Pathophysiology of acute meningitis caused by Streptococcus pneumoniae and adjunctive therapy approaches

Abstract

Pneumococcal meningitis is a life-threatening disease characterized by an acute purulent infection affecting piamater, arachnoid and the subarachnoid space. The intense inflammatory host's response is potentially fatal and contributes to the neurological sequelae. Streptococcus pneumoniae colonizes the nasopharynx, followed by bacteremia, microbial invasion and blood-brain barrier traversal. S. pneumoniae is recognized by antigen-presenting cells through the binding of Toll-like receptors inducing the activation of factor nuclear kappa B or mitogen-activated protein kinase pathways and subsequent up-regulation of lymphocyte populations and expression of numerous proteins involved in inflammation and immune response. Many brain cells can produce cytokines, chemokines and others pro-inflammatory molecules in response to bacteria stimuli, as consequence, polymorphonuclear are attracted, activated and released in large amounts of superoxide anion and nitric oxide, leading to the peroxynitrite formation, generating oxidative stress. This cascade leads to lipid peroxidation, mitochondrial damage, blood-brain barrier breakdown contributing to cell injury during pneumococcal meningitis.

Structural determinants for ligand capture by a class II preQ 1 riboswitch

“…High-resolution X-ray crystal and solution NMR structures have revealed that preQ 1 -I aptamers form H-type pseudoknots with two stems and three loops (33)(34)(35)(36). Subsequent studies detailing preQ 1 -I riboswitch dynamics and folding pathway have shown that divalent cations bind loop 1 and stabilize the bound conformation (21, 37).To date, preQ 1 -II riboswitches have been found primarily in virulent streptococcal strains, such as Streptococcus pneumoniae (Spn) (27), a significant pathogen that is one of the leading causes of bacterial meningitis (16,38), making this riboswitch an excellent candidate for antibacterial therapeutic targeting. An X-ray crystal structure of the Lactobacillus rhamnosus (Lra) preQ 1 -II riboswitch aptamer bound to preQ 1 was recently determined at 2.3 Å (39), revealing a mode of preQ 1 recognition different from that of preQ 1 -I riboswitches, as predicted by in-line probing and mutagenesis experiments (27).…”

“…To date, preQ 1 -II riboswitches have been found primarily in virulent streptococcal strains, such as Streptococcus pneumoniae (Spn) (27), a significant pathogen that is one of the leading causes of bacterial meningitis (16,38), making this riboswitch an excellent candidate for antibacterial therapeutic targeting. An X-ray crystal structure of the Lactobacillus rhamnosus (Lra) preQ 1 -II riboswitch aptamer bound to preQ 1 was recently determined at 2.3 Å (39), revealing a mode of preQ 1 recognition different from that of preQ 1 -I riboswitches, as predicted by in-line probing and mutagenesis experiments (27).…”

“…In general, the aptamer domain enfolds the ligand, forming a highly complex 3D conformation using a host of tertiary interactions, including base triples, kink turns, ribose zippers, A-minor motifs, loop-loop interactions, and pseudoknots (9)(10)(11). Some riboswitches require divalent cations for ligand binding (9,(12)(13)(14)(15)(16), whereas in others divalent cations stabilize the bound state (17)(18)(19)(20)(21). Some ligands, including S-adenosyl methionine (22), S-adenosyl homocysteine (22,23), cyclic di-GMP (24,25), and prequeuosine (preQ 1 ) (26,27), have more than one class of riboswitch, with each class adopting a different 3D fold to achieve recognition of the same ligand.…”

B7 homolog 3 aggravates brain injury in a murine model of Streptococcus pneumoniae-induced meningitis

“…In the brain, NSE is concentrated exclusively in the cytoplasm of neurons (10) and has been suggested to be a specific serum marker for neuronal damage. In the results of the present study, the reduction of NSE expression in the brain tissues of the mice treated with SP plus B7-H3 may reflect the following: i) NSE is primarily localized in the cytoplasm of neurons (10) and is not secreted; thus, an increase in its levels in the CSF or blood indicates structural damage of neuronal cells (8); ii) The number of existing functional neurons in the brain tissues that are available to be stained as NSE-positive by immunohistochemical analysis is markedly decreased due to apoptosis or necrosis caused by multiple factors exerting injurious effects, including exacerbated inflammation in (5), oxidative stress, lipid peroxidation, mitochondrial damage and BBB breakdown (1). Further reductions in NSE expression in brain tissues in response to combined SP and B7-H3 challenge indicate a greater degree of neuronal loss and structural neuronal damage, which is consistent with our previous study where it was identified that B7-H3 exacerbated the SP infection-induced proinflammatory response and BBB disruption (6).…”

Adjunctive N -Acetyl- l -Cysteine in Treatment of Murine Pneumococcal Meningitis

“…Furthermore, an attenuation of acute and long-term hearing loss and its morphological correlates was found in rats with pneumococcal meningitis (25). Just recently, NAC was reported to reduce neurocognitive deficits in adult rats who survived experimental pneumococcal meningitis (26). Thus, NAC was considered a promising therapeutic agent for adjunctive therapy of pneumococcal meningitis.…”