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

Abstract

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 sepsisassociated 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 microgliacontaining 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.

Leveraging iPSC technology to assess neuro-immune interactions in neurological and psychiatric disorders

“…Induction of interferon responses and its potentially beneficial effects have also been demonstrated in iPSC-models for other neurotropic pathogens including La Crosse virus (54), Japanese Encephalitis Virus (55), Toxoplasma gondii (56), and Herpes Simplex Virus (HSV) (58). For example, HSV infection of iPSC-derived NSCs or neurons resulted in apoptosis and impaired neuronal differentiation, which was also validated in brain organoid models where HSV led to reduced cortical plate thickness and gliosis (57).…”

“…Interestingly, integration of microglia in a choroid plexus organoid model limited viral load and barrier disruption induced by HSV. This protective effect was conferred through cGAS-STING pathway activation in microglia, resulting in IFN-α secretion (58).…”

Breakthroughs in choroid plexus and CSF biology from the first European Choroid plexus Scientific Forum (ECSF)

“…SARS-CoV-2 infection and barrier damage was shown in ChP organoids [ 15 , 31 ] and these findings were demonstrated also in adult Covid patients [ 50 ] as well as in fetal brain tissue associated with infection [ 24 ]. ChP organoids incorporating microglia have also been used to model HSV-1 infection [ 33 ]. New exciting use of this technology has been presented at ECSF, as organoids infected with other pathogens such as S.suis or organoids employed to measure the turnover of CSF proteins in neurodegenerative diseases.…”

cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation

“…Neutrophils play an important role in the progression of sepsis as major effector cells against infection and as important regulators of innate immunity [ 123 ]. During sepsis, large amounts of bacterial products (e.g., CpG DNA) as well as the host’s own DNA (including nuclear and mitochondrial DNA) were released into the cytoplasm, leading to the activation of cGAS-STING and pyroptosis [ 124 ]. NAT10 was a negative regulator of neutrophil pyroptosis, and its reduced expression led to increased neutrophil pyroptosis and secretion of large amounts of the pro-inflammatory cytokines IL-1β and IL-18 [ 83 ].…”