Abstract
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.
Highlights
The blood-brain barrier (BBB) largely prevents toxins and pathogens from accessing the brain
While viral antigens were detected in cells at 6 dpi (MOI, 0.1), suggesting viral replication (Fig. 1a), global endothelium architecture did not appear massively perturbed, even at 10 dpi and a higher MOI (MOI, 1) (Fig. 1b and c), in contrast to what we previously showed in retinal pigment epithelium, which was very sensitive to Zika virus (ZIKV) infection [32]
Albeit viral replication was not deleterious, ZIKV in hBLECs, pericytes, and astrocytes led to the upregulation of some inflammatory cytokines (i.e., interleukin 6 (IL-6) and IL-8) and some chemokines involved in immune cell recruitment (i.e., CCL5 and CXCL10)
Summary
The blood-brain barrier (BBB) largely prevents toxins and pathogens from accessing the brain. The virus 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 observed in a mouse model of ZIKV infection. Brain access can occur by different mechanisms, including axonal transport and direct or indirect passage through brain barriers [4, 5] Some viruses such as the human immunodeficiency virus (HIV) or West Nile virus (WNV) use the “Trojan horse” mechanism to cross the BBB: this occurs when infected cells of the immune system, with their natural ability to transcytose and reach the brain, allow viruses to penetrate the parenchyma [6, 7]. Similar observations were obtained in a mouse model of ZIKV infection as well in plasma samples from ZIKV-infected patients
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