Karolinska Institutet
Neuroscience
I am an Associate Professor and Principal Investigator at the Department of Neuroscience at Karolinska Institute in Stockholm, Sweden. In my laboratory we investigate host-pathogen interactions during pneumococcal infections of the Central Nervous System (CNS). The major burden of pneumococcal infections of the CNS and pneumococcal meningitis are the neurological dysfunctions (sequelae) experienced by 50% of the survivors due to a neuronal damage and cell death caused by the infection. Damaged and dead neurons cannot be either repaired or replaced in most of the cases. Our research has two main objectives: 1) Understanding the molecular mechanisms regulating neuronal damage caused by bacterial interaction and establish the blockade of pneumococcal-neuron interaction as new therapeutic approach to protect neurons and prevent neurological sequelae, 2) Identifying the molecules on pneumococci that trigger the phagocytosis process by microglia, the immune sentinels of the brain, and ultimately use these molecules as immuno-stimulatory agents to enhance the phagocytic capacity of microglia for an efficient elimination of the pathogens and providing protection for neurons.

Presenter of 1 Presentation

O062 - MOLECULAR MECHANISMS OF NEURONAL DAMAGE CAUSED BY PNEUMOCOCCAL INFECTION (ID 818)

Session Type
Parallel Session
Date
Wed, 22.06.2022
Session Time
15:05 - 16:50
Room
Grand Ballroom Centre
Lecture Time
16:11 - 16:19

Abstract

Background

Streptococcus pneumoniae (the pneumococcus) is the main etiological cause of bacterial meningitis globally. 50% of survivors suffer from permanent neurological dysfunctions, such as cognitive and motor delay, hearing loss, and psychiatric disorders, due to a neuronal injury caused by the bacterial infection.

Methods

Through cell-culture assays, we have investigated the cytotoxicity inflicted by pneumococci to human neurons, and the capacity of pneumococci to interact (adhesion/invasion) with neurons. In vitro assays using purified proteins were performed to investigate pneumococcal-neuron interaction. Results were confirmed with our in vivo meningitis mouse model combined with ex vivo high-resolution immunofluorescence microscopy analysis.

Results

Thanks to their elasticity and motility, neurons present some cytoskeleton β-actin filaments exposed on their plasma membrane. S. pneumoniae can invade and kill neurons through interaction with the pneumococcal pilus-1 adhesin RrgA and pneumolysin with the neuronal β-actin filaments exposed on the neuronal plasma membrane. S. pneumoniae can then exploit the interaction with neuronal β-actin to invade neurons causing disruption of the cytoskeleton. Importantly, when the surface-exposed β-actin filaments are blocked with specific antibodies, pneumococcal adhesion to neurons is prevented and neurons in vitro survive from pneumococcal infection.

Conclusions

For the first time in literature, our study published in 2021 in PLOS Pathogens has shed light into important aspects of pneumococcal-neuron interactions: 1. Pneumococci adhere to and invade neurons through interaction of the pilus-1 tip-protein RrgA and pneumolysin with β-actin exposed on neuronal plasma membrane 2. Blockade of this interaction can prevent neuronal death during a pneumococcal infection in vitro opening new avenues for new therapeutic approaches.

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