Maturation of the glymphatic system confers innate resistance of the brain to Zika virus infection

Background

Zika virus (ZIKV) is a mosquito-borne flavivirus that gained global attention due to its devastating effects on foetal brain development. Clinical evidence supports the idea that ZIKV can cross the placental barrier and infect the developing foetus, leading to microcephaly, brain malformations, and severe neurodevelopmental impairments. Importantly, the later the ZIKV infection occurs, the less risk it poses to neurodevelopment¹.

The glymphatic system (GS) represents an exchange system between cerebrospinal fluid and interstitial fluid, mediated mainly by astrocytic aquaporin-4 (AQP4) water channels. Metabolic waste in the brain, such as Aβ, can be cleared from the brain via highly polarised perivascular AQP4 channels in endfeet surrounding blood vessels, but its potential protective function against viral infections has remained largely unexplored².

In this preprint, the role of the glymphatic system in Zika virus infection is explored. Doerl and colleagues provide convincing evidence that the developmental state of the glymphatic system determines the severity of ZIKV infection.

Key findings

The preprint authors provide a detailed characterisation of how the timing of postnatal infection influences the severity of symptoms, from weight loss to difficulty moving. They showed that later ZIKV infection results in milder symptoms and suggested this is primarily due to the immaturity of the glymphatic system. They further found that when the glymphatic system is immature, ZIKV infection affects the development of this system, accompanied by abnormal cellular patterns of AQP4. Infection of the immature glymphatic system by the ZIKV resulted in a decrease in AQP4 astrocyte coverage on blood vessels and the recruitment of CD45+ leukocytes. Notably, in a developed glymphatic system, similar effects could be reproduced by direct contraction of brain arteries.

Importance

1. This study supplements as a functional mechanism to ZIKV infection, in which the existing molecular mechanisms primarily focused on neural progenitor cells. It is known that ZIKV has strong infection preference for neural progenitor cells, leading to malformation by increasing apoptosis and pyroptosis ³. Mild results from infection occur after the glymphatic system mature demonstrate the significant role of this functional anatomical structure in ZIKV infection.
2. During viral infections, it is suggested that clearance of Aβ and Tau, considered as brain metabolic waste related to cognitive decline, impaired, but compared to previous research based on the clearance of metabolic waste function, Doerl and colleagues innovatively explored the role of the glymphatic system in protecting the brain from ZIKV infection. They compared and found functional glymphatic system can “wash out” viral particles from the brain. The findings highlight the glymphatic system’s critical innate immune function in controlling central nervous system viral infections beyond its traditional waste clearance role.

Questions for the authors

1. You mention that ZIKV infection affects body weight, which led me to check the hypothalamic situation in Figure 2E and Figure 4B. Interestingly, I noticed that the hypothalamus seems to have less obvious alterations following infection. This contrasts with recent reports showing ZIKV infection causes profound hypothalamic inflammation and persistent metabolic dysfunction. What are your thoughts on this^4,5?

2. Given that V1Ra signalling has been implicated in regulating glymphatic function, do you think, from a translational perspective, early-stage ZIKV infection could be ameliorated by manipulating V1Ra activity to enhance glymphatic clearance? And how could this be developed for clinical use?

References

1. Nielsen-Saines K, Brasil P, Kerin T, et al. Delayed childhood neurodevelopment and neurosensory alterations in the second year of life in a prospective cohort of ZIKV-exposed children. Nat Med. 2019;25(8):1213-1217. doi:10.1038/s41591-019-0496-1
2. Wang Y, Huang C, Guo Q, Chu H. Aquaporin-4 and Cognitive Disorders. Aging Dis. 2022;13(1):61-72. Published 2022 Feb 1. doi:10.14336/AD.2021.0731
3. Sanami S, Banihashemian SZ, Amirpour S, et al. Neuroteratogenic mechanisms of Zika virus (ZIKV) infection: Insights into fetal brain development disruption and congenital Zika syndrome: A systematic review. Mol Aspects Med. Published online October 26, 2025. doi:10.1016/j.mam.2025.101418
4. Wu YH, Cui XY, Yang W, et al. Zika Virus Infection in Hypothalamus Causes Hormone Deficiencies and Leads to Irreversible Growth Delay and Memory Impairment in Mice. Cell Rep. 2018;25(6):1537-1547.e4. doi:10.1016/j.celrep.2018.10.025
5. de Lima EV, Nogueira CO, Christoff RR, et al. Central Zika virus infection causes hypothalamic inflammation and persistent insulin resistance in adult mice. Cell Death Dis. 2025;16(1):722. Published 2025 Oct 13. doi:10.1038/s41419-025-08046-5

Note: To improve clarity and readability, I used Perplexity AI (https://www.perplexity.ai) to polish the draft preLight.

 

doi: https://doi.org/10.1242/prelights.42195

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