Zika virus causes testicular atrophy

Uraki, Ryuta; Hwang, Jesse; Jurado, Kellie Ann; Householder, Sarah; Yockey, Laura J.; Hastings, Andrew K.; Homer, Robert J.; Iwasaki, Akiko; Fikrig, Erol

doi:10.1126/sciadv.1602899

Cited by 115 publications

(121 citation statements)

References 46 publications

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“…To accomplish this, we built a metabolic network containing the biosynthesis pathways of each subclass in our lipidomics dataset (Supplementary Fig. 8a) then surveyed the network for metabolites associated with seven Medical Subject Heading (MeSH) terms selected for their similarity to clinical outcomes of ZIKV infection 65–67 . As a consequence of including all compounds and genes from the constituent lipid biosynthesis pathways in our metabolic model (Supplementary Data 5), nearly every node of the resulting disease-metabolite network was a non-lipid compound capable of participating in other aspects of cellular metabolism (Fig.…”

Section: Resultsmentioning

confidence: 99%

A global lipid map defines a network essential for Zika virus replication

Leier

Weinstein

Kyle

et al. 2020

Preprint

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26Zika virus (ZIKV), an arbovirus of global concern, remodels intracellular membranes to form 27 replication sites. How ZIKV dysregulates lipid networks to allow this, and consequences for 28 disease, is poorly understood. Here, we performed comprehensive lipidomics to create a lipid 29 network map during ZIKV infection. We found that ZIKV significantly alters host lipid 30 composition, with the most striking changes seen within subclasses of sphingolipids. Ectopic 31 expression of ZIKV NS4B protein resulted in similar changes, demonstrating a role for NS4B in 32 modulating sphingolipid pathways. Disruption of sphingolipid biosynthesis in various cell types, 33including human neural progenitor cells, blocked ZIKV infection. Additionally, the sphingolipid 34 ceramide redistributes to ZIKV replication sites and increasing ceramide levels by multiple 35 pathways sensitizes cells to ZIKV infection. Thus, we identify a sphingolipid metabolic network 36 with a critical role in ZIKV replication and show that ceramide flux is a key mediator of ZIKV 37 infection. Results 112 ZIKV alters the lipid landscape of host cells 113To understand how cellular lipid metabolism is altered by ZIKV infection, we carried out 114 a global lipidomic survey of the model Huh7 human hepatic carcinoma cell line 20 infected for 24 115 or 48 hours with Asian lineage ZIKV strain FSS13025 (Fig. 1a). Lipids extracted from 116 populations of mock and infected cells (n = 5 biological replicates per condition) were analyzed 117 with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) (Supplementary Data 118 1 and Supplementary Fig. 1a-f). We identified 340 lipid species spanning the phospholipid, 119 sphingolipid, glycerolipid, and sterol classes for which pairwise comparisons of normalized 120 abundance between mock and infected cells could be made (Supplementary Data 1). Of these, 121 80 species (23.5%) showed significant changes in abundance by 24 hours post-infection (hpi) 122 and 172 species (50.6%) were significantly altered by 48 hpi (P < 0.05, ANOVA or g-test) 123( Supplementary Data 1). Principal component analysis (PCA) of these observations confirmed 124 that infection status (mock or ZIKV) and timepoint (24 or 48 hpi) accounted most of these 125 changes, with changes in lipid composition between mock and infected cells increasing over 126 time (Fig. 1b). 127Next, we examined how ZIKV-induced changes in host lipid composition broke down by 128 subclass and species (Fig. 1c, d). A map of the pairwise correlations of all 340 species at 48 hpi 129 ( Supplementary Fig. 2a) revealed that lipid subclasses largely fell into two groups of species 130 that were either enriched or depleted in abundance ( Supplementary Fig. 2b), suggesting that 131 individual metabolic pathways are up-or down-regulated to create a specific lipid milieu around 132 the events of the viral replication cycle. Supporting this, many of the trends we observed were 133 consistent with earlier reports of functional roles for lipids during flavivirus infection. In ...

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Section: Resultsmentioning

confidence: 99%

A global lipid map defines a network essential for Zika virus replication

Leier

Weinstein

Kyle

et al. 2020

Preprint

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“…Although our studies were focused on protection against trans-placental transmission and fetal infection, the robust responses to the prM-E mRNA and ZIKV-NS1-LAV vaccines indicate they could diminish infection in other target populations and decrease the epidemic force of infection. Immunization of males may be important if the ZIKV-induced damage to the testes reported in mice (Govero et al, 2016; Ma et al, 2016; Uraki et al, 2017) becomes apparent in humans or to prevent sexual transmission. An additional consideration is whether in the context of pregnancy the systemic immunity that is generated by vaccination is sufficient to prevent local vaginal infection and spread via organs of the reproductive tract that occurs during sexual transmission (Khan et al, 2016; Shin and Iwasaki, 2013; Yockey et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease

Richner

Jagger

Shan

et al. 2017

Cell

229

201

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SUMMARY The emergence of Zika virus (ZIKV) and its association with congenital malformations has prompted the rapid development of vaccines. Although efficacy with nucleic acid or inactivated viral vaccine platforms has been established in animals, no study has addressed protection during pregnancy. We tested in mice two vaccine platforms, a lipid nanoparticle-encapsulated modified mRNA vaccine encoding ZIKV prM and E genes and a live-attenuated ZIKV strain encoding an NS1 protein without glycosylation, for their ability to protect against transmission to the fetus. Vaccinated dams challenged with a heterologous ZIKV strain at embryo day 6 (E6) and evaluated at E13 showed markedly diminished levels of viral RNA in maternal, placental, and fetal tissues, which resulted in protection against placental damage and fetal demise. As modified mRNA and live-attenuated vaccine platforms can restrict in utero transmission of ZIKV in mice, their further development in humans to prevent congenital ZIKV syndrome is warranted.

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“…Although these limitations exist, mouse models of ZIKV infection have been instrumental in identifying potential tissue and cellular targets of ZIKV in vivo [44, 59, 60]. However, studies of ZIKV infection in mice have also reported findings such as testicular atrophy, which has not been reported in human clinical cases to date [61]. Both the chick embryo and neonatal pig models may be very useful for testing therapeutics and/or understanding ZIKV infection outcomes in the early neonatal period respectively, and are relatively inexpensive [49, 55].…”

Section: Animal Models Of Zika Virus Infectionmentioning

confidence: 99%

Macaque monkeys in Zika virus research: 1947–present

Newman

Friedrich²,

O’Connor

2017

Current Opinion in Virology

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Zika virus was first isolated in 1947 from an exotic rhesus macaque. Nearly 70 years later, the emergence of Zika virus in the Americas and its newly described association with birth defects has motivated the development of captive macaque monkey models of human Zika virus infection. This review describes similarities between macaque and human Zika virus pathogenesis and discusses specific advantages and disadvantages of using macaques instead of other laboratory animal models. In particular, macaques provide an outstanding model for understanding in-utero Zika virus infections that are essential for evaluating preclinical interventions for use in pregnancy.

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Zika virus causes testicular atrophy

Abstract: Zika virus replicates in mouse testes and causes testicular atrophy, with implication on sexual transmission and male fertility.

Cited by 115 publications

References 46 publications

A global lipid map defines a network essential for Zika virus replication

A global lipid map defines a network essential for Zika virus replication

Vaccine Mediated Protection Against Zika Virus-Induced Congenital Disease

Macaque monkeys in Zika virus research: 1947–present

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