RAGE and CCR7 mediate the transmigration of Zika-infected monocytes through the blood-brain barrier

Carvalho, Gabriel Costa de; Borget, Marie-Yolande; Bernier, Stéphane; Garneau, Daniel; Duarte, Alberto José da Silva; Dumais, Nancy

doi:10.1016/j.imbio.2019.08.007

Cited by 27 publications

(21 citation statements)

References 82 publications

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“…For instance, WNV can reach the CNS by infecting monocytes, dendritic cells, or macrophages ( 40 , 41 ). ZIKV has been also suggested to use this mechanism ( 42 – 44 ), and here we show that some CD45 + cells are recruited to cells lining blood vessels and display ZIKV antigen staining ( Fig. 9d ).…”

Section: Discussionsupporting

confidence: 66%

Zika Virus Infection Promotes Local Inflammation, Cell Adhesion Molecule Upregulation, and Leukocyte Recruitment at the Blood-Brain Barrier

Clé

Desmetz

Barthélémy

et al. 2020

mBio

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The blood-brain barrier (BBB) largely prevents toxins and pathogens from accessing the brain. Some viruses have the ability to cross this barrier and replicate in the central nervous system (CNS). Zika virus (ZIKV) was responsible in 2015 to 2016 for a major epidemic in South America and was associated in some cases with neurological impairments. Here, we characterized some of the mechanisms behind its neuroinvasion using an innovative in vitro human BBB model. ZIKV efficiently replicated, was released on the BBB parenchyma side, and triggered subtle modulation of BBB integrity as well as an upregulation of inflammatory and cell adhesion molecules (CAMs), which in turn favored leukocyte recruitment. Finally, we showed that ZIKV-infected mouse models displayed similar CAM upregulation and that soluble CAMs were increased in plasma samples from ZIKV-infected patients. Our observations suggest a complex interplay between ZIKV and the BBB, which may trigger local inflammation, leukocyte recruitment, and possible cerebral vasculature impairment. IMPORTANCE Zika virus (ZIKV) can be associated with neurological impairment in children and adults. To reach the central nervous system, viruses have to cross the blood-brain barrier (BBB), a multicellular system allowing a tight separation between the bloodstream and the brain. Here, we show that ZIKV infects cells of the BBB and triggers a subtle change in its permeability. Moreover, ZIKV infection leads to the production of inflammatory molecules known to modulate BBB integrity and participate in immune cell attraction. The virus also led to the upregulation of cellular adhesion molecules (CAMs), which in turn favored immune cell binding to the BBB and potentially increased infiltration into the brain. These results were also observed in a mouse model of ZIKV infection. Furthermore, plasma samples from ZIKV-infected patients displayed an increase in CAMs, suggesting that this mechanism could be involved in neuroinflammation triggered by ZIKV.

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Section: Discussionsupporting

confidence: 66%

Zika Virus Infection Promotes Local Inflammation, Cell Adhesion Molecule Upregulation, and Leukocyte Recruitment at the Blood-Brain Barrier

Clé

Desmetz

Barthélémy

et al. 2020

mBio

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“…Considering that Zika has tropism and may infect endothelial cells, as demonstrated in models using human vein and artery cells [ 89 , 100 , 101 ], and due to its phylogenetic relationship to DENV in genus Flavivirus [ 102 ], and the eventual similarity among their components, including NS1 [ 103 ], it is reasonable to admit a correlation between this protein and strokes or brain hemorrhage. Besides, ZIKV-infected monocytes may have transmigrated through BBB in a model based on inflammatory activation, with essential role of T and B lymphocytes, TLR, receptor for advanced glycation end products (RAGE) and microvascular endothelial dysregulation [ 104 ]. The end of RAGE pathway is the production of IL-1 β among other cytokine by monocytes [ 105 ].…”

Section: Discussionmentioning

confidence: 99%

Flavivirus Infection Associated with Cerebrovascular Events

Estofolete

Milhim

Zini

et al. 2020

Viruses

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Arthropod-borne viruses (arboviruses) of the genus Flavivirus are distributed globally and cause significant human disease and mortality annually. Flavivirus infections present a spectrum of clinical manifestations, ranging from asymptomatic to severe manifestations, including hemorrhage, encephalitis and death. Herein, we describe 3 case reports of cerebrovascular involvement in patients infected by dengue and Zika viruses in Sao Jose do Rio Preto, São Paulo State, Brazil, a hyperendemic area for arbovirus circulation, including dengue, yellow fever, chikungunya and Saint Louis encephalitis viruses. Our findings highlight the potential threat that unusual clinical manifestations may pose to arbovirus disease management and recovery.

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“…Interestingly, CD14 + CD16 + monocytes isolated from HIV-infected patients have increased expression of JAM-A and ALCAM, and both molecules participate in CD14 + CD16 + monocyte migration across the BBB (121), as well as CXCR7 (122). On the other hand, Zika virus-infected monocytes depend on CCR7 and receptor for advanced glycation end (RAGE) for transmigration across the human BBB (123).…”

Section: Monocytes and Dendritic Cellsmentioning

confidence: 99%

Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation

2020

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To maintain the homeostatic environment required for proper function of CNS neurons the endothelial cells of CNS microvessels tightly regulate the movement of ions and molecules between the blood and the CNS. The unique properties of these blood vascular endothelial cells are termed blood-brain barrier (BBB) and extend to regulating immune cell trafficking into the immune privileged CNS during health and disease. In general, extravasation of circulating immune cells is a multi-step process regulated by the sequential interaction of adhesion and signalling molecules between the endothelial cells and the immune cells. Accounting for the unique barrier properties of CNS microvessels, immune cell migration across the BBB is distinct and characterized by several adaptations. Here we describe the mechanisms that regulate immune cell trafficking across the BBB during immune surveillance and neuroinflammation, with a focus on the current state-of-the-art in vitro and in vivo imaging observations.

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RAGE and CCR7 mediate the transmigration of Zika-infected monocytes through the blood-brain barrier

Cited by 27 publications

References 82 publications

Zika Virus Infection Promotes Local Inflammation, Cell Adhesion Molecule Upregulation, and Leukocyte Recruitment at the Blood-Brain Barrier

Zika Virus Infection Promotes Local Inflammation, Cell Adhesion Molecule Upregulation, and Leukocyte Recruitment at the Blood-Brain Barrier

Flavivirus Infection Associated with Cerebrovascular Events

Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation

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