Biology subjects

Farmen, K.

Publications and source records attributed to Farmen, K..

3 recordsLinked to original sources

bioRxiv2026

Bioengineered extracellular vesicles mitigate neuroinflammation by neutralizing pneumolysin and delaying disease onset in experimental pneumococcal meningitis

Bacterial meningitis is a life-threatening neurological disorder frequently caused by a Streptococcus pneumoniae (the pneumococcus) infection of the brain. Standard treatment consists of antibiotics to eliminate bacteria and dexamethasone to reduce inflammation. Despite this, mortality reaches 20% in treated individuals, and half of the survivors suffer long-term neurological sequelae. This is largely due to the poor capacity of antibiotics to reach the brain and the lack of antimicrobial treatment capable of neutralizing the pneumococcal toxin pneumolysin (Ply). To address these limitations, we isolated extracellular vesicles (EVs) derived from human HEK293T cells and evaluated their therapeutic potential in pneumococcal meningitis. Alongside wild-type EVs (WT.EVs), we bioengineered EVs to express RVG peptides (RVG.EV) for targeting neuronal acetylcholine receptors, signal incompetent IL-6 signal transducer (IL-6ST) decoy receptors (IL-6.EV) to block the pro-inflammatory signalling of IL-6, or EVs expressing both RVG peptides and IL-6ST (DB.EV). In vitro, all EVs reduced pneumococcal adhesion to neurons and mitigated cytotoxicity by binding and sequestering Ply. In a bacteremia-derived pneumococcal meningitis model, EV treatment significantly increased the survival of the mice without affecting bacterial load in the brain or the periphery. Among all groups, RVG.EV treatment was most effective in reducing pro-inflammatory cytokine release in the periphery and brain. These findings highlight the therapeutic potential of bioengineered EVs, particularly RVG peptides expressing EVs, as an adjunctive treatment for pneumococcal meningitis thanks to their (i) sequestration and neutralization of Ply, (ii) increased blood-brain barrier crossing, and (iii) dampening of inflammation.

neuroscience↗

bioRxiv2025

Bacteriophage-derived endolysins restore antibiotic susceptibility in penicillin- and erythromycin-resistant Streptococcus pneumoniae infections

Streptococcus pneumoniae, the pneumococcus, is a cause of major illness globally. Invasive pneumococcal disease (IPD) is characterized by pneumococci invading blood (bacteremia), lungs (pneumonia), or brain and cerebrospinal fluid (meningitis). Meningitis remains an important global health concern because half of the survivors experience long-term neurological damage. The antibiotics commonly used to treat pneumococcal infections are {beta}-lactams and macrolides, however, S. pneumoniae is nowadays often resistant to one or several antibiotics, therefore novel antimicrobials are needed. Here, we found that the bacteriophage-derived Cpl-1 endolysin showed consistent antibacterial activity against {beta}-lactam- and macrolide-resistant pneumococcal clinical strains grown in human blood and human cerebrospinal fluid. Exploiting synergistic and additive mechanisms, supplementation of cpl-1 to either penicillin or erythromycin rescued human neuronal cells from the cytotoxicity of antibiotic-resistant pneumococcal infections. Finally, systemic administration of cpl-1 supplemented to penicillin in mice infected with penicillin-resistant pneumococci successfully reduced bacteremia, and, thanks to the efficient penetration across the blood-brain barrier, abolished bacterial load in the brain, resulting in increased (89%) survival accompanied by an asymptomatic course of infection. These findings strongly indicate that cpl-1 can restore antibiotic sensitivity against {beta}-lactam- and macrolide-resistant S. pneumoniae, representing a fundamental adjunct therapy to standard-of-care antibiotics against multidrug-resistant IPD.

microbiology↗

bioRxiv2023

Spatio-temporal brain invasion pattern of Streptococcus pneumoniae and dynamic changes of the cellular environment in meningitis pathogenesis.

Streptococcus pneumoniae (the pneumococcus) is the major cause of bacterial meningitis globally, and pneumococcal meningitis is associated with increased risk of long-term neurological sequelae. These include several sensorimotor functions that are controlled by specific brain regions which, during bacterial meningitis, are damaged by the vast neuroinflammation and bacterial toxins. Little is known about the invasion pattern of the pneumococcus into the brain. Using a bacteremia-derived meningitis mouse model, we combined 3D whole brain imaging with brain microdissection to show that all brain regions were equally affected during disease progression, with pneumococci in close association to the microvasculature. In the hippocampus, the invasion provoked a dynamic microglial response, while the dentate gyrus showed a significant loss of neuroblasts. Our results indicate that, even before symptom occur, the bacterial load throughout the brain causes neuroinflammation and cell death, a pathological scenario which ultimately leads to a failing regeneration of new neurons.

neuroscience↗