Dengue Virus Infection Perturbs Lipid Homeostasis in Infected Mosquito Cells

Perera, Rushika; Riley, Catherine P.; Isaac, Giorgis; Hopf-Jannasch, Amber S.; Moore, Ronald J.; Weitz, Karl; Paša‐Tolić, Ljiljana; Metz, Thomas O.; Adamec, Jiřı́; Kühn, Richard

doi:10.1371/journal.ppat.1002584

Cited by 305 publications

(410 citation statements)

References 61 publications

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“…1 A and B). The 28% increase in PC content (P < 0.05) was comparable to the 35% and 37% increase in PC content seen during FHV (18) and poliovirus (19) infections, respectively, but lower than the 70% increase detected during DENV infection in mosquito cells (17). In addition, the amount of phosphatidylserine (PS) increased by 40%, whereas phophatidylglycerol (PG) increased by 56% (Fig.…”

Section: Bmv Specifically Promotes Pc Accumulation At the Site Of Viralsupporting

confidence: 53%

“…Although DENV and polioviruses stimulate PC synthesis (17,20), it is not clear whether HCV infection increases total PC levels. Nevertheless, certain PC species, such as PC 30:0, increased significantly, whereas some decreased (e.g., PC 35:1) upon HCV infection (35).…”

Section: Virus-stimulated and Viral Replication Site-localized Pc Accmentioning

confidence: 99%

“…A 70% and 35% increase of total PC levels was recorded in DENV-infected mosquito cells (17) and FHVinfected Drosophila cells (18), respectively. At the peak time of poliovirus replication in HeLa cells, a ∼37% increase of PC content was observed after a 30-min chase (19).…”

mentioning

confidence: 93%

“…Dengue virus (DENV) (17), Flock House virus (FHV) (18), and poliovirus (19,20). A 70% and 35% increase of total PC levels was recorded in DENV-infected mosquito cells (17) and FHVinfected Drosophila cells (18), respectively.…”

mentioning

confidence: 99%

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Positive-strand RNA viruses stimulate host phosphatidylcholine synthesis at viral replication sites

Zhang

Chukkapalli

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

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All positive-strand RNA viruses reorganize host intracellular membranes to assemble their viral replication complexes (VRCs); however, how these viruses modulate host lipid metabolism to accommodate such membrane proliferation and rearrangements is not well defined. We show that a significantly increased phosphatidylcholine (PC) content is associated with brome mosaic virus (BMV) replication in both natural host barley and alternate host yeast based on a lipidomic analysis. Enhanced PC levels are primarily associated with the perinuclear ER membrane, where BMV replication takes place. More specifically, BMV replication protein 1a interacts with and recruits Cho2p (choline requiring 2), a host enzyme involved in PC synthesis, to the site of viral replication. These results suggest that PC synthesized at the site of VRC assembly, not the transport of existing PC, is responsible for the enhanced accumulation. Blocking PC synthesis by deleting the CHO2 gene resulted in VRCs with wider diameters than those in wild-type cells; however, BMV replication was significantly inhibited, highlighting the critical role of PC in VRC formation and viral replication. We further show that enhanced PC levels also accumulate at the replication sites of hepatitis C virus and poliovirus, revealing a conserved feature among a group of positive-strand RNA viruses. Our work also highlights a potential broad-spectrum antiviral strategy that would disrupt PC synthesis at the sites of viral replication but would not alter cellular processes.positive-strand RNA viruses | viral replication complexes | virus-host interactions | virus control | phospholipids A ll positive-strand RNA viruses [(+)RNA viruses], which include numerous important human, animal, and plant pathogens, share similar strategies for genomic replication. A highly conserved and indispensable feature of their replication is the proliferation and reorganization of host cellular membranes to assemble viral replication complexes (VRCs). Despite this central importance, it is largely unknown how cellular membranes are rearranged by the viral replication proteins and how cellular lipid metabolism is modulated to accommodate membrane proliferation and remodeling.Brome mosaic virus (BMV) serves as a model for understanding VRC formation of (+)RNA viruses (1). BMV is the type member of the plant virus family Bromoviridae and a representative member of the alphavirus-like superfamily, which includes many human, animal, and plant-infecting viruses (2). BMV encodes two replication proteins, 1a and 2a pol . 2a pol serves as the replicase, whereas 1a has an N-terminal methyltransferase domain (3, 4) and a C-terminal ATPase/helicase-like domain (5). Together, 1a and 2a pol are necessary and sufficient for BMV replication. BMV induces vesicular structures in its surrogate host, the yeast Saccharomyces cerevisiae, and its natural host, barley (6, 7). These structures, termed spherules, have been shown to be the VRCs in yeast as 1a, 2a pol , and nascent viral RNAs reside in the interior of th...

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Section: Bmv Specifically Promotes Pc Accumulation At the Site Of Viralsupporting

confidence: 53%

Section: Virus-stimulated and Viral Replication Site-localized Pc Accmentioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

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Positive-strand RNA viruses stimulate host phosphatidylcholine synthesis at viral replication sites

Zhang

Chukkapalli

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

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“…Similar to enteroviruses, the flavivirus Hepatitis C virus (HCV) requires PI4P lipids for replication, which are generated via the recruitment of PI4KIIIα [46][47][48][49][50][51][52][53]. West Nile virus attracts the cholesterol-synthesizing enzyme 3-HMGA-CoA reductase to replication sites [54,55], while dengue virus recruits fatty acid synthase and stimulates its activity [56,57]. The recruitment of lipid biosynthesis machinery can lead to membrane expansion and alteration of the fluidity and curvature of the membrane by for instance accumulation of cholesterol or desaturation of lipid fatty acid tails.…”

Section: Discussionmentioning

confidence: 99%

Coxsackievirus mutants that can bypass host factor PI4KIIIβ and the need for high levels of PI4P lipids for replication

et al. 2012

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RNA viruses can rapidly mutate and acquire resistance to drugs that directly target viral enzymes, which poses serious problems in a clinical context. Therefore, there is a growing interest in the development of antiviral drugs that target host factors critical for viral replication, since they are unlikely to mutate in response to therapy. We recently demonstrated that phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) and its product phosphatidylinositol-4-phosphate (PI4P) are essential for replication of enteroviruses, a group of medically important RNA viruses including poliovirus (PV), coxsackievirus, rhinovirus, and enterovirus 71. Here, we show that enviroxime and GW5074 decreased PI4P levels at the Golgi complex by directly inhibiting PI4KIIIβ. Coxsackievirus mutants resistant to these inhibitors harbor single point mutations in the non-structural protein 3A. These 3A mutations did not confer compound-resistance by restoring the activity of PI4KIIIβ in the presence of the compounds. Instead, replication of the mutant viruses no longer depended on PI4KIIIβ, since their replication was insensitive to siRNA-mediated depletion of PI4KIIIβ. The mutant viruses also did not rely on other isoforms of PI4K. Consistently, no high level of PI4P could be detected at the replication sites induced by the mutant viruses in the presence of the compounds. Collectively, these findings indicate that through specific single point mutations in 3A, CVB3 can bypass an essential host factor and lipid for its propagation, which is a new example of RNA viruses acquiring resistance against antiviral compounds, even when they directly target host factors.

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The role of brain innate immune response in lysosomal storage disorders: fundamental process or evolutionary side effect?

Vitner

2020

FEBS Letters

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Sphingolipidoses are diseases caused by mutations in genes responsible for sphingolipid degradation and thereby lead to sphingolipid accumulation. Most sphingolipidoses have a neurodegenerative manifestation characterized by innate immune activation in the brain. However, the role of the immune response in disease progression is ill-understood. In contrast to infectious diseases, immune activation is unable to eliminate the offending agent in sphingolipidoses resulting in ineffective, chronic inflammation. This paradox begs two fundamental questions: Why has this immune response evolved in sphingolipidoses? What role does it play in disease progression? Here, starting from the observation that sphingolipids (SLs) are elevated also in infectious diseases, I discuss the possibility that the activation of the brain immune response by SLs has evolved as a part of the immune response against pathogens and plays no major role in sphingolipidoses.

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Dengue Virus Infection Perturbs Lipid Homeostasis in Infected Mosquito Cells

Cited by 305 publications

References 61 publications

Positive-strand RNA viruses stimulate host phosphatidylcholine synthesis at viral replication sites

Positive-strand RNA viruses stimulate host phosphatidylcholine synthesis at viral replication sites

Coxsackievirus mutants that can bypass host factor PI4KIIIβ and the need for high levels of PI4P lipids for replication

The role of brain innate immune response in lysosomal storage disorders: fundamental process or evolutionary side effect?

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