release, which may be a consequence of cholesterol depletion within virions. Thus, our work highlights the metabolic connection between polyamines and cholesterol synthesis to impact bunyavirus infection. These data demonstrate the connectedness between cellular metabolic pathways and reveal potential avenues of therapeutic intervention.
MeSH term(s)	Animals ; Cholesterol ; Polyamines ; Rift Valley fever virus/genetics ; Virion/genetics
Chemical Substances	Polyamines ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2022-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.2c00071
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Persistent Coxsackievirus B3 Infection in Pancreatic Ductal Cells

Mastrodomenico, Vincent / LoMascolo, Natalie J / Firpo, Mason R / Villanueva Guzman, Maria Del Mar / Zaporowski, Adam / Mounce, Bryan C

mSphere

2023 Volume 8, Issue 3, Page(s) e0003623

Abstract: Picornaviruses infect a wide variety of cell ... ...

Abstract	Picornaviruses infect a wide variety of cell types
MeSH term(s)	Animals ; Chlorocebus aethiops ; Humans ; Vero Cells ; Enterovirus B, Human/genetics ; Persistent Infection ; Polyamines/metabolism ; Enterovirus/physiology ; Coxsackievirus Infections/metabolism ; Coxsackievirus Infections/pathology
Chemical Substances	Polyamines
Language	English
Publishing date	2023-04-25
Publishing country	United States
Document type	Journal Article
ISSN	2379-5042
ISSN (online)	2379-5042
DOI	10.1128/msphere.00036-23
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity.

Tate, Patrick M / Mastrodomenico, Vincent / Cunha, Christina / McClure, Joshua / Barron, Annelise E / Diamond, Gill / Mounce, Bryan C / Kirshenbaum, Kent

ACS infectious diseases

2023 Volume 9, Issue 8, Page(s) 1508–1522

Abstract: The development of durable new antiviral therapies is challenging, as viruses can evolve rapidly to establish resistance and attenuate therapeutic efficacy. New compounds that selectively target conserved viral features are attractive therapeutic ... ...

Abstract	The development of durable new antiviral therapies is challenging, as viruses can evolve rapidly to establish resistance and attenuate therapeutic efficacy. New compounds that selectively target conserved viral features are attractive therapeutic candidates, particularly for combating newly emergent viral threats. The innate immune system features a sustained capability to combat pathogens through production of antimicrobial peptides (AMPs); however, these AMPs have shortcomings that can preclude clinical use. The essential functional features of AMPs have been recapitulated by peptidomimetic oligomers, yielding effective antibacterial and antifungal agents. Here, we show that a family of AMP mimetics, called peptoids, exhibit direct antiviral activity against an array of enveloped viruses, including the key human pathogens Zika, Rift Valley fever, and chikungunya viruses. These data suggest that the activities of peptoids include engagement and disruption of viral membrane constituents. To investigate how these peptoids target lipid membranes, we used liposome leakage assays to measure membrane disruption. We found that liposomes containing phosphatidylserine (PS) were markedly sensitive to peptoid treatment; in contrast, liposomes formed exclusively with phosphatidylcholine (PC) showed no sensitivity. In addition, chikungunya virus containing elevated envelope PS was more susceptible to peptoid-mediated inactivation. These results indicate that peptoids mimicking the physicochemical characteristics of AMPs act through a membrane-specific mechanism, most likely through preferential interactions with PS. We provide the first evidence for the engagement of distinct viral envelope lipid constituents, establishing an avenue for specificity that may enable the development of a new family of therapeutics capable of averting the rapid development of resistance.
MeSH term(s)	Animals ; Humans ; Antiviral Agents/pharmacology ; Peptidomimetics/pharmacology ; Phosphatidylserines ; Liposomes ; Peptoids/pharmacology ; Peptoids/chemistry ; Zika Virus ; Zika Virus Infection
Chemical Substances	Antiviral Agents ; Peptidomimetics ; Phosphatidylserines ; Liposomes ; Peptoids
Language	English
Publishing date	2023-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.3c00063
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Ribavirin Induces Polyamine Depletion via Nucleotide Depletion to Limit Virus Replication.

Tate, Patrick M / Mastrodomenico, Vincent / Mounce, Bryan C

Cell reports

2019 Volume 28, Issue 10, Page(s) 2620–2633.e4

Abstract: Common antivirals include nucleoside or nucleotide analogs with base prodrugs. The antiviral ribavirin, a US Food and Drug Administration (FDA)-approved nucleoside antimetabolite, halts guanine production, mutagenizes viral genomes, and activates ... ...

Abstract	Common antivirals include nucleoside or nucleotide analogs with base prodrugs. The antiviral ribavirin, a US Food and Drug Administration (FDA)-approved nucleoside antimetabolite, halts guanine production, mutagenizes viral genomes, and activates interferon signaling. Here, we find that ribavirin induces spermidine-spermine N1-acetyltransferase (SAT1), a polyamine catabolic enzyme. Polyamines are small, positively charged molecules involved in cellular functions such as transcription and translation. Previous work showed that SAT1 activation and polyamine depletion interfere with RNA virus replication. We show ribavirin depletes polyamines via SAT1, in conjunction with its known mechanisms. SAT1 transcripts, protein, and activity are induced in a dose-dependent manner, which depletes polyamine levels and reduces viral titers. Inhibition of SAT1 activity, pharmacologically or genetically, reduces ribavirin's effectiveness against three virus infection models. Additionally, ribavirin-mediated polyamine depletion results from nucleotide pool depletion. These data demonstrate another mechanism of ribavirin that inform its clinical effectiveness, which may provide insight for improved therapies.
MeSH term(s)	Acetyltransferases/metabolism ; Cell Line, Tumor ; Guanosine/metabolism ; HEK293 Cells ; Humans ; Interferon Type I/metabolism ; Nucleotides/metabolism ; Polyamines/metabolism ; Ribavirin/chemistry ; Ribavirin/pharmacology ; Transcription, Genetic/drug effects ; Virus Replication/drug effects
Chemical Substances	Interferon Type I ; Nucleotides ; Polyamines ; Guanosine (12133JR80S) ; Ribavirin (49717AWG6K) ; Acetyltransferases (EC 2.3.1.-) ; diamine N-acetyltransferase (EC 2.3.1.57)
Language	English
Publishing date	2019-09-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.07.099
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A non-canonical sensing pathway mediates Plasmodium adaptation to amino acid deficiency.

Marreiros, Inês M / Marques, Sofia / Parreira, Ana / Mastrodomenico, Vincent / Mounce, Bryan C / Harris, Chantal T / Kafsack, Björn F / Billker, Oliver / Zuzarte-Luís, Vanessa / Mota, Maria M

Communications biology

2023 Volume 6, Issue 1, Page(s) 205

Abstract: Eukaryotes have canonical pathways for responding to amino acid (AA) availability. Under AA-limiting conditions, the TOR complex is repressed, whereas the sensor kinase GCN2 is activated. While these pathways have been highly conserved throughout ... ...

Abstract	Eukaryotes have canonical pathways for responding to amino acid (AA) availability. Under AA-limiting conditions, the TOR complex is repressed, whereas the sensor kinase GCN2 is activated. While these pathways have been highly conserved throughout evolution, malaria parasites are a rare exception. Despite auxotrophic for most AA, Plasmodium does not have either a TOR complex nor the GCN2-downstream transcription factors. While Ile starvation has been shown to trigger eIF2α phosphorylation and a hibernation-like response, the overall mechanisms mediating detection and response to AA fluctuation in the absence of such pathways has remained elusive. Here we show that Plasmodium parasites rely on an efficient sensing pathway to respond to AA fluctuations. A phenotypic screen of kinase knockout mutant parasites identified nek4, eIK1 and eIK2-the last two clustering with the eukaryotic eIF2α kinases-as critical for Plasmodium to sense and respond to distinct AA-limiting conditions. Such AA-sensing pathway is temporally regulated at distinct life cycle stages, allowing parasites to actively fine-tune replication and development in response to AA availability. Collectively, our data disclose a set of heterogeneous responses to AA depletion in malaria parasites, mediated by a complex mechanism that is critical for modulating parasite growth and survival.
MeSH term(s)	Amino Acids/deficiency ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism ; Phosphorylation ; Phosphotransferases/metabolism ; Plasmodium/enzymology ; Plasmodium/genetics
Chemical Substances	Amino Acids ; eIF-2 Kinase (EC 2.7.11.1) ; Phosphotransferases (EC 2.7.-)
Language	English
Publishing date	2023-02-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-04566-y
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Article ; Online: Targeting Polyamines Inhibits Coronavirus Infection by Reducing Cellular Attachment and Entry.

Firpo, Mason R / Mastrodomenico, Vincent / Hawkins, Grant M / Prot, Matthieu / Levillayer, Laura / Gallagher, Tom / Simon-Loriere, Etienne / Mounce, Bryan C

ACS infectious diseases

2020 Volume 7, Issue 6, Page(s) 1423–1432

Abstract: Coronaviruses first garnered widespread attention in 2002 when the severe acute respiratory syndrome coronavirus (SARS-CoV) emerged from bats in China and rapidly spread in human populations. Since then, Middle East respiratory syndrome coronavirus (MERS- ...

Abstract	Coronaviruses first garnered widespread attention in 2002 when the severe acute respiratory syndrome coronavirus (SARS-CoV) emerged from bats in China and rapidly spread in human populations. Since then, Middle East respiratory syndrome coronavirus (MERS-CoV) emerged and still actively infects humans. The recent SARS-CoV-2 outbreak and the resulting disease (coronavirus disease 2019, COVID19) have rapidly and catastrophically spread and highlighted significant limitations to our ability to control and treat infection. Thus, a basic understanding of entry and replication mechanisms of coronaviruses is necessary to rationally evaluate potential antivirals. Here, we show that polyamines, small metabolites synthesized in human cells, facilitate coronavirus replication and the depletion of polyamines with FDA-approved molecules significantly reduces coronavirus replication. We find that diverse coronaviruses, including endemic and epidemic coronaviruses, exhibit reduced attachment and entry into polyamine-depleted cells. We further demonstrate that several molecules targeting the polyamine biosynthetic pathway are antiviral
MeSH term(s)	Antiviral Agents/pharmacology ; COVID-19 ; Humans ; Middle East Respiratory Syndrome Coronavirus ; Polyamines ; SARS-CoV-2
Chemical Substances	Antiviral Agents ; Polyamines
Keywords	covid19
Language	English
Publishing date	2020-10-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.0c00491
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Article ; Online: Virion-Associated Polyamines Transmit with Bunyaviruses to Maintain Infectivity and Promote Entry.

Mastrodomenico, Vincent / Esin, Jeremy J / Qazi, Shefah / Khomutov, Maxim A / Ivanov, Alexander V / Mukhopadhyay, Suchetana / Mounce, Bryan C

ACS infectious diseases

2020 Volume 6, Issue 9, Page(s) 2490–2501

Abstract: Viruses require host cell metabolites to productively infect, and the mechanisms by which viruses usurp these molecules are diverse. One group of cellular metabolites important in virus infection is the polyamines, small positively charged molecules ... ...

Abstract	Viruses require host cell metabolites to productively infect, and the mechanisms by which viruses usurp these molecules are diverse. One group of cellular metabolites important in virus infection is the polyamines, small positively charged molecules involved in cell cycle, translation, and nucleic acid metabolism, among other cellular functions. Polyamines support replication of diverse viruses, and they are important for processes such as transcription, translation, and viral protein enzymatic activity. Rift Valley fever virus (RVFV) is a negative and ambisense RNA virus that requires polyamines to produce infectious particles. In polyamine depleted conditions, noninfectious particles are produced that interfere with virus replication and stimulate immune signaling. Here, we find that RVFV relies on virion-associated polyamines to maintain infectivity and enhance viral entry. We show that RVFV replication is facilitated by a limited set of polyamines and that spermidine and closely related molecules associate with purified virions and transmit from cell to cell during infection. Virion-associated spermidine maintains virion infectivity, as virions devoid of polyamines rapidly lose infectivity and are temperature sensitive. Further, virions without polyamines bind to cells but exhibit a defect in entry, requiring more acidic conditions than virions containing spermidine. These data highlight a unique role for polyamines, and spermidine particularly, to maintain virus infectivity. Further, these studies are the first to identify polyamines associated with RVFV virions. Targeting polyamines represents a promising antiviral strategy, and this work highlights a new mechanism by which we can inhibit virus replication through FDA-approved polyamine depleting pharmaceuticals.
MeSH term(s)	Animals ; Polyamines ; Rift Valley fever virus ; Viral Proteins ; Virion ; Virus Replication
Chemical Substances	Polyamines ; Viral Proteins
Language	English
Publishing date	2020-08-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2373-8227
ISSN (online)	2373-8227
DOI	10.1021/acsinfecdis.0c00402
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Article ; Online: Tools for Rapid Genetic Engineering of Vibrio fischeri.

Visick, Karen L / Hodge-Hanson, Kelsey M / Tischler, Alice H / Bennett, Allison K / Mastrodomenico, Vincent

Applied and environmental microbiology

2018 Volume 84, Issue 14

Abstract: ... Vibrio ... ...

Abstract	Vibrio fischeri
MeSH term(s)	Aliivibrio fischeri/genetics ; Cellulose ; Cloning, Molecular ; DNA Nucleotidyltransferases ; Gene Deletion ; Gene Expression Regulation, Bacterial ; Genes, Bacterial/genetics ; Genetic Engineering/methods ; Mutagenesis, Insertional ; Mutation ; Promoter Regions, Genetic ; Quorum Sensing ; Symbiosis
Chemical Substances	Cellulose (9004-34-6) ; DNA Nucleotidyltransferases (EC 2.7.7.-) ; FLP recombinase (EC 2.7.7.-)
Language	English
Publishing date	2018-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	223011-2
ISSN	1098-5336 ; 0099-2240
ISSN (online)	1098-5336
ISSN	0099-2240
DOI	10.1128/AEM.00850-18
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Article: Targeting Polyamines Inhibits Coronavirus Infection by Reducing Cellular Attachment and Entry

Firpo, Mason R / Mastrodomenico, Vincent / Hawkins, Grant M / Prot, Matthieu / Levillayer, Laura / Gallagher, Tom / Simon-Loriere, Etienne / Mounce, Bryan C

ACS infect. dis

Abstract	Coronaviruses first garnered widespread attention in 2002 when the severe acute respiratory syndrome coronavirus (SARS-CoV) emerged from bats in China and rapidly spread in human populations. Since then, Middle East respiratory syndrome coronavirus (MERS-CoV) emerged and still actively infects humans. The recent SARS-CoV-2 outbreak and the resulting disease (coronavirus disease 2019, COVID19) have rapidly and catastrophically spread and highlighted significant limitations to our ability to control and treat infection. Thus, a basic understanding of entry and replication mechanisms of coronaviruses is necessary to rationally evaluate potential antivirals. Here, we show that polyamines, small metabolites synthesized in human cells, facilitate coronavirus replication and the depletion of polyamines with FDA-approved molecules significantly reduces coronavirus replication. We find that diverse coronaviruses, including endemic and epidemic coronaviruses, exhibit reduced attachment and entry into polyamine-depleted cells. We further demonstrate that several molecules targeting the polyamine biosynthetic pathway are antiviral in vitro. In sum, our data suggest that polyamines are critical to coronavirus replication and represent a highly promising drug target in the current and any future coronavirus outbreaks.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #786550
Database	COVID19

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Article ; Online: Polyamine Depletion Inhibits Bunyavirus Infection via Generation of Noninfectious Interfering Virions.

Mastrodomenico, Vincent / Esin, Jeremy J / Graham, Marion L / Tate, Patrick M / Hawkins, Grant M / Sandler, Zachary J / Rademacher, David J / Kicmal, Thomas M / Dial, Courtney N / Mounce, Bryan C

Journal of virology

2019 Volume 93, Issue 14

Abstract: Several host and viral processes contribute to forming infectious virions. Polyamines are small host molecules that play diverse roles in viral replication. We previously demonstrated that polyamines are crucial for RNA viruses; however, the mechanisms ... ...

Abstract	Several host and viral processes contribute to forming infectious virions. Polyamines are small host molecules that play diverse roles in viral replication. We previously demonstrated that polyamines are crucial for RNA viruses; however, the mechanisms by which polyamines function remain unknown. Here, we investigated the role of polyamines in the replication of the bunyaviruses Rift Valley fever virus (vaccine strain MP-12) and La Crosse virus (LACV). We found that polyamine depletion did not impact viral RNA or protein accumulation, despite significant decreases in titer. Viral particles demonstrated no change in morphology, size, or density. Thus, polyamine depletion promotes the formation of noninfectious particles. These particles interfere with virus replication and stimulate innate immune responses. We extended this phenotype to Zika virus; however, coxsackievirus did not similarly produce noninfectious particles. In sum, polyamine depletion results in the accumulation of noninfectious particles that interfere with replication and stimulate immune signaling, with important implications for targeting polyamines therapeutically, as well as for vaccine strategies.
MeSH term(s)	Biogenic Polyamines/immunology ; Bunyaviridae Infections/genetics ; Bunyaviridae Infections/immunology ; Bunyaviridae Infections/pathology ; Cell Line, Tumor ; Defective Viruses/physiology ; Encephalitis Virus, California/physiology ; Humans ; Rift Valley fever virus/physiology ; Virion/physiology ; Virus Replication/immunology
Chemical Substances	Biogenic Polyamines
Language	English
Publishing date	2019-06-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00530-19
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