Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

Jurado, Kellie Ann; Yockey, Laura J.; Wong, Patrick; Lee, Sarah; Hüttner, Anita; Iwasaki, Akiko

doi:10.1038/s41564-017-0060-z

Cited by 96 publications

(112 citation statements)

References 23 publications

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“…Furthermore, although in vivo experiment models proposed that the ZIKV crosses the BBB with no severe disruption, barrier breakdown was detected at a later post-infection time (Papa et al, 2017). Because ZIKV infection may recruit leukocyte to the brain and induce neuron lesion and death (Jurado et al, 2018;Mustafa et al, 2019), it is possible that later BBB disruption may be triggered by inflammatory response rather than ZIKV-induced proteasomal degradation.…”

Section: Discussionmentioning

confidence: 99%

The Mechanism of the Zika Virus Crossing the Placental Barrier and the Blood-Brain Barrier

Chiu¹,

Chu²,

Liao³

et al. 2020

Front. Microbiol.

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Zika virus (ZIKV) infection causes severe neurological symptoms in adults and fetal microcephaly and the virus is detected in the brain of microcephaly and meningoencephalitis patient. However, the mechanism of ZIKV crossing the physiological barrier to the central nervous systems (CNS) remains elusive. The placental barrier and the blood brain barrier (BBB) protect the fetus from pathogens and ensure healthy brain development during pregnancy. In this study, we used human placenta trophoblasts cells (JEG-3) and human brain-derived endothelial cells (hCMEC/D3) as in vitro models of the physiological barriers. Results showed that ZIKV could infect JEG-3 cells effectively and reduce the amounts of ZO-1 and occludin between adjacent cells by the proteasomal degradation pathway, suggesting that the permeability of the barrier differentially changed in response to ZIKV infection, allowing the virus particle to cross the host barrier. In contrast, ZIKV could infect hCMEC/D3 cells without disrupting the BBB barrier permeability and tight junction protein expression. Although no disruption to the BBB was observed during ZIKV infection, ZIKV particles were released on the basal side of the BBB model and infected underlying cells. In addition, we observed that fluorescence-labeled ZIKV particles could cross the in vitro placenta barrier and BBB model by transcytosis and the action of transcytosis could be blocked by either low temperature or pharmacological inhibitors of endocytosis. In summary, the ZIKV uses a cell-type specific paracellular pathway to cross the placenta monolayer barrier by disrupting cellular tight junction. In addition, the ZIKV can also cross both the placenta barrier and the BBB by transcytosis. Our study provided new insights into on the mechanism of the cellular barrier penetration of ZIKV particles.

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Section: Discussionmentioning

confidence: 99%

The Mechanism of the Zika Virus Crossing the Placental Barrier and the Blood-Brain Barrier

Chiu¹,

Chu²,

Liao³

et al. 2020

Front. Microbiol.

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“…In certain circumstances, flavivirus-specific CD8 + T cells can cause immunopathology. The antiviral activity of CD8 + T cells within the brain markedly limited ZIKV infection of neurons, but also triggered ZIKV-associated paralysis in mice 129 . CD8 + T cells induced immunopathology in the brain after infection with TBEV 130 , and for DENV, a pathogenic role of CD8 + T cells has been described during secondary infection.…”

Section: Immune Response To Flavivirus Infectionmentioning

confidence: 99%

The continued threat of emerging flaviviruses

Pierson

Diamond²

2020

Nat Microbiol

658

627

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F laviviruses are single-stranded RNA viruses vectored principally by arthropods that cause severe illnesses in humans. The extensive global spread and epidemic transmission of flaviviruses during the last seven decades has been remarkable. The mosquito-borne dengue viruses (DENV) infect an estimated 400 million humans each year; more than a quarter of the world's population lives in areas where DENV is now endemic 1 . By comparison, only sporadic DENV epidemics were documented before the Second World War 2 . The introductions of West Nile (WNV) and Zika (ZIKV) viruses into the Western Hemisphere was followed by rapid geographical spread, large numbers of human infections and considerable morbidity 3,4 . Ongoing yellow fever virus (YFV) transmission and its encroachment on urban environments, despite the existence of an effective vaccine, poses a serious public health challenge 5-7 . Other flaviviruses present ongoing health risks or are beginning to emerge in different parts of the world, including Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV) and Usutu virus (USUV).The epidemic potential of flaviviruses reflects many factors related to the unique characteristics of their insect vectors, the consequences of poorly planned urbanization that creates ideal arthropod breeding habitats, the geographical expansion of vectors, changing environmental conditions and extensive global travel 8,9 . Beyond arthropods and humans, flaviviruses are also known to infect a wide array of animal species and can be important veterinary pathogens that threaten economically important domesticated animals 10-14 . These vertebrate animal hosts may constitute important stable reservoirs and contribute to defining conditions that support the introduction of new viral species and transmission among humans 15 . The continued threat of flavivirus emergence and re-emergence highlights a need for a detailed fundamental understanding of the biology of these viruses, the immune responses that can contain them and the possible countermeasures that can blunt their impact on public health should new outbreaks occur. Flavivirus structure and replicationFlaviviruses are small (~50 nm) spherical virus particles that incorporate a single genomic RNA of positive-sense polarity encoding three structural and seven non-structural proteins (Fig. 1a). Our knowledge of the biology of flaviviruses has advanced considerably with the availability of high-resolution structures of viral structural proteins and of virions at different stages of the replication cycle or in complex with antibodies or host factors 16 . Crystal structures of the enzymatic non-structural proteins also have been solved, accelerating advances in an understanding of virus replication and pathogenesis [17][18][19] and enabling structure-guided drug discovery, as reviewed elsewhere 20 .Virion structure and morphogenesis. Flaviviruses are assembled using three viral structural proteins (C, prM and E), a host lipid envelope and the viral genomic RNA. The structure of ...

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“…This result confirmed our findings with the chromogenic in situ RNA hybridization assay. The negative control group, cage mate IFNAR+/-mice infected with ZIKV, did not show any measurable amounts of viral RNA in all three tissues, confirming that spread to the brain might require IFNAR1 deficiency (16).…”

Section: Zikv Infection Of the Choroid Plexus And The Meninges Precedmentioning

confidence: 84%

“…The infection of astrocytes, which are in close contact with endothelial cells, is known to be associated with breakdown of the BBB (16), which could provide a route to the brain.…”

Section: Introductionmentioning

confidence: 99%

Zika virus infects pericytes in the choroid plexus and enters the central nervous system through the blood-cerebrospinal fluid barrier

Kim

Hetman

Hattab

et al. 2019

Preprint

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ABSTRACTZika virus (ZIKV) can infect and cause microcephaly and Zika-associated neurological complications in the developing fetal and adult brains. In terms of pathogenesis, a critical question is how ZIKV overcomes the barriers separating the brain from the circulation and gains access to the central nervous system (CNS). Despite the importance of ZIKV pathogenesis, the route ZIKV utilizes to cross CNS barriers remains unclear.Here we show that in mouse models, ZIKV-infected cells initially appeared in the periventricular regions of the brain, including the choroid plexus and the meninges, prior to infection of the cortex. The appearance of ZIKV in cerebrospinal fluid (CSF) preceded infection of the brain parenchyma. We show that ZIKV infects pericytes in the choroid plexus, and that ZIKV infection of pericytes is dependent on AXL receptor tyrosine kinase. Using an in vitro Transwell system, we highlight the possibility of ZIKV to move from the blood side to CSF side, across the choroid plexus epithelial layers, via a nondestructive pathway (e.g., transcytosis). Finally, we demonstrate that brain infection is significantly attenuated by neutralization of the virus in the CSF, indicating that ZIKV in the CSF at the early stage of infection might be responsible for establishing a lethal infection of the brain. Taken together, our results suggest that ZIKV invades the host brain by exploiting the blood-CSF barrier rather than the blood-brain barrier.AUTHOR SUMMARYZika virus invades the human brains and causes Zika-associated neurological complications; however, the mechanism(s) by which Zika virus accesses the central nerves system remain unclear. Understanding of the cellular and molecular mechanisms will shed light on development of novel therapeutic and prophylactic targets for Zika virus and other neurotropic viruses. Here we use in vivo and in vitro models to understand how Zika virus enters the brain. In mouse models, we found that Zika virus infects pericytes in the choroid plexus at very early stages of infection and neutralization of Zika virus in the cerebrospinal fluid significantly attenuate the brain infection. Further we show evidence that Zika virus can cross the epithelial cell layers in the choroid plexus from the blood side. Our research highlights that ZIKV invades the host brain by exploiting the blood-CSF barrier rather than the blood-brain barrier.

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Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice

Cited by 96 publications

References 23 publications

The Mechanism of the Zika Virus Crossing the Placental Barrier and the Blood-Brain Barrier

The Mechanism of the Zika Virus Crossing the Placental Barrier and the Blood-Brain Barrier

The continued threat of emerging flaviviruses

Zika virus infects pericytes in the choroid plexus and enters the central nervous system through the blood-cerebrospinal fluid barrier

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