SARS-CoV-2 induces blood-brain barrier and choroid plexus barrier impairments and vascular inflammation in mice.

The coronavirus disease of 2019 (COVID-19) pandemic has led to more than 700 million confirmed cases and nearly 7 million deaths. Although severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus mainly infects the respiratory system, neurological complications are widely reported in both acute infection and long-COVID cases. Despite the success of vaccines and antiviral treatments, neuroinvasiveness of SARS-CoV-2 remains an important question, which is also centered on the mystery of whether the virus is capable of breaching the barriers into the central nervous system. By studying the K18-hACE2 infection model, we observed clear evidence of microvascular damage and breakdown of the blood-brain barrier (BBB). Mechanistically, SARS-CoV-2 infection caused pericyte damage, tight junction loss, endothelial activation and vascular inflammation, which together drive microvascular injury and BBB impairment. In addition, the blood-cerebrospinal fluid barrier at the choroid plexus was also impaired after infection. Therefore, cerebrovascular and choroid plexus dysfunctions are important aspects of COVID-19 and may contribute to neurological complications both acutely and in long COVID.

Microglia innate immune response contributes to the antiviral defense and blood-CSF barrier function in human choroid plexus organoids during HSV-1 infection.

The choroid plexus (ChP) is the source of cerebrospinal fluid (CSF). The ChP-CSF system not only provides the necessary cushion for the brain but also works as a sink for waste clearance. During sepsis, pathogens and host immune cells can weaken the ChP barrier and enter the brain, causing cerebral dysfunctions known as sepsis-associated encephalophagy. Here, we used human ChP organoid (ChPO) to model herpes simplex virus type 1 (HSV-1) infection and found ChP epithelial cells were highly susceptible to HSV-1. Since the current ChPO model lacks a functional innate immune component, particularly microglia, we next developed a new microglia-containing ChPO model, and found microglia could effectively limit HSV-1 infection and protect epithelial barrier in ChPOs. Furthermore, we found the innate immune cyclic GMP-AMP synthase (cGAS)-STING pathway and its downstream interferon response were essential, as cGAS inhibitor RU.512 or STING inhibitor H-151 abolished microglia antiviral function and worsened ChP barrier in organoids. These results together indicated that cGAS-STING pathway coordinates antiviral response in ChP and contributes to treating sepsis or related neurological conditions.