Zika virus degrades the ω-3 fatty acid transporter Mfsd2a in brain microvascular endothelial cells and impairs lipid homeostasis

Zhou, Jia; Chi, Xiaojing; Cheng, Min; Huang, Xing‐Yao; Liu, Xiuying; Fan, Jingjing; Xu, Hua; Lin, Tianli; Shi, Lei; Qin, Cheng‐Feng; Yang, Wei

doi:10.1126/sciadv.aax7142

Cited by 39 publications

(39 citation statements)

References 22 publications

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“…Recently, Zika virus (ZIKV) has caused devastating outbreaks of fetal congenital malformations in South and Central America and now transmitted in more than 70 countries, including many previously unaffected regions. ZIKV infection during pregnancy increases the risk of neurological disorders in newborns (Zhou et al 2019 ), such as microcephaly. In adults, ZIKV causes Guillain-Barré syndrome and other neurologic disorders (Mendez et al 2017 ).…”

Section: Introductionmentioning

confidence: 99%

T cell immunity rather than antibody mediates cross-protection against Zika virus infection conferred by a live attenuated Japanese encephalitis SA14-14-2 vaccine

Wang

Zhen

Turtle

et al. 2020

Appl Microbiol Biotechnol

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Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are closely related to mosquito-borne flaviviruses. Japanese encephalitis (JE) vaccine SA14-14-2 has been in the Chinese national Expanded Program on Immunization since 2007. The recent recognition of severe disease syndromes associated with ZIKV, and the identification of ZIKV from mosquitoes in China, prompts an urgent need to investigate the potential interaction between the two. In this study, we showed that SA14-14-2 is protective against ZIKV infection in mice. JE vaccine SA14-14-2 triggered both Th1 and Th2 cross-reactive immune responses to ZIKV; however, it was cellular immunity that predominantly mediated cross-protection against ZIKV infection. Passive transfer of immune sera did not result in significant cross-protection but did mediate antibody-dependent enhancement in vitro, though this did not have an adverse impact on survival. This study suggests that the SA14-14-2 vaccine can protect against ZIKV through a cross-reactive T cell response. This is vital information in terms of ZIKV prevention or precaution in those ZIKV-affected regions where JEV circulates or SA14-14-2 is in widespread use, and opens a promising avenue to develop a novel bivalent vaccine against both ZIKV and JEV. Key points • JEV SA14-14-2 vaccine conferred cross-protection against ZIKV challenge in mice. • T cell immunity rather than antibody mediated the cross-protection. • It provides important information in terms of ZIKV prevention or precaution.

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Section: Introductionmentioning

confidence: 99%

T cell immunity rather than antibody mediates cross-protection against Zika virus infection conferred by a live attenuated Japanese encephalitis SA14-14-2 vaccine

Wang

Zhen

Turtle

et al. 2020

Appl Microbiol Biotechnol

View full text Add to dashboard Cite

show abstract

“…Recently, Zika virus (ZIKV) has caused devastating outbreaks of fetal congenital malformations in South and Central America and now transmitted in more than 70 countries, including many previously unaffected regions. ZIKV infection during pregnancy increases the risk of neurological disorders in newborns (1), such as microcephaly. In adults, ZIKV causes Guillain-Barré syndrome and other neurologic disorders (2).…”

Section: Introductionmentioning

confidence: 99%

Cross-Protection Against Zika Virus Infection Conferred by a Live Attenuated Japanese Encephalitis SA14-14-2 Vaccine

Wang

Zhen

Turtle

et al. 2020

Preprint

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24Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are closely related 25 mosquito-borne flaviviruses. Japanese encephalitis (JE) vaccine SA14-14-2 has been in 26 the Chinese national Expanded Program on Immunization since 2007. The recent 27 recognition of severe disease syndromes associated with ZIKV, and the identification of 28 ZIKV from mosquitoes in China, prompts an urgent need to investigate the potential 29 interaction between the two. In this study, we showed that SA14-14-2 is protective against 30 ZIKV infection in mice. JE vaccine SA14-14-2 triggered both Th1 and Th2 cross-reactive 31 immune responses to ZIKV; however, it was cellular immunity that predominantly 32 mediated cross-protection against ZIKV infection. Passive transfer of immune sera did not 33 result in significant cross-protection, but did mediate antibody dependent enhancement in 34 vitro, though this did not have an adverse impact on survival. This study suggests that 35 SA14-14-2 vaccine can protect against ZIKV through a cross-reactive T cell response. 36This is vital information in terms of ZIKV prevention or precaution in those ZIKV-affected 37 regions where JEV circulates or SA14-14-2 is in widespread use, and opens a promising 38 avenue into developing a novel bivalent vaccine against both ZIKV and JEV. 40Importance 43 Japanese encephalitis is a controllable disease in many countries in Asia, especially in 44 China, where many people have Japanese encephalitis virus (JEV) immunity due to 45 extensive JEV vaccination campaigns or natural exposure. Live-attenuated SA14-14-2 46 strain is a safe and effective vaccine recommended by the World Health Organization and 47 has been vaccinated more than 600 million doses since 1989. As the prevalence of Zika 48 virus (ZIKV) and rising risk in above regions, the cross-reactive immune response 49 between these two antigenically closely related flaviviruses, JEV and ZIKV, should also be 50 fully recognized, which is presumed to be based on those ambiguous cross-reactive 51 immunity between dengue virus and ZIKV. In this study, we found that JEV SA14-14-2 52 vaccine conferred cross-protection against ZIKV challenge in mice, which is mainly due to 53 cellular immunity rather than neutralizing antibody response. However, specific protective 54 components or cooperation between components warrant to be explored in subsequent 55 experiments. In conclusion, this study can provide important evidence for those who live in 56 JEV-endemic areas and are at risk for ZIKV infection.57 4 Introduction 58 Recently, Zika virus (ZIKV) has caused devastating outbreaks of fetal congenital 59 malformations in South and Central America and now transmitted in more than 70 60 countries, including many previously unaffected regions. ZIKV infection during pregnancy 61 increases the risk of neurological disorders in newborns (1), such as microcephaly. In 62 adults, ZIKV causes Guillain-Barré syndrome and other neurologic disorders (2). So far, 63 no specific vaccine or antiviral for prevention and treatment of Z...

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“…The reasons underlying the different fatty acid profiles between brain and retina tissue in Wnt signaling–deficient mice still need further investigation, but may be a reflection of the cellular structural differences in retina versus brain, as well as the differential presence of other redundant lipid transport mechanisms ( 56 ) or differential mechanisms related to MFSD2A stability and function. For example, the Zika virus was recently shown to be capable of disrupting MFSD2A and promoting its ubiquitination and degradation to impair MFSD2A-mediated DHA uptake in the brain ( 57 ). The transportation function of MFSD2A relates to its transcytosis regulatory function.…”

Section: Discussionmentioning

confidence: 99%

Wnt signaling activates MFSD2A to suppress vascular endothelial transcytosis and maintain blood-retinal barrier

et al. 2020

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Breakdown of the blood-retinal barrier (BRB) causes retinal edema and vision loss. We investigated the role of Wnt signaling in maintaining the BRB by limiting transcytosis. Mice lacking either the Wnt co-receptor low-density lipoprotein receptor–related protein 5 (Lrp5−/−) or the Wnt ligand Norrin (Ndpy/−) exhibit increased retinal vascular leakage and enhanced endothelial transcytosis. Wnt signaling directly controls the transcription of an endothelium-specific transcytosis inhibitor, major facilitator superfamily domain–containing protein 2a (MFSD2A), in a β-catenin–dependent manner. MFSD2A overexpression reverses Wnt deficiency–induced transcytosis in endothelial cells and in retinas. Moreover, Wnt signaling mediates MFSD2A-dependent vascular endothelium transcytosis through a caveolin-1 (CAV-1)–positive caveolae pathway. In addition, levels of omega-3 fatty acids are also decreased in Wnt signaling–deficient retinas, reflecting the basic function of MFSD2A as a lipid transporter. Our findings uncovered the Wnt/β-catenin/MFSD2A/CAV-1 axis as a key pathway governing endothelium transcytosis and inner BRB integrity.

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Zika virus degrades the ω-3 fatty acid transporter Mfsd2a in brain microvascular endothelial cells and impairs lipid homeostasis

Abstract: Both the endothelial transporter Mfsd2a and docosahexaenoic acid uptake are disrupted in Zika virus–induced microcephaly models.

Cited by 39 publications

References 22 publications

T cell immunity rather than antibody mediates cross-protection against Zika virus infection conferred by a live attenuated Japanese encephalitis SA14-14-2 vaccine

T cell immunity rather than antibody mediates cross-protection against Zika virus infection conferred by a live attenuated Japanese encephalitis SA14-14-2 vaccine

Cross-Protection Against Zika Virus Infection Conferred by a Live Attenuated Japanese Encephalitis SA14-14-2 Vaccine

Wnt signaling activates MFSD2A to suppress vascular endothelial transcytosis and maintain blood-retinal barrier

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