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

Abstract

Abstract. Despite the application of antibiotics, Streptococcus pneumoniae (SP)-induced meningitis continues to be a life-threatening disease with a high fatality rate and an elevated risk of serious neurological sequelae, particularly in developing countries. In this study, the contribution of the co-stimulatory molecule B7 homolog 3 (B7-H3) to the pathogenesis of experimental SP-induced meningitis was investigated. Mice were challenged with the intracerebroventricular injection of serotype 3 SP with or without B7-H3. The clinical status of mice with SP-induced meningitis was examined by body weight loss and spontaneous motor activity with neurological scoring. Coronal brain sections were analyzed by counting Nissl-positive neurons and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells. Protein expression of neuron-specific enolase (NSE) and S100B in brain tissues was examined with immunohistochemical staining. All experiments were performed in a randomized and blinded setting. By the intracerebroventricular injection of SP suspension, a murine model of pneumococcal meningitis was successfully established. In this SP-induced meningitis model, B7-H3 deteriorated the clinical status, as manifested by a decreased neurological score and increased body weight loss. Following the B7-H3 challenge, the number of Nissl-positive cells decreased and TUNEL-stained positive cells increased in the brain tissues of mice with SP meningitis, which demonstrates the enhancement of neuronal necrosis and apoptosis, respectively. Protein expression of NSE was decreased, while that of S100B was increased. These in vivo findings indicate that B7-H3 aggravates brain injury during the pathological process of experimental SP-induced meningitis. IntroductionDespite treatment with effective antibiotics, Streptococcus pneumoniae (SP) meningitis remains a serious infectious disease of the central nervous system (CNS) with mortality rates between 16 and 37% (1) and neurological sequelae in up to 30% of survivors (2). Therefore, further study of the pathological mechanisms of SP meningitis and the identification of new means of intervention has a great clinical significance. SP-induced meningitis can cause disruption of the blood-brain barrier (BBB), and most severely it can result in brain damage, which affects the prognosis of patients with SP meningitis. Emerging studies have demonstrated that necrosis and apoptosis of brain neurons occur while brain damage is taking place. Neuron-specific enolase (NSE) and S100B have been confirmed to be specific markers of brain damage (3). B7 homolog 3 (B7-H3) is a newly identified member of the B7 superfamily, which serves a key function in the regulation of immune responses (4). Our previous study (5) found an abnormally high expression level of soluble B7-H3 (sB7H3) protein in children with bacterial meningitis. In a murine model of SP-induced meningitis, we also demonstrated that B7-H3 further augmented the inflammatory response, exacerbated BBB disruption, a...

B7-H3 Augments Inflammatory Responses and Exacerbates Brain Damage via Amplifying NF-κB p65 and MAPK p38 Activation during Experimental Pneumococcal Meningitis

“…Pneumococcal meningitis was induced by intracerebral ventricular injection of 15 μl sterile PBS containing 0.75×10 7 CFU/ml S . pneumoniae (SP) into the lateral ventricle as described previously [ 13 , 23 ].…”

“…pneumoniae -stimulated proinflammatory cytokine and chemokine expression in the brain via a TLR2-dependent mechanism, and this B7-H3-amplified inflammatory response further exacerbated S . pneumoniae -induced disruption of blood-brain barrier (BBB) integrity and brain damage [ 13 , 23 ], indicating that B7-H3 participates in the development of pneumococcal meningitis via augmentation of the innate immunity-associated inflammatory response.…”

IL-10-Mediated Regulation of Microglial Inflammation in Brain Meningitis: Novel Insights and Therapeutic Potential

“…The mice were either actively immunized and challenged with S. pneumoniae after two weeks or passively immunized and immediately challenged to establish the meningitis model. The intracerebroventricular injection method [21,22] was used, with the injection site located approximately 0.5 mm posterior to the bregma and 1.0 mm right of the midline at a vertical depth of 3.0 mm. A volume of 15 µL of the standard strain of S. pneumoniae serotype III was injected at a dose of 5 × 10 6 CFU/mouse.…”

“…The infrared detection device was utilized to capture the mice's locomotor activity, and the data analysis system was employed to collect and analyze the recorded data. The clinical disease status was examined by spontaneous motor activity [21]. The following scores were used to assess the spontaneous motor activity of mice as described previously (7): 5 points, normal motor activity and turned upright in <5 sec when put on its back; 4 points, decreased spontaneous activity, but turned upright in <5 sec; 3 points, turned upright in >5 sec; 2 points, did not turn upright; and 1 point, did not move or coma.…”