Choroid plexus organoids reveal mechanisms of Streptococcus suis translocation at the blood-cerebrospinal fluid barrier.

Abstract

Streptococcus suis is a globally emerging zoonotic pathogen that can cause invasive disease commonly associated with meningitis in pigs and humans. To cause meningitis, S. suis must invade the central nervous system (CNS) by crossing the neurovascular unit, also known as the blood-brain barrier (BBB), or vascularized choroid plexus (ChP) epithelium known as the blood-cerebrospinal fluid barrier (BCSFB). Recently developed ChP organoids have been shown to accurately replicate the cytoarchitecture and physiological functions of the ChP epithelium in vivo. Here, we used human induced pluripotent stem cells (iPSC)-derived ChP organoids as an in vitro model to investigate S. suis interaction and infection at the BCSFB. Our study revealed that S. suis is capable of translocating across the epithelium of ChP organoids without causing significant cell death or compromising the barrier integrity. Plasminogen (Plg) binding to S. suis in the presence of tissue plasminogen activator (tPA), which converts immobilized Plg to plasmin (Pln), significantly increased the basolateral to apical translocation across ChP organoids into the CSF-like fluid in the lumen. S. suis was able to replicate at the same rate in CSF and laboratory S. suis culture medium but reached a lower final density. The analysis of transcriptomes in ChP organoids after S. suis infection indicated inflammatory responses, while the addition of Plg further suggested extracellular matrix (ECM) remodeling. To our knowledge, this is the first study using ChP organoids to investigate bacterial infection of the BCSFB. Our findings highlight the potential of ChP organoids as a valuable tool for studying the mechanisms of bacterial interaction and infection of the human ChP in vitro.