Pneumococcal DNA-binding proteins released through autolysis induce the production of proinflammatory cytokines via toll-like receptor 4

Nagai, Koichi; Domon, Hisanori; Maekawa, Tomoki; Oda, Masataka; Hiyoshi, Takumi; Tamura, Hikaru; Yonezawa, Daisuke; Arai, Yoshiaki; Yokoji, Mai; Tabeta, Koichi; Habuka, Rie; Saitoh, Akihiko; Yamaguchi, M.; Kawabata, Shigetada; Terao, Yutaka

doi:10.1016/j.cellimm.2018.01.006

Cited by 20 publications

(19 citation statements)

References 42 publications

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“…Additionally, LytA plays a role in a variety of physiological cell functions associated with cell wall growth, its turnover, and cell separation in pneumococci (28). In addition to the release of PLY, LytA contributes to the release of intracellular virulence factors, which induce the production of proinflammatory cytokines in macrophages via Toll-like receptor 4 (33). Mutations of the lytA gene in S. pneumoniae lead to a significantly decreased virulence of this organism compared to that of the wild-type strain in a mouse intraperitoneal infection model (34).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Macrolide-Induced Inhibition of Pneumolysin Release Involves Impairment of Autolysin Release in Macrolide-Resistant Streptococcus pneumoniae

Domon

Maekawa

Yonezawa

et al. 2018

Antimicrob Agents Chemother

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is a leading cause of community-acquired pneumonia. Over the past 2 decades, macrolide resistance among organisms has been increasing steadily and has escalated at an alarming rate worldwide. However, the use of macrolides in the treatment of community-acquired pneumonia has been reported to be effective regardless of the antibiotic susceptibility of the causative pneumococci. Although previous studies suggested that sub-MICs of macrolides inhibit the production of the pneumococcal pore-forming toxin pneumolysin by macrolide-resistant (MRSP), the underlying mechanisms of the inhibitory effect have not been fully elucidated. Here, we show that the release of pneumococcal autolysin, which promotes cell lysis and the release of pneumolysin, was inhibited by treatment with azithromycin and erythromycin, whereas replenishing with recombinant autolysin restored the release of pneumolysin from MRSP. Additionally, macrolides significantly downregulated transcription followed by a slight decrease of the intracellular pneumolysin level. These findings suggest the mechanisms involved in the inhibition of pneumolysin in MRSP, which may provide an additional explanation for the benefits of macrolides on the outcome of treatment for pneumococcal diseases.

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Section: Discussionmentioning

confidence: 99%

Mechanism of Macrolide-Induced Inhibition of Pneumolysin Release Involves Impairment of Autolysin Release in Macrolide-Resistant Streptococcus pneumoniae

Domon

Maekawa

Yonezawa

et al. 2018

Antimicrob Agents Chemother

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“…Elongation factor Tu (EF-Tu) Surface protein Catalyzes the binding of an aminoacyl-tRNA (aa-tRNA) to the ribosome. Inhibit protein synthesis [68] Pneumococcal peptide 27 (Pep27) Cell membrane Enable the bacteria to attach or colonize in the lungs, blood, and brain [15] Pneumococcal surface protein A (PspA) is a choline-binding protein present on the cell surface of almost all pneumococcal strains. The N-terminal domain of PspA is exposed on the surface and the sequence variations are used to classify pneumococcal strains into three families and six clades.…”

Section: Protein-based Vaccinesmentioning

confidence: 99%

“…EF-Tu displays molecular chaperone activity and it is involved in peptide biosynthesis, protein folding and cell response to stress [91]. Nagai et al showed that S. pneumoniae released EF-Tu through autolysis and this was followed by the induction of proinflammatory cytokines in macrophages via the toll-like receptor 4 [68]. A recombinant vaccine was developed containing only the EF-Tu protein of S. pneumoniae strain D39 against pneumococcal infection.…”

Section: Protein-based Vaccinesmentioning

confidence: 99%

Development of Next Generation Streptococcus pneumoniae Vaccines Conferring Broad Protection

et al. 2020

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Streptococcus pneumoniae is a major pathogen causing pneumonia with over 2 million deaths annually, especially in young children and the elderly. To date, at least 98 different pneumococcal capsular serotypes have been identified. Currently, the vaccines for prevention of S. pneumoniae infections are the 23-valent pneumococcal polysaccharide-based vaccine (PPV23) and the pneumococcal conjugate vaccines (PCV10 and PCV13). These vaccines only cover some pneumococcal serotypes and are unable to protect against non-vaccine serotypes and unencapsulated S. pneumoniae. This has led to a rapid increase in antibiotic-resistant non-vaccine serotypes. Hence, there is an urgent need to develop new, effective, and affordable pneumococcal vaccines, which could cover a wide range of serotypes. This review discusses the new approaches to develop effective vaccines with broad serotype coverage as well as recent development of promising pneumococcal vaccines in clinical trials. New vaccine candidates are the inactivated whole-cell vaccine strain (Δpep27ΔcomD mutant) constructed by mutations of specific genes and several protein-based S. pneumoniae vaccines using conserved pneumococcal antigens, such as lipoprotein and surface-exposed protein (PspA). Among the vaccines in Phase 3 clinical trials are the pneumococcal conjugate vaccines, PCV-15 (V114) and 20vPnC. The inactivated whole-cell and several protein-based vaccines are either in Phase 1 or 2 trials. Furthermore, the recent progress of nanoparticles that play important roles as delivery systems and adjuvants to improve the performance, as well as the immunogenicity of the nanovaccines, are reviewed.

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“…The resulting presence of the mature ply pore in host cells drives protein influx and imbalances in signal transduction [ 75 ]. Pneumolysin is also a stimulator of classical complement pathways [ 75 ], and of both TLR and the nucleotide-binding oligomerisation domain (Nod)-like receptor (NLR)-activated inflammasome pathways [ 76 , 77 ]. It also activates NADPH oxidase and induces reactive oxygen species production in neutrophils in a manner dependent on pneumococcal autolysin LytA [ 78 ].…”

Section: The Bbb In Acute Pmmentioning

confidence: 99%

“…In PM, a number of virulence factors or pneumococcal proteins can trigger these receptors [ 95 ]. For instance, surface-bound TLR2 on glial cells is activated upon recognition of peptidoglycan and lipoteichoic acid in the S. pneumoniae cell wall [ 96 , 97 , 98 ], while ply stimulates TLR4 [ 76 , 99 ]. Endosomal TLR9 responds to S. pneumoniae CpG motifs in genomic DNA [ 100 ], but requires prior surface recognition and uptake of S. pneumoniae into endolysosomes or phagolysosomes [ 101 ].…”

Section: The Bbb In Acute Pmmentioning

confidence: 99%

Blood‒Brain Barrier Pathology and CNS Outcomes in Streptococcus pneumoniae Meningitis

Yau

Hunt

Mitchell

et al. 2018

IJMS

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Streptococcus pneumoniae is a major meningitis-causing pathogen globally, bringing about significant morbidity and mortality, as well as long-term neurological sequelae in almost half of the survivors. Subsequent to nasopharyngeal colonisation and systemic invasion, translocation across the blood‒brain barrier (BBB) by S. pneumoniae is a crucial early step in the pathogenesis of meningitis. The BBB, which normally protects the central nervous system (CNS) from deleterious molecules within the circulation, becomes dysfunctional in S. pneumoniae invasion due to the effects of pneumococcal toxins and a heightened host inflammatory environment of cytokines, chemokines and reactive oxygen species intracranially. The bacteria‒host interplay within the CNS likely determines not only the degree of BBB pathological changes, but also host survival and the extent of neurological damage. This review explores the relationship between S. pneumoniae bacteria and the host inflammatory response, with an emphasis on the BBB and its roles in CNS protection, as well as both the acute and long-term pathogenesis of meningitis.

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Pneumococcal DNA-binding proteins released through autolysis induce the production of proinflammatory cytokines via toll-like receptor 4

Cited by 20 publications

References 42 publications

Mechanism of Macrolide-Induced Inhibition of Pneumolysin Release Involves Impairment of Autolysin Release in Macrolide-Resistant Streptococcus pneumoniae

Mechanism of Macrolide-Induced Inhibition of Pneumolysin Release Involves Impairment of Autolysin Release in Macrolide-Resistant Streptococcus pneumoniae

Development of Next Generation Streptococcus pneumoniae Vaccines Conferring Broad Protection

Blood‒Brain Barrier Pathology and CNS Outcomes in Streptococcus pneumoniae Meningitis

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