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Review
. 2021 Feb;27(2):109-117.
doi: 10.1177/1753425920954281. Epub 2020 Sep 9.

Immune response and blood-brain barrier dysfunction during viral neuroinvasion

Zhuangzhuang Chen  1 , Guozhong Li  1
Affiliations
Review

Immune response and blood-brain barrier dysfunction during viral neuroinvasion

Zhuangzhuang Chen et al. Innate Immun. 2021 Feb.

Abstract

The blood-brain barrier (BBB), which protects the CNS from pathogens, is composed of specialized brain microvascular endothelial cells (BMECs) joined by tight junctions and ensheathed by pericytes and astrocyte endfeet. The stability of the BBB structure and function is of great significance for the maintenance of brain homeostasis. When a neurotropic virus invades the CNS via a hematogenous or non-hematogenous route, it may cause structural and functional disorders of the BBB, and also activate the BBB anti-inflammatory or pro-inflammatory innate immune response. This article focuses on the structural and functional changes that occur in the three main components of the BBB (endothelial cells, astrocytes, and pericytes) in response to infection with neurotropic viruses transmitted by hematogenous routes, and also briefly describes the supportive effect of three cells on the BBB under normal physiological conditions. For example, all three types of cells express several PRRs, which can quickly sense the virus and make corresponding immune responses. The pro-inflammatory immune response will exacerbate the destruction of the BBB, while the anti-inflammatory immune response, based on type I IFN, consolidates the stability of the BBB. Exploring the details of the interaction between the host and the pathogen at the BBB during neurotropic virus infection will help to propose new treatments for viral encephalitis. Enhancing the defense function of the BBB, maintaining the integrity of the BBB, and suppressing the pro-inflammatory immune response of the BBB provide more ideas for limiting the neuroinvasion of neurotropic viruses. In the future, these new treatments are expected to cooperate with traditional antiviral methods to improve the therapeutic effect of viral encephalitis.

Keywords: Blood-brain barrier (BBB); IFN signaling; SARS-CoV-2; innate immune response; viral neuroinvasion.

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Conflict of interest statement

Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Three main ways by which viruses pass through the blood-brain barrier (BBB): (1) the paracellular pathway (between cells), (2) the transcellular pathway (through cells), or (3) a ‘Trojan Horse’ mechanism through diapedesis of infected immune cells.
Figure 2.
Figure 2.
Receptors expressed by endothelial cells, such as PRRs, TAM, and major facilitator super family domain containing 2a (Mfsd2a), have the function of stabilizing the BBB. Endothelial cells express a variety of PRRs, and after recognizing PAMPs of viruses, they can activate the IFN signaling pathway and induce the production of type I IFN (IFN-1) and type III IFN in endothelial cells. The combination of IFN-1s and their receptor, IFNAR, can activate the JAK-STAT signaling cascade, and promote the expression of a series of antiviral gene IFN-stimulated genes. In addition, IFN-1 can activate Rac1 in endothelial cells to stabilize the integrity of the BBB.
Figure 3.
Figure 3.
Pericytes and astrocytes induce pro-inflammatory and anti-inflammatory innate immune responses. The released chemotactic molecules promote the infiltration of leukocytes. Neuroinvasion characteristics of severe acute respiratory syndrome coronavirus 2.
See this image and copyright information in PMC

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