Combining antibiotic with anti-TLR2/TLR13 therapy prevents brain pathology in pneumococcal meningitis

Dyckhoff-Shen, Susanne; Masouris, Ilias; Islam, Heba; Hammerschmidt, Sven; Angele, Barbara; Marathe, Veena; Buer, Jan; Völk, Stefanie; Pfister, Hans-Walter; Klein, Matthias; Koedel, Uwe; Kirschning, Carsten J. (2024): Combining antibiotic with anti-TLR2/TLR13 therapy prevents brain pathology in pneumococcal meningitis. JCI Insight. ISSN 2379-3708

Abstract

Despite effective antibiotic therapy, brain destructive inflammation often cannot be avoided in pneumococcal meningitis. The causative signals are mediated predominantly through TLR recruited myeloid differentiation primary response adaptor (MyD) 88 as indicated by a dramatic pneumococcal meningitis phenotype of Myd88-/- mice. Because lipoproteins and ssRNA are crucial for recognition of Gram-positive bacteria such as Streptococcus pneumoniae by the host immune system, we comparatively analyzed the disease courses of Myd88-/- and Tlr2/13-/- mice. Their phenotype resemblance indicated TLR2 and -13 as master sensors of Streptococcus pneumoniae in the cerebrospinal fluid. The neutralizing anti-TLR2 antibody (T2.5) and chloroquine (CQ) – the latter applied here as an inhibitor for murine TLR13 and its human orthologue TLR8 – abrogated activation of murine and human primary immune cells exposed to antibiotic-treated Streptococcus pneumoniae. The inhibitory effect of the T2.5/CQ cocktail was stronger than that of dexamethasone, the current standard adjunctive drug for pneumococcal meningitis. Accordingly, TLR2/13 blockade concomitant with ceftriaxone application significantly improved the clinical course of pneumococcal meningitis compared to treatment with ceftriaxone alone or in combination with dexamethasone. Our study implicates the importance of murine TLR13 and human TLR8, besides TLR2, in pneumococcal meningitis pathology, and suggests their blockade as a promising antibiotic therapy adjunct.

• Dokumententyp: Artikel (Klinikum der LMU)
• Organisationseinheit (Fakultäten): 07 Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut
• DFG-Fachsystematik der Wissenschaftsbereiche: Lebenswissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - KO1974/7-1, KI-596/6-1, ausgelaufen 05/2019
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892