Interferon-Induced Spermidine-Spermine Acetyltransferase and Polyamine Depletion Restrict Zika and Chikungunya Viruses

Mounce, Bryan C.; Poirier, Enzo Z.; Passoni, Gabriella; Simon‐Lorière, Etienne; Cesaro, Teresa; Prot, Matthieu; Stapleford, Kenneth A.; Moratorio, Gonzalo; Sakuntabhai, Anavaj; Levraud, Jean‐Pierre; Vignuzzi, Marco

doi:10.1016/j.chom.2016.06.011

Cited by 109 publications

(171 citation statements)

References 48 publications

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“…To determine how CHIKV may adapt to a polyamine-depleted environment, we passaged virus in BHK-21 cells that were treated with 500 μM DFMO (or left untreated for controls) for 4 days prior to infection, which we demonstrated previously to inhibit CHIKV replication but not alter cell viability or cycling (9). After each passage, viral titers were determined and used to infect the next passage at a constant multiplicity of infection (MOI) of 0.1.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to their roles within the cell, polyamines are crucial for replication of RNA viruses, including CHIKV. We previously reported that CHIKV relies on polyamines at the levels of translation and RNA-dependent RNA polymerase activity in infected cells (9). In fact, diverse RNA viruses rely on polyamines for their replication both in vitro and in vivo (10, 11).…”

Section: Introductionmentioning

confidence: 99%

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Chikungunya Virus Overcomes Polyamine Depletion by Mutation of nsP1 and the Opal Stop Codon To Confer Enhanced Replication and Fitness

Mounce

Cesaro

Vlajnić

et al. 2017

J Virol

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Polyamines, which are small positively charge molecules present in all cells, play important roles in the replication of DNA and RNA viruses. Chikungunya virus (CHIKV) relies on polyamines for translation of the viral genome upon viral entry, and pharmacological depletion of polyamines limits viral replication. However, the potential development of antiviral resistance necessitates a better understanding of how polyamines function and can be targeted via compounds that alter polyamine levels. We have isolated CHIKV that is resistant to polyamine depletion and contains two mutations in the nonstructural protein 1 (nsP1)-coding region in combination with a mutation to the opal stop codon preceding nsP4. These mutations, in addition to promoting viral replication in polyamine-depleted cells, confer enhanced viral replication in vitro and in vivo. The nsP1 mutations enhance membrane binding and methyltransferase activities, while the stop codon mutation allows increased downstream translation. These mutations, when combined, enhance viral fitness, but individual mutants are attenuated in mosquitoes. Together, our results suggest that CHIKV can evolve resistance to polyamine depletion and that pharmaceuticals targeting the polyamine biosynthetic pathway may be best used in combination with other established antivirals to mitigate the development of resistance.IMPORTANCE Chikungunya virus is a mosquito-borne virus that has infected millions worldwide. Its expansion into the Americas and rapid adaptation to new mosquito hosts present a serious threat to human health, which we can combat with the development of antiviral therapies as well as understanding how these viruses will mutate when exposed to antiviral therapies. Targeting polyamines, small positively charged molecules in the cell, may be a potential strategy against RNA viruses, including chikungunya virus. Here, we have described a virus that is resistant to polyamine depletion and has increased fitness in cells and in full organisms. Mutations in viral genome capping machinery, membrane binding activity, and a stop codon arise, and their altered activities enhance replication in the absence of polyamines. These results highlight strategies by which chikungunya virus can overcome polyamine depletion and emphasize continued research on developing improved antiviral therapies.KEYWORDS antiviral, antiviral resistance, chikungunya virus, polyamines, viral replication C hikungunya virus (CHIKV) is an arthropod-borne virus (arbovirus) from the Alphavirus family that has caused several severe outbreaks worldwide. Clinical manifestations can be severe and long lasting, including fever and chronic joint pain, and rapid

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chikungunya Virus Overcomes Polyamine Depletion by Mutation of nsP1 and the Opal Stop Codon To Confer Enhanced Replication and Fitness

Mounce

Cesaro

Vlajnić

et al. 2017

J Virol

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“…The ODC inhibitor DL-alpha-difluoromethylornithine (DFMO) was used as a positive control for polyamine depletion in these experiments 31 . Our results reveal that the amount of polyamines in Huh7 cells is decreased under conditions of down-modulated SLC7A2 expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

Uptake and metabolism of arginine impact Plasmodium development in the liver

Meireles

Mendes

Aroeira

et al. 2017

Sci Rep

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Prior to infecting erythrocytes and causing malaria symptoms, Plasmodium parasites undergo an obligatory phase of invasion and extensive replication inside their mammalian host’s liver cells that depends on the parasite’s ability to obtain the nutrients it requires for its intra-hepatic growth and multiplication. Here, we show that L-arginine (Arg) uptake through the host cell’s SLC7A2-encoded transporters is essential for the parasite’s development and maturation in the liver. Our data suggest that the Arg that is taken up is primarily metabolized by the arginase pathway to produce the polyamines required for Plasmodium growth. Although the parasite may hijack the host’s biosynthesis pathway, it relies mainly upon its own arginase-AdoMetDC/ODC pathway to acquire the polyamines it needs to develop. These results identify for the first time a pivotal role for Arg-dependent polyamine production during Plasmodium’s hepatic development and pave the way to the exploitation of strategies to impact liver infection by the malaria parasite through the modulation of Arg uptake and polyamine synthesis.

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“…Spermidine–spermine acetyltransferase (SAT1 or SSAT) acetylates spermidine and spermine, which promotes either their conversion back to putrescine or their export from the cell (102, 103). Interestingly, type I IFNs induce the expression of SAT1 and, therefore, deplete spermidine and spermine levels (104). The depletion of these two polyamines has a strong antiviral effect and inhibits replication of the RNA viruses, Zika virus and Chikungunya virus (104).…”

Section: Amino Acid Metabolism and Ifnsmentioning

confidence: 99%

“…Interestingly, type I IFNs induce the expression of SAT1 and, therefore, deplete spermidine and spermine levels (104). The depletion of these two polyamines has a strong antiviral effect and inhibits replication of the RNA viruses, Zika virus and Chikungunya virus (104). Mechanistically, polyamines seem to be important for transcription and translation of viral RNA and proteins.…”

Section: Amino Acid Metabolism and Ifnsmentioning

confidence: 99%

Effects of Interferons and Viruses on Metabolism

2016

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Interferons (IFNs) are potent pleiotropic cytokines that broadly alter cellular functions in response to viral and other infections. These alterations include changes in protein synthesis, proliferation, membrane composition, and the nutritional microenvironment. Recent evidence suggests that antiviral responses are supported by an IFN-induced rewiring of the cellular metabolism. In this review, we discuss the roles of type I and type II IFNs in regulating the cellular metabolism and biosynthetic reactions. Furthermore, we give an overview of how viruses themselves affect these metabolic activities to promote their replication. In addition, we focus on the lipid as well as amino acid metabolisms, through which IFNs exert potent antiviral and immunomodulatory activities. Conversely, the expression of IFNs is controlled by the nutrient sensor mammalian target of rapamycin or by direct reprograming of lipid metabolic pathways. These findings establish a mutual relationship between IFN production and metabolic core processes.

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Interferon-Induced Spermidine-Spermine Acetyltransferase and Polyamine Depletion Restrict Zika and Chikungunya Viruses

Cited by 109 publications

References 48 publications

Chikungunya Virus Overcomes Polyamine Depletion by Mutation of nsP1 and the Opal Stop Codon To Confer Enhanced Replication and Fitness

Chikungunya Virus Overcomes Polyamine Depletion by Mutation of nsP1 and the Opal Stop Codon To Confer Enhanced Replication and Fitness

Uptake and metabolism of arginine impact Plasmodium development in the liver

Effects of Interferons and Viruses on Metabolism

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